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Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®): Treatment - Health Professional Information [NCI]

Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®): Treatment - Health Professional Information [NCI]

This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.

General Information About Childhood Acute Lymphoblastic Leukemia (ALL)

Cancer in children and adolescents is rare, although the overall incidence of childhood cancer, including ALL, has been slowly increasing since 1975.[1] Dramatic improvements in survival have been achieved in children and adolescents with cancer.[1,2,3] Between 1975 and 2010, childhood cancer mortality decreased by more than 50%.[1,2,3] For ALL, the 5-year survival rate has increased over the same time from 60% to approximately 90% for children younger than 15 years and from 28% to more than 75% for adolescents aged 15 to 19 years.[4] Childhood and adolescent cancer survivors require close monitoring because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

Incidence

ALL is the most common cancer diagnosed in children and represents approximately 25% of cancer diagnoses among children younger than 15 years.[2,3] In the United States, ALL occurs at an annual rate of approximately 41 cases per 1 million people aged 0 to 14 years and approximately 17 cases per 1 million people aged 15 to 19 years.[4] There are approximately 3,100 children and adolescents younger than 20 years diagnosed with ALL each year in the United States.[5] Since 1975, there has been a gradual increase in the incidence of ALL.[4,6]

A sharp peak in ALL incidence is observed among children aged 2 to 3 years (>90 cases per 1 million per year), with rates decreasing to fewer than 30 cases per 1 million by age 8 years.[2,3] The incidence of ALL among children aged 2 to 3 years is approximately fourfold greater than that for infants and is likewise fourfold to fivefold greater than that for children aged 10 years and older.[2,3]

The incidence of ALL appears to be highest in Hispanic children (43 cases per 1 million).[2,3,7,8] The incidence is substantially higher in White children than in Black children, with a nearly threefold higher incidence of ALL from age 2 to 3 years in White children than in Black children.[2,3,7]

Anatomy

Childhood ALL originates in the T and B lymphoblasts in the bone marrow (refer to Figure 1). Blood cell development; drawing shows the steps a blood stem cell goes through to become a red blood cell, platelet, or white blood cell. A myeloid stem cell becomes a red blood cell, a platelet, or a myeloblast, which then becomes a granulocyte (the types of granulocytes are eosinophils, basophils, and neutrophils). A lymphoid stem cell becomes a lymphoblast and then becomes a B-lymphocyte, T-lymphocyte, or natural killer cell.
Figure 1. Blood cell development. Different blood and immune cell lineages, including T and B lymphocytes, differentiate from a common blood stem cell.

Marrow involvement of acute leukemia as seen by light microscopy is defined as follows:

  • M1: Fewer than 5% blast cells.
  • M2: 5% to 25% blast cells.
  • M3: Greater than 25% blast cells.

Almost all patients with ALL present with an M3 marrow.

Morphology

In the past, ALL lymphoblasts were classified using the French-American-British (FAB) criteria as having L1 morphology, L2 morphology, or L3 morphology.[9] However, because of the lack of independent prognostic significance and the subjective nature of this classification system, it is no longer used.

Most cases of ALL that show L3 morphology express surface immunoglobulin (Ig) and have a MYC gene translocation identical to those seen in Burkitt lymphoma (i.e., t(8;14)(q24;q32), t(2;8)) that join MYC to one of the Ig genes. Patients with this specific rare form of leukemia (mature B-cell or Burkitt leukemia) should be treated according to protocols for Burkitt lymphoma. (Refer to the PDQ summary on Childhood Non-Hodgkin Lymphoma Treatment for more information about the treatment of mature B-cell lymphoma/leukemia and Burkitt lymphoma/leukemia.) Rarely, blasts with L1/L2 (not L3) morphology will express surface Ig.[10] These patients should be treated in the same way as are patients with B-ALL.[10]

Risk Factors for Developing ALL

Few factors associated with an increased risk of ALL have been identified. The primary accepted risk factors for ALL and associated genes (when relevant) include the following:

  • Prenatal exposure to x-rays.
  • Postnatal exposure to high doses of radiation (e.g., therapeutic radiation as previously used for conditions such as tinea capitis and thymus enlargement).
  • Previous treatment with chemotherapy.
  • Genetic conditions that include the following:
    • Down syndrome. (Refer to the Down syndrome section of this summary for more information.)
    • Neurofibromatosis (NF1).[11]
    • Bloom syndrome (BLM).[12]
    • Fanconi anemia (multiple genes; ALL is observed much less frequently than acute myeloid leukemia [AML]).[13]
    • Ataxia telangiectasia (ATM).[14]
    • Li-Fraumeni syndrome (TP53).[15,16,17]
    • Constitutional mismatch repair deficiency (biallelic mutation of MLH1, MSH2, MSH6, and PMS2).[18,19]
  • Low- and high-penetrance inherited genetic variants.[20] (Refer to the Low- and high-penetrance inherited genetic variants section of this summary for more information.)
  • Carriers of a constitutional Robertsonian translocation that involves chromosomes 15 and 21 are specifically and highly predisposed to developing intrachromosomal amplification of chromosome 21 (iAMP21) ALL.[21]

Down syndrome

Children with Down syndrome have an increased risk of developing both ALL and AML,[22,23] with a cumulative risk of developing leukemia of approximately 2.1% by age 5 years and 2.7% by age 30 years.[22,23]

Approximately one-half to two-thirds of cases of acute leukemia in children with Down syndrome are ALL, and about 2% to 3% of childhood ALL cases occur in children with Down syndrome (noting a prevalence of Down syndrome during childhood of approximately 0.1%).[24,25,26,27] ALL in children with Down syndrome has an age distribution similar to that of ALL in children without Down syndrome, with a median age of 3 to 4 years.[24,25] In contrast, the vast majority of cases of AML in children with Down syndrome occur before the age of 4 years (median age, 1 year).[28]

Patients with ALL and Down syndrome have a lower incidence of both favorable (t(12;21)(p13;q22)/ETV6-RUNX1 [TEL-AML1] and hyperdiploidy [51–65 chromosomes]) and unfavorable (t(9;22)(q34;q11.2) or t(4;11)(q21;q23) and hypodiploidy [<44 chromosomes]) cytogenetic findings and a near absence of T-cell phenotype.[24,25,26,28,29]

Approximately 50% to 60% of cases of ALL in children with Down syndrome have genomic alterations affecting CRLF2 that generally result in overexpression of the protein produced by this gene, which dimerizes with the interleukin-7 receptor alpha to form the receptor for the cytokine thymic stromal lymphopoietin.[30,31,32]CRLF2 genomic alterations are observed at a much lower frequency (<10%) in children with B-ALL who do not have Down syndrome.[32,33,34] Based on the relatively small number of published series, it does not appear that genomic CRLF2 aberrations in patients with Down syndrome and ALL have prognostic relevance, but more studies are needed to address this issue.[29,31]

Approximately 20% of ALL cases arising in children with Down syndrome have somatically acquired JAK2 mutations,[30,31,35,36,37] a finding that is uncommon among younger children with ALL but that is observed in a subset of primarily older children and adolescents with high-risk B-ALL.[38] Almost all Down syndrome ALL cases with JAK2 mutations also have CRLF2 genomic alterations.[30,31,32] Preliminary evidence suggests no correlation between JAK2 mutation status and 5-year event-free survival (EFS) in children with Down syndrome and ALL,[31,36] but more study is needed to address this issue.

A genome-wide association study found that four susceptibility loci associated with B-ALL in the non-Down syndrome population (IKZF1, CDKN2A, ARID5B, and GATA3) were also associated with susceptibility to ALL in children with Down syndrome.[39]CDKN2A risk allele penetrance appeared to be higher for children with Down syndrome.

IKZF1 gene deletions, observed in up to 35% of patients with Down syndrome and ALL, have been associated with a significantly worse outcome in this group of patients.[31,40]

Low- and high-penetrance inherited genetic variants

Genetic predisposition to ALL can be divided into several broad categories, as follows:

  • Association with genetic syndromes. Increased risk can be associated with the genetic syndromes listed above in which ALL is observed, although it is not the primary manifestation of the condition.
  • Common alleles. Another category for genetic predisposition includes common alleles with relatively small effect sizes that are identified by genome-wide association studies. Genome-wide association studies have identified a number of germline (inherited) genetic polymorphisms that are associated with the development of childhood ALL.[20] For example, the risk alleles of ARID5B are associated with the development of hyperdiploid (51–65 chromosomes) B-ALL. ARID5B is a gene that encodes a transcriptional factor important in embryonic development, cell type–specific gene expression, and cell growth regulation.[41,42] Other genes with polymorphisms associated with increased risk of ALL include GATA3,[43]IKZF1,[41,42,44]CDKN2A,[45]CDKN2B,[44,45]CEBPE,[41]PIP4K2A,[43,46] and TP63.[47]

    A genome-wide association study found that four susceptibility loci associated with B-ALL in the non-Down syndrome population (IKZF1, CDKN2A, ARID5B, and GATA3) were also associated with susceptibility to ALL in children with Down syndrome.[39]CDKN2A risk allele penetrance appeared to be higher for children with Down syndrome.

    Genetic risk factors for T-ALL share some overlap with the genetic risk factors for B-ALL, but unique risk factors also exist. A genome-wide association study identified a risk allele near USP7 that was associated with an increased risk of developing T-ALL (odds ratio, 1.44) but not B-ALL. The risk allele was shown to be associated with reduced USP7 transcription, which is consistent with the finding that somatic loss-of-function mutations in USP7 are observed in patients with T-ALL. USP7 germline and somatic mutations are generally mutually exclusive and are most commonly observed in T-ALL patients with TAL1 alterations.[48]

    Genetic risk factors that have similar impact for developing both B-ALL and T-ALL include CDKN2A/B and 8q24.21 (cis distal enhancer region variants for MYC).[48]

  • Rare germline variants with high penetrance. Germline variants that cause pathogenic changes in genes associated with ALL and that are observed in kindreds with familial ALL (i.e., large effect sizes) comprise another category of genetic predisposition to ALL.
    • PAX5. A germline variant in PAX5 that substitutes serine for glycine at amino acid 183 and that reduces PAX5 activity has been identified in several families that experienced multiple cases of ALL.[49,50]
    • ETV6. Several germline ETV6 variants that lead to loss of ETV6 function have been identified in kindreds affected by both thrombocytopenia and ALL.[51,52,53,54,55] Sequencing of ETV6 in remission (i.e., germline) specimens identified variants that were potentially related to ALL in approximately 1% of children with ALL that were evaluated.[51] Most of the germline mutations (approximately 75%) were shown to be deleterious for ETV6 function, and 70% of cases with a deleterious germline ETV6 variant had a hyperdiploid karyotype. The remaining cases with a deleterious mutation had diploid ALL, with a transcriptional profile similar to that of cases with ETV6-RUNX1 fusion–positive ALL.[55]
    • TP53. Pathogenic germline TP53 variants are associated with an increased risk of ALL.[56] A study of 3,801 children with ALL observed that 26 patients (0.7%) had a pathogenic TP53 germline variant, with an associated odds ratio of 5.2 for ALL development.[56] Compared with ALL in children with TP53 wild-type status or TP53 variants of unknown significance, ALL in children with pathogenic germline TP53 variants was associated with older age at diagnosis (15.5 years vs. 7.3 years), hypodiploidy (65% vs. 1%), inferior EFS and overall survival, and a higher risk of second cancers.
    • IKZF1. Germline IKZF1 variants were identified in a kindred with familial ALL and in 43 of 4,963 (0.9%) children with sporadic ALL. Most (22 of 28) IKZF1 variants were shown to adversely affect IKZF1 gene function.[57] Germline variants in IKZF1 have been identified in hereditary hypogammaglobulinemia, and in one series, 2 of 29 affected patients developed B-ALL during childhood.[58]

Prenatal origin of childhood ALL

Development of ALL is a multistep process in most cases, with more than one genomic alteration required for frank leukemia to develop. In at least some cases of childhood ALL, the initial genomic alteration appears to occur in utero. Evidence to support this comes from the observation that the immunoglobulin or T-cell receptor antigen rearrangements that are unique to each patient's leukemia cells can be detected in blood samples obtained at birth.[59,60] Similarly, in ALL characterized by specific chromosomal abnormalities, some patients have blood cells that carry at least one leukemic genomic abnormality at the time of birth, with additional cooperative genomic changes acquired postnatally.[59,60,61] Genomic studies of identical twins with concordant leukemia further support the prenatal origin of some leukemias.[59,62]

Evidence also exists that some children who never develop ALL are born with rare blood cells carrying a genomic alteration associated with ALL. Initial studies focused on the ETV6-RUNX1 translocation and used reverse transcriptase (RT)–polymerase chain reaction (PCR) to identify RNA transcripts indicating the presence of the gene fusion. For example, in one study, 1% of neonatal blood spots (Guthrie cards) tested positive for the ETV6-RUNX1 translocation.[63] While subsequent reports generally confirmed the presence of the ETV6-RUNX1 translocation at birth in some children, rates and extent of positivity varied widely.

To more definitively address this question, a highly sensitive and specific DNA-based approach (genomic inverse PCR for exploration of ligated breakpoints [GIPFEL]) was applied to DNA from 1,000 cord blood specimens and found that 5% of specimens had the ETV6-RUNX1 translocation.[64] When the same method was applied to 340 cord blood specimens to detect the TCF3-PBX1 fusion, two cord specimens (0.6%) were positive for its presence.[65] For both ETV6-RUNX1 and TCF3-PBX1, the percentage of cord blood specimens positive for one of the translocations far exceeds the percentage of children who will develop either type of ALL (<0.01%).

Clinical Presentation

The typical and atypical symptoms and clinical findings of childhood ALL have been published.[66,67,68]

Diagnosis

The evaluation needed to definitively diagnose childhood ALL has been published.[66,67,68,69,70]

Overall Prognosis

Among children with ALL, approximately 98% attain remission. Approximately 85% of patients aged 1 to 18 years with newly diagnosed ALL treated on current regimens are expected to be long-term event-free survivors, with over 90% surviving at 5 years.[71,72,73,74] Cytogenetic and genomic findings combined with minimal residual disease (MRD) results can define subsets of ALL with EFS rates exceeding 95% and, conversely, subsets with EFS rates of 50% or lower (refer to the Cytogenetics/Genomics of Childhood ALL and Prognostic Factors Affecting Risk-Based Treatment sections of this summary for more information).

Despite the treatment advances in childhood ALL, numerous important biologic and therapeutic questions remain to be answered before the goal of curing every child with ALL with the least associated toxicity can be achieved. The systematic investigation of these issues requires large clinical trials, and the opportunity to participate in these trials is offered to most patients and families.

Clinical trials for children and adolescents with ALL are generally designed to compare therapy that is currently accepted as standard with investigational regimens that seek to improve cure rates and/or decrease toxicity. In certain trials in which the cure rate for the patient group is very high, therapy reduction questions may be asked. Much of the progress made in identifying curative therapies for childhood ALL and other childhood cancers has been achieved through investigator-driven discovery and tested in carefully randomized, controlled, multi-institutional clinical trials. Information about ongoing clinical trials is available from the NCI website.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

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  73. Place AE, Stevenson KE, Vrooman LM, et al.: Intravenous pegylated asparaginase versus intramuscular native Escherichia coli L-asparaginase in newly diagnosed childhood acute lymphoblastic leukaemia (DFCI 05-001): a randomised, open-label phase 3 trial. Lancet Oncol 16 (16): 1677-90, 2015.
  74. Pieters R, de Groot-Kruseman H, Van der Velden V, et al.: Successful Therapy Reduction and Intensification for Childhood Acute Lymphoblastic Leukemia Based on Minimal Residual Disease Monitoring: Study ALL10 From the Dutch Childhood Oncology Group. J Clin Oncol 34 (22): 2591-601, 2016.

World Health Organization (WHO) Classification System for Childhood ALL

The 2016 revision to the WHO classification of tumors of the hematopoietic and lymphoid tissues lists the following entities for acute lymphoid leukemias:[1]

2016 WHO Classification of B-Lymphoblastic Leukemia/Lymphoma

  • B-lymphoblastic leukemia/lymphoma, not otherwise specified (NOS).
  • B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities.
  • B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2); BCR-ABL1.
  • B-lymphoblastic leukemia/lymphoma with t(v;11q23.3); KMT2A rearranged.
  • B-lymphoblastic leukemia/lymphoma with t(12;21)(p13.2;q22.1); ETV6-RUNX1.
  • B-lymphoblastic leukemia/lymphoma with hyperdiploidy.
  • B-lymphoblastic leukemia/lymphoma with hypodiploidy.
  • B-lymphoblastic leukemia/lymphoma with t(5;14)(q31.1;q32.3); IL3-IGH.
  • B-lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3); TCF3-PBX1.
  • Provisional entity: B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like.
  • Provisional entity: B-lymphoblastic leukemia/lymphoma with iAMP21.

2016 WHO Classification of T-Lymphoblastic Leukemia/Lymphoma

  • Provisional entity: Early T-cell precursor lymphoblastic leukemia.

2016 WHO Classification of Acute Leukemias of Ambiguous Lineage

For acute leukemias of ambiguous lineage, the group of acute leukemias that have characteristics of both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), the WHO classification system is summarized in Table 1.[2,3] The criteria for lineage assignment for a diagnosis of mixed phenotype acute leukemia (MPAL) are provided in Table 2.[1]

Table 1. Acute Leukemias of Ambiguous Lineage According to the World Health Organization Classification of Tumors of Hematopoietic and Lymphoid Tissuesa
Condition Definition
NOS = not otherwise specified.
a Adapted from Béné MC: Biphenotypic, bilineal, ambiguous or mixed lineage: strange leukemias! Haematologica 94 (7): 891-3, 2009.[2]Obtained from Haematologica/the Hematology Journal websitehttp://www.haematologica.org.
Acute undifferentiated leukemia Acute leukemia that does not express any marker considered specific for either lymphoid or myeloid lineage
Mixed phenotype acute leukemia with t(9;22)(q34;q11.2);BCR-ABL1(MPAL withBCR-ABL1) Acute leukemia meeting the diagnostic criteria for mixed phenotype acute leukemia in which the blasts also have the (9;22) translocation or theBCR-ABL1rearrangement
Mixed phenotype acute leukemia with t(v;11q23);KMT2A(MLL) rearranged (MPAL withKMT2A) Acute leukemia meeting the diagnostic criteria for mixed phenotype acute leukemia in which the blasts also have a translocation involving theKMT2Agene
Mixed phenotype acute leukemia, B/myeloid, NOS (B/M MPAL) Acute leukemia meeting the diagnostic criteria for assignment to both B and myeloid lineage, in which the blasts lack genetic abnormalities involvingBCR-ABL1orKMT2A
Mixed phenotype acute leukemia, T/myeloid, NOS (T/M MPAL) Acute leukemia meeting the diagnostic criteria for assignment to both T and myeloid lineage, in which the blasts lack genetic abnormalities involvingBCR-ABL1orKMT2A
Mixed phenotype acute leukemia, B/myeloid, NOS—rare types Acute leukemia meeting the diagnostic criteria for assignment to both B and T lineage
Other ambiguous lineage leukemias Natural killer–cell lymphoblastic leukemia/lymphoma
Table 2. Lineage Assignment Criteria for Mixed Phenotype Acute Leukemia According to the 2016 Revision to the World Health Organization Classification of Myeloid Neoplasms and Acute Leukemiaa
Lineage Criteria
a Adapted from Arber et al.[1]
b Strong defined as equal to or brighter than the normal B or T cells in the sample.
Myeloid lineage Myeloperoxidase (flow cytometry, immunohistochemistry, or cytochemistry);or monocytic differentiation (at least two of the following: nonspecific esterase cytochemistry, CD11c, CD14, CD64, lysozyme)
T lineage Strongb cytoplasmic CD3 (with antibodies to CD3 epsilon chain);or surface CD3
B lineage Strongb CD19 with at least one of the following strongly expressed: CD79a, cytoplasmic CD22, or CD10;or weak CD19 with at least two of the following strongly expressed: CD79a, cytoplasmic CD22, or CD10

Leukemias of mixed phenotype may be seen in various presentations, including the following:

  1. Bilineal leukemias in which there are two distinct populations of cells, usually one lymphoid and one myeloid.
  2. Biphenotypic leukemias in which individual blast cells display features of both lymphoid and myeloid lineage.

Biphenotypic cases represent the majority of mixed phenotype leukemias.[4] Patients with B-myeloid biphenotypic leukemias lacking the TEL-AML1 fusion have lower rates of complete remission (CR) and significantly worse event-free survival (EFS) rates compared with patients with B-ALL.[4] Some studies suggest that patients with biphenotypic leukemia may fare better with a lymphoid, as opposed to a myeloid, treatment regimen.[5,6,7,8]; [9][Level of evidence: 3iiiA] A large retrospective study from the international Berlin-Frankfurt-Münster (BFM) group demonstrated that initial therapy with an ALL-type regimen was associated with a superior outcome compared with AML-type or combined ALL/AML regimens, particularly in cases with CD19 positivity or other lymphoid antigen expression. In this study, hematopoietic stem cell transplantation (HSCT) in first CR was not beneficial, with the possible exception of cases with morphologic evidence of persistent marrow disease (≥5% blasts) after the first month of treatment.[8]

Key clinical and biological characteristics, as well as the prognostic significance for these entities, are discussed in the Cytogenetics/Genomics of Childhood ALL section of this summary.

References:

  1. Arber DA, Orazi A, Hasserjian R, et al.: The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 127 (20): 2391-405, 2016.
  2. Béné MC: Biphenotypic, bilineal, ambiguous or mixed lineage: strange leukemias! Haematologica 94 (7): 891-3, 2009.
  3. Borowitz MJ, Béné MC, Harris NL: Acute leukaemias of ambiguous lineage. In: Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. International Agency for Research on Cancer, 2008, pp 150-5.
  4. Gerr H, Zimmermann M, Schrappe M, et al.: Acute leukaemias of ambiguous lineage in children: characterization, prognosis and therapy recommendations. Br J Haematol 149 (1): 84-92, 2010.
  5. Rubnitz JE, Onciu M, Pounds S, et al.: Acute mixed lineage leukemia in children: the experience of St Jude Children's Research Hospital. Blood 113 (21): 5083-9, 2009.
  6. Al-Seraihy AS, Owaidah TM, Ayas M, et al.: Clinical characteristics and outcome of children with biphenotypic acute leukemia. Haematologica 94 (12): 1682-90, 2009.
  7. Matutes E, Pickl WF, Van't Veer M, et al.: Mixed-phenotype acute leukemia: clinical and laboratory features and outcome in 100 patients defined according to the WHO 2008 classification. Blood 117 (11): 3163-71, 2011.
  8. Hrusak O, de Haas V, Stancikova J, et al.: International cooperative study identifies treatment strategy in childhood ambiguous lineage leukemia. Blood 132 (3): 264-276, 2018.
  9. Orgel E, Alexander TB, Wood BL, et al.: Mixed-phenotype acute leukemia: A cohort and consensus research strategy from the Children's Oncology Group Acute Leukemia of Ambiguous Lineage Task Force. Cancer 126 (3): 593-601, 2020.

Cytogenetics / Genomics of Childhood ALL

Genomics of childhood ALL

The genomics of childhood ALL has been extensively investigated, and multiple distinctive subtypes have been defined on the basis of cytogenetic and molecular characterizations, each with its own pattern of clinical and prognostic characteristics.[1] Figure 2 illustrates the distribution of ALL cases by cytogenetic/molecular subtype.[1]

Pie chart showing subclassification of childhood ALL.
Figure 2. Subclassification of childhood ALL. Blue wedges refer to B-progenitor ALL, yellow to recently identified subtypes of B-ALL, and red wedges to T-lineage ALL. Reprinted from Seminars in Hematology, Volume 50, Charles G. Mullighan, Genomic Characterization of Childhood Acute Lymphoblastic Leukemia, Pages 314–324, Copyright (2013), with permission from Elsevier.

B-ALL cytogenetics/genomics

The genomic landscape of B-ALL is typified by a range of genomic alterations that disrupt normal B-cell development and, in some cases, by mutations in genes that provide a proliferation signal (e.g., activating mutations in RAS family genes or mutations/translocations leading to kinase pathway signaling). Genomic alterations leading to blockage of B-cell development include translocations (e.g., TCF3-PBX1 and ETV6-RUNX1), point mutations (e.g., IKZF1 and PAX5), and intragenic/intergenic deletions (e.g., IKZF1, PAX5, EBF, and ERG).[2]

The genomic alterations in B-ALL tend not to occur at random, but rather to cluster within subtypes that can be delineated by biological characteristics such as their gene expression profiles. Cases with recurring chromosomal translocations (e.g., TCF3-PBX1, ETV6-RUNX1, and KMT2A [MLL]-rearranged ALL) have distinctive biological features and illustrate this point, as do the examples below of specific genomic alterations within distinctive biological subtypes:

  • IKZF1 deletions and mutations are most commonly observed within cases of Philadelphia (Ph) chromosome–positive (Ph+) ALL and Ph-like (BCR-ABL1-like) ALL.[3,4]
  • Intragenic ERG deletions occur within a distinctive subtype characterized by gene rearrangements involving DUX4.[5,6]
  • TP53 mutations, often germline, occur at high frequency in patients with low hypodiploid ALL with 32 to 39 chromosomes.[7]TP53 mutations are uncommon in other patients with B-ALL.

Activating point mutations in kinase genes are uncommon in high-risk B-ALL. JAK genes are the primary kinases that are found to be mutated. These mutations are generally observed in patients with Ph-like ALL that have CRLF2 abnormalities, although JAK2 mutations are also observed in approximately 15% of children with Down syndrome ALL.[4,8,9] Several kinase genes and cytokine receptor genes are activated by translocations, as described below in the discussion of Ph+ ALL and Ph-like ALL. FLT3 mutations occur in a minority of cases (approximately 10%) of hyperdiploid ALL and KMT2A-rearranged ALL, and are rare in other subtypes.[10]

Understanding of the genomics of B-ALL at relapse is less advanced than the understanding of ALL genomics at diagnosis. Childhood ALL is often polyclonal at diagnosis and under the selective influence of therapy, some clones may be extinguished and new clones with distinctive genomic profiles may arise.[11] Of particular importance are new mutations that arise at relapse that may be selected by specific components of therapy. As an example, mutations in NT5C2 are not found at diagnosis, whereas specific mutations in NT5C2 were observed in 7 of 44 (16%) and 9 of 20 (45%) cases of B-ALL with early relapse that were evaluated for this mutation in two studies.[11,12]NT5C2 mutations are uncommon in patients with late relapse, and they appear to induce resistance to mercaptopurine (6-MP) and thioguanine.[12] Another gene that is found mutated only at relapse is PRSP1, a gene involved in purine biosynthesis.[13] Mutations were observed in 13.0% of a Chinese cohort and 2.7% of a German cohort, and were observed in patients with on-treatment relapses. The PRSP1 mutations observed in relapsed cases induce resistance to thiopurines in leukemia cell lines. CREBBP mutations are also enriched at relapse and appear to be associated with increased resistance to glucocorticoids.[11,14] With increased understanding of the genomics of relapse, it may be possible to tailor upfront therapy to avoid relapse or detect resistance-inducing mutations early and intervene before a frank relapse.

A number of recurrent chromosomal abnormalities have been shown to have prognostic significance, especially in B-ALL. Some chromosomal alterations are associated with more favorable outcomes, such as high hyperdiploidy (51–65 chromosomes) and the ETV6-RUNX1 fusion.[15][Level of evidence: 2A] Other alterations historically have been associated with a poorer prognosis, including the Ph chromosome (t(9;22)(q34;q11.2)), rearrangements of the KMT2A gene, hypodiploidy, and intrachromosomal amplification of the AML1 gene (iAMP21).[16]

In recognition of the clinical significance of many of these genomic alterations, the 2016 revision of the World Health Organization classification of tumors of the hematopoietic and lymphoid tissues lists the following entities for B-ALL:[17]

  • B-lymphoblastic leukemia/lymphoma, not otherwise specified (NOS).
  • B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities.
  • B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2); BCR-ABL1.
  • B-lymphoblastic leukemia/lymphoma with t(v;11q23.3); KMT2A rearranged.
  • B-lymphoblastic leukemia/lymphoma with t(12;21)(p13.2;q22.1); ETV6-RUNX1.
  • B-lymphoblastic leukemia/lymphoma with hyperdiploidy.
  • B-lymphoblastic leukemia/lymphoma with hypodiploidy.
  • B-lymphoblastic leukemia/lymphoma with t(5;14)(q31.1;q32.3); IL3-IGH.
  • B-lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3); TCF3-PBX1.
  • Provisional entity: B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like.
  • Provisional entity: B-lymphoblastic leukemia/lymphoma with iAMP21.

These and other chromosomal and genomic abnormalities for childhood ALL are described below.

  1. Chromosome number.
    • High hyperdiploidy (51–65 chromosomes).

      High hyperdiploidy, defined as 51 to 65 chromosomes per cell or a DNA index greater than 1.16, occurs in 20% to 25% of cases of B-ALL, but very rarely in cases of T-ALL.[18] Hyperdiploidy can be evaluated by measuring the DNA content of cells (DNA index) or by karyotyping. In cases with a normal karyotype or in which standard cytogenetic analysis was unsuccessful, interphase fluorescence in situ hybridization (FISH) may detect hidden hyperdiploidy.

      High hyperdiploidy generally occurs in cases with clinically favorable prognostic factors (patients aged 1 to <10 years with a low white blood cell [WBC] count) and is an independent favorable prognostic factor.[18,19,20] Within the hyperdiploid range of 51 to 65 chromosomes, patients with higher modal numbers (58–66) appeared to have a better prognosis in one study.[20] Hyperdiploid leukemia cells are particularly susceptible to undergoing apoptosis and accumulate higher levels of methotrexate and its active polyglutamate metabolites,[21] which may explain the favorable outcome commonly observed in these cases.

      While the overall outcome of patients with high hyperdiploidy is considered to be favorable, factors such as age, WBC count, specific trisomies, and early response to treatment have been shown to modify its prognostic significance.[22,23]

      Patients with trisomies of chromosomes 4, 10, and 17 (triple trisomies) have been shown to have a particularly favorable outcome, as demonstrated by both Pediatric Oncology Group (POG) and Children's Cancer Group analyses of National Cancer Institute (NCI) standard-risk ALL.[24] POG data suggest that NCI standard-risk patients with trisomies of 4 and 10, without regard to chromosome 17 status, have an excellent prognosis.[25]

      Chromosomal translocations may be seen with high hyperdiploidy, and in those cases, patients are more appropriately risk-classified on the basis of the prognostic significance of the translocation. For instance, in one study, 8% of patients with the Ph chromosome (t(9;22)(q34;q11.2)) also had high hyperdiploidy,[26] and the outcome of these patients (treated without tyrosine kinase inhibitors) was inferior to that observed in non-Ph+ high hyperdiploid patients.

      Certain patients with hyperdiploid ALL may have a hypodiploid clone that has doubled (masked hypodiploidy).[27] These cases may be interpretable based on the pattern of gains and losses of specific chromosomes (hyperdiploidy with two and four copies of chromosomes rather than three copies). These patients have an unfavorable outcome, similar to those with hypodiploidy.[28]

      Near triploidy (68–80 chromosomes) and near tetraploidy (>80 chromosomes) are much less common and appear to be biologically distinct from high hyperdiploidy.[29] Unlike high hyperdiploidy, a high proportion of near tetraploid cases harbor a cryptic ETV6-RUNX1 fusion.[29,30,31] Near triploidy and tetraploidy were previously thought to be associated with an unfavorable prognosis, but later studies suggest that this may not be the case.[29,31]

      The genomic landscape of hyperdiploid ALL is characterized by mutations in genes of the receptor tyrosine kinase (RTK)/RAS pathway in approximately one-half of cases. Genes encoding histone modifiers are also present in a recurring manner in a minority of cases. Analysis of mutation profiles demonstrates that chromosomal gains are early events in the pathogenesis of hyperdiploid ALL.[32]

    • Hypodiploidy (<44 chromosomes).

      B-ALL cases with fewer than the normal number of chromosomes have been subdivided in various ways, with one report stratifying on the basis of modal chromosome number into the following four groups:[28]

      • Near-haploid: 24 to 29 chromosomes (n = 46).
      • Low-hypodiploid: 33 to 39 chromosomes (n = 26).
      • High-hypodiploid: 40 to 43 chromosomes (n = 13).
      • Near-diploid: 44 chromosomes (n = 54).

      Most patients with hypodiploidy are in the near-haploid and low-hypodiploid groups, and both of these groups have an elevated risk of treatment failure compared with nonhypodiploid cases.[28,33] Patients with fewer than 44 chromosomes have a worse outcome than do patients with 44 or 45 chromosomes in their leukemic cells.[28] A number of studies have shown that patients with high minimal residual disease (MRD) (≥0.01%) after induction do very poorly, with 5-year event-free survival (EFS) rates ranging from 25% to 47%. Although hypodiploid patients with low MRD after induction fare better (5-year EFS, 64%–75%), their outcomes are still inferior to most children with other types of ALL.[34,35,36]

      The recurring genomic alterations of near-haploid and low-hypodiploid ALL appear to be distinctive from each other and from other types of ALL.[7] In near-haploid ALL, alterations targeting RTK signaling, RAS signaling, and IKZF3 are common.[37] In low-hypodiploid ALL, genetic alterations involving TP53, RB1, and IKZF2 are common. Importantly, the TP53 alterations observed in low-hypodiploid ALL are also present in nontumor cells in approximately 40% of cases, suggesting that these mutations are germline and that low-hypodiploid ALL represents, in some cases, a manifestation of Li-Fraumeni syndrome.[7] Approximately two-thirds of patients with ALL and germline pathogenic TP53 variants have hypodiploid ALL.[38]

  2. Chromosomal translocations and gains/deletions of chromosomal segments.
    • t(12;21)(p13.2;q22.1); ETV6-RUNX1 (formerly known as TEL-AML1).

      Fusion of the ETV6 gene on chromosome 12 to the RUNX1 gene on chromosome 21 is present in 20% to 25% of cases of B-ALL but is rarely observed in T-ALL.[30] The t(12;21)(p13;q22) produces a cryptic translocation that is detected by methods such as FISH, rather than conventional cytogenetics, and it occurs most commonly in children aged 2 to 9 years.[39,40] Hispanic children with ALL have a lower incidence of t(12;21)(p13;q22) than do White children.[41]

      Reports generally indicate favorable EFS and overall survival (OS) in children with the ETV6-RUNX1 fusion; however, the prognostic impact of this genetic feature is modified by the following factors:[42,43,44,45,46]

      • Early response to treatment.
      • NCI risk category (age and WBC count at diagnosis).
      • Treatment regimen.

      In one study of the treatment of newly diagnosed children with ALL, multivariate analysis of prognostic factors found age and leukocyte count, but not ETV6-RUNX1, to be independent prognostic factors.[42] It does not appear that the presence of secondary cytogenetic abnormalities, such as deletion of ETV6 (12p) or CDKN2A/B (9p), impacts the outcome of patients with the ETV6-RUNX1 fusion.[46,47]

      There is a higher frequency of late relapses in patients with ETV6-RUNX1 fusions compared with other relapsed B-ALL patients.[42,48] Patients with the ETV6-RUNX1 fusion who relapse seem to have a better outcome than other relapse patients,[49] with an especially favorable prognosis for patients who relapse more than 36 months from diagnosis.[50] Some relapses in patients with t(12;21)(p13;q22) may represent a new independent second hit in a persistent preleukemic clone (with the first hit being the ETV6-RUNX1 translocation).[51,52]

    • t(9;22)(q34.1;q11.2); BCR-ABL1 (Ph+).

      The Ph chromosome t(9;22)(q34.1;q11.2) is present in approximately 3% of children with ALL and leads to production of a BCR-ABL1 fusion protein with tyrosine kinase activity (refer to Figure 3). Philadelphia chromosome; three-panel drawing shows a piece of chromosome 9 and a piece of chromosome 22 breaking off and trading places, creating a changed chromosome 22 called the Philadelphia chromosome. In the left panel, the drawing shows a normal chromosome 9 with the ABL gene and a normal chromosome 22 with the BCR gene. In the center panel, the drawing shows chromosome 9 breaking apart in the ABL gene and chromosome 22 breaking apart below the BCR gene. In the right panel, the drawing shows chromosome 9 with the piece from chromosome 22 attached and chromosome 22 with the piece from chromosome 9 containing part of the ABL gene attached. The changed chromosome 22 with the BCR-ABLgene is called the Philadelphia chromosome.
      Figure 3. The Philadelphia chromosome is a translocation between the ABL1 oncogene (on the long arm of chromosome 9) and the BCR gene (on the long arm of chromosome 22), resulting in the fusion gene BCR-ABL1. BCR-ABL1 encodes an oncogenic protein with tyrosine kinase activity.

      This subtype of ALL is more common in older children with B-ALL and high WBC count, with the incidence of the t(9;22)(q34.1;q11.2) increasing to about 25% in young adults with ALL.

      Historically, the Ph chromosome t(9;22)(q34.1;q11.2) was associated with an extremely poor prognosis (especially in those who presented with a high WBC count or had a slow early response to initial therapy), and its presence had been considered an indication for allogeneic hematopoietic stem cell transplantation (HSCT) in patients in first remission.[26,53,54,55] Inhibitors of the BCR-ABL1 tyrosine kinase, such as imatinib mesylate, are effective in patients with Ph+ ALL.[56] A study by the Children's Oncology Group (COG), which used intensive chemotherapy and concurrent imatinib mesylate given daily, demonstrated a 5-year EFS rate of 70% (± 12%), which was superior to the EFS rate of historical controls in the pre-tyrosine kinase inhibitor (imatinib mesylate) era.[57,58]

    • t(v;11q23.3); KMT2A-rearranged.

      Rearrangements involving the KMT2A gene occur in approximately 5% of childhood ALL cases overall, but in up to 80% of infants with ALL. These rearrangements are generally associated with an increased risk of treatment failure.[59,60,61,62] The t(4;11)(q21;q23) is the most common rearrangement involving the KMT2A gene in children with ALL and occurs in approximately 1% to 2% of childhood ALL.[60,63]

      Patients with the t(4;11)(q21;q23) are usually infants with high WBC counts; they are more likely than other children with ALL to have central nervous system (CNS) disease and to have a poor response to initial therapy.[64] While both infants and adults with the t(4;11)(q21;q23) are at high risk of treatment failure, children with the t(4;11)(q21;q23) appear to have a better outcome than either infants or adults.[59,60] Irrespective of the type of KMT2A gene rearrangement, infants with leukemia cells that have KMT2A gene rearrangements have a worse treatment outcome than older patients whose leukemia cells have a KMT2A gene rearrangement.[59,60]

      Whole-genome sequencing has determined that cases of infant ALL with KMT2A gene rearrangements have few additional genomic alterations, none of which have clear clinical significance.[10] Deletion of the KMT2A gene has not been associated with an adverse prognosis.[65]

      Of interest, the t(11;19)(q23;p13.3) involving KMT2A and MLLT1/ENL occurs in approximately 1% of ALL cases and occurs in both early B-lineage and T-ALL.[66] Outcome for infants with the t(11;19) is poor, but outcome appears relatively favorable in older children with T-ALL and t(11;19).[66]

    • t(1;19)(q23;p13.3); TCF3-PBX1 and t(17;19)(q22;p13); TCF3-HLF.

      The t(1;19) occurs in approximately 5% of childhood ALL cases and involves fusion of the TCF3 gene on chromosome 19 to the PBX1 gene on chromosome 1.[67,68] The t(1;19) may occur as either a balanced translocation or as an unbalanced translocation and is the primary recurring genomic alteration of the pre-B–ALL immunophenotype (cytoplasmic immunoglobulin positive).[69] Black children are relatively more likely than White children to have pre-B–ALL with the t(1;19).[70]

      The t(1;19) had been associated with inferior outcome in the context of antimetabolite-based therapy,[71] but the adverse prognostic significance was largely negated by more aggressive multiagent therapies.[68,72] However, in a trial conducted by St. Jude Children's Research Hospital (SJCRH) on which all patients were treated without cranial radiation, patients with the t(1;19) had an overall outcome comparable to children lacking this translocation, with a higher risk of CNS relapse and a lower rate of bone marrow relapse, suggesting that more intensive CNS therapy may be needed for these patients.[73,74]

      The t(17;19) resulting in the TCF3-HLF fusion occurs in less than 1% of pediatric ALL cases. ALL with the TCF3-HLF fusion is associated with disseminated intravascular coagulation and hypercalcemia at diagnosis. Outcome is very poor for children with the t(17;19), with a literature review noting mortality for 20 of 21 cases reported.[75] In addition to the TCF3-HLF fusion, the genomic landscape of this ALL subtype was characterized by deletions in genes involved in B-cell development (PAX5, BTG1, and VPREB1) and by mutations in RAS pathway genes (NRAS, KRAS, and PTPN11).[69]

    • DUX4-rearranged ALL with frequent ERG deletions.

      Approximately 5% of standard-risk and 10% of high-risk pediatric B-ALL patients have a rearrangement involving DUX4 that leads to its overexpression.[5,6] The frequency in older adolescents (aged >15 years) is approximately 10%. The most common rearrangement produces IGH-DUX4 fusions, with ERG-DUX4 fusions also observed.[76]DUX4-rearranged cases show a distinctive gene expression pattern that was initially identified as being associated with focal deletions in ERG,[76,77,78,79] and one-half to more than two-thirds of these cases have focal intragenic deletions involving ERG that are not observed in other ALL subtypes.[5,76]ERG deletions often appear to be clonal, but using sensitive detection methodology, it appears that most cases are polyclonal.[76]IKZF1 alterations are observed in 20% to 40% of DUX4-rearranged ALL.[5,6]

      ERG deletion connotes an excellent prognosis, with OS rates exceeding 90%; even when the IZKF1 deletion is present, prognosis remains highly favorable.[77,78,79] While DUX4-rearranged ALL has an overall favorable prognosis, there is uncertainty as to whether this applies to both ERG-deleted and ERG-intact cases. In a study of 50 patients with DUX4-rearranged ALL, patients with ERG deletion detected by genomic polymerase chain reaction (PCR) (n = 33) had a more favorable EFS rate of approximately 90% than did patients with intact ERG (n = 17), with an EFS rate of approximately 70%.

    • MEF2D-rearranged ALL.

      Gene fusions involving MEF2D, a transcription factor that is expressed during B-cell development, are observed in approximately 4% of childhood ALL cases.[80,81] Although multiple fusion partners may occur, most cases involve BCL9, which is located on chromosome 1q21, as is MEF2D.[80,82] The interstitial deletion producing the MEF2D-BCL9 fusion is too small to be detected by conventional cytogenetic methods. Cases with MEF2D gene fusions show a distinctive gene expression profile, except for rare cases with MEF2D-CSFR1 that have a Ph-like gene expression profile.[80,83]

      The median age at diagnosis for cases of MEF2D-rearranged ALL in studies that included both adult and pediatric patients was 12 to 14 years.[80,81] For 22 children with MEF2D-rearranged ALL enrolled in a high-risk ALL clinical trial, the 5-year EFS rate was 72% (standard error, ± 10%), which was inferior to that for other patients.[80]

    • ZNF384-rearranged ALL.

      ZNF384 is a transcription factor that is rearranged in approximately 4% to 5% of pediatric B-ALL cases.[80,84,85] Multiple fusion partners for ZNF384 have been reported, including ARID1B, CREBBP, EP300, SMARCA2, TAF15, and TCF3. Regardless of the fusion partner, ZNF384-rearranged ALL cases show a distinctive gene expression profile.[80,84,85]ZNF384 rearrangement does not appear to confer independent prognostic significance.[80,84,85] The immunophenotype of B-ALL with ZNF384 rearrangement is characterized by weak or negative CD10 expression, with expression of CD13 and/or CD33 commonly observed.[84,85] Cases of mixed phenotype acute leukemia (MPAL) (B/myeloid) that have ZNF384 gene fusions have been reported, [86,87] and a genomic evaluation of MPAL found that ZNF384 gene fusions were present in approximately one-half of B/myeloid cases.[88]

    • t(5;14)(q31.1;q32.3); IL3-IGH.

      This entity is included in the 2016 revision of the WHO classification of tumors of the hematopoietic and lymphoid tissues.[17] The finding of t(5;14)(q31.1;q32.3) in patients with ALL and hypereosinophilia in the 1980s was followed by the identification of the IL3-IGH fusion as the underlying genetic basis for the condition.[89,90] The joining of the IGH locus to the promoter region of the IL3 gene leads to dysregulation of IL3 expression.[91] Cytogenetic abnormalities in children with ALL and eosinophilia are variable, with only a subset resulting from the IL3-IGH fusion.[92]

      The number of cases of IL3-IGH ALL described in the published literature is too small to assess the prognostic significance of the IL3-IGH fusion. Diagnosis of cases of IL3-IGH ALL may be delayed because it can present with hypereosinophilia in the absence of cytopenias and circulating blasts.[17]

    • Intrachromosomal amplification of chromosome 21 (iAMP21).

      iAMP21 is generally diagnosed using FISH and is defined by the presence of greater than or equal to five RUNX1 signals per cell (or ≥3 extra copies of RUNX1 on a single abnormal chromosome).[17] It occurs in approximately 2% of B-ALL cases and is associated with older age (median, approximately 10 years), presenting WBC of less than 50 × 109 /L, a slight female preponderance, and high end-induction MRD.[93,94,95]

      The United Kingdom Acute Lymphoblastic Leukaemia (UKALL) clinical trials group initially reported that the presence of iAMP21 conferred a poor prognosis in patients treated in the MRC ALL 97/99 trial (5-year EFS, 29%).[16] In their subsequent trial (UKALL2003 [NCT00222612]), patients with iAMP21 were assigned to a more intensive chemotherapy regimen and had a markedly better outcome (5-year EFS, 78%).[94] Similarly, the COG has reported that iAMP21 was associated with a significantly inferior outcome in NCI standard-risk patients (4-year EFS, 73% for iAMP21 vs. 92% in others), but not in NCI high-risk patients (4-year EFS, 73% vs. 80%).[93] On multivariate analysis, iAMP21 was an independent predictor of inferior outcome only in NCI standard-risk patients.[93] The results of the UKALL2003 and COG studies suggest that treatment of iAMP21 patients with high-risk chemotherapy regimens abrogates its adverse prognostic significance and obviates the need for HSCT in first remission.[95]

    • PAX5 alterations.

      Gene expression analysis identified two distinctive ALL subsets with PAX5 genomic alterations, termed PAX5alt and PAX5 p.Pro80Arg.[96] The alterations in the PAX5alt subtype included rearrangements, sequence mutations, and focal intragenic amplifications.

      PAX5alt. PAX5 rearrangements have been reported to represent 2% to 3% of pediatric ALL.[97] More than 20 partner genes for PAX5 have been described,[96] with PAX5-ETV6, the primary genomic alteration in dic(9;12)(p13;p13),[98] being the most common gene fusion.[96]

      Intragenic amplification of PAX5 was identified in approximately 1% of B-ALL cases, and it was usually detected in cases lacking known leukemia-driver genomic alterations.[99] Cases with PAX5 amplification show male predominance (66%), with most (55%) having NCI high-risk status. For a cohort of patients with PAX5 amplification diagnosed between 1993 and 2015, the 5-year EFS rate was 49% (95% confidence interval [CI], 36%–61%), and the OS rate was 67% (95% CI, 54%–77%), suggesting a relatively poor prognosis for this B-ALL subtype.

      PAX5 p.Pro80Arg. PAX5 with a p.Pro80Arg mutation shows a gene expression profile distinctive from that of other cases with PAX5 alterations.[96] Cases with PAX5 p.Pro80Arg appear to be more common in the adolescent and young adult (AYA) and adult populations (3%–4% frequency) than in children with NCI standard-risk or high-risk ALL (0.4% and 1.9% frequency, respectively). Outcome for the pediatric patients with PAX5 p.Pro80Arg and PAX5alt treated on a COG clinical trial appears to be intermediate (5-year EFS, approximately 75%).[96]

    • Ph-like (BCR-ABL1-like).

      BCR-ABL1–negative patients with a gene expression profile similar to BCR-ABL1–positive patients have been referred to as Ph-like.[100,101,102] This occurs in 10% to 20% of pediatric ALL patients, increasing in frequency with age, and has been associated with an IKZF1 deletion or mutation.[8,100,101,103,104]

      Retrospective analyses have indicated that patients with Ph-like ALL have a poor prognosis.[4,100] In one series, the 5-year EFS for NCI high-risk children and adolescents with Ph-like ALL was 58% and 41%, respectively.[4] While it is more frequent in older and higher-risk patients, the Ph-like subtype has also been identified in NCI standard-risk patients. In a COG study, 13.6% of 1,023 NCI standard-risk B-ALL patients were found to have Ph-like ALL; these patients had an inferior EFS compared with non–Ph-like standard-risk patients (82% vs. 91%), although no difference in OS (93% vs. 96%) was noted.[105] In one study of 40 Ph-like patients, the adverse prognostic significance of this subtype appeared to be abrogated when patients were treated with risk-directed therapy on the basis of MRD levels.[106]

      The hallmark of Ph-like ALL is activated kinase signaling, with 50% containing CRLF2 genomic alterations [102,107] and half of those cases containing concomitant JAK mutations.[108]

      Many of the remaining cases of Ph-like ALL have been noted to have a series of translocations with a common theme of involvement of kinases, including ABL1, ABL2, CSF1R, JAK2, and PDGFRB.[4,103] Fusion proteins from these gene combinations have been noted in some cases to be transformative and have responded to tyrosine kinase inhibitors both in vitro and in vivo,[103] suggesting potential therapeutic strategies for these patients. The prevalence of targetable kinase fusions in Ph-like ALL is lower in NCI standard-risk patients (3.5%) than in NCI high-risk patients (approximately 30%).[105] Point mutations in kinase genes, aside from those in JAK1 and JAK2, are uncommon in Ph-like ALL cases.[8]

      Approximately 9% of Ph-like ALL cases result from rearrangements that lead to overexpression of a truncated erythropoietin receptor (EPOR).[109] The C-terminal region of the receptor that is lost is the region that is mutated in primary familial congenital polycythemia and that controls stability of the EPOR. The portion of the EPOR remaining is sufficient for JAK-STAT activation and for driving leukemia development.

      CRLF2. Genomic alterations in CRLF2, a cytokine receptor gene located on the pseudoautosomal regions of the sex chromosomes, have been identified in 5% to 10% of cases of B-ALL; they represent approximately 50% of cases of Ph-like ALL.[110,111,112] The chromosomal abnormalities that commonly lead to CRLF2 overexpression include translocations of the IGH locus (chromosome 14) to CRLF2 and interstitial deletions in pseudoautosomal regions of the sex chromosomes, resulting in a P2RY8-CRLF2 fusion.[8,107,110,111] These two genomic alterations are associated with distinctive clinical and biological characteristics.

      The P2RY8-CRLF2 fusion is observed in 70% to 75% of pediatric patients with CRLF2 genomic alterations, and it occurs in younger patients (median age, approximately 4 years vs. 14 years for patients with IGH-CRLF2).[113,114]P2RY8-CRLF2 occurs not infrequently with established chromosomal abnormalities (e.g., hyperdiploidy, iAMP21, dic(9;20)), while IGH-CRLF2 is generally mutually exclusive with known cytogenetic subgroups. CRLF2 genomic alterations are observed in approximately 60% of patients with Down syndrome ALL, with P2RY8-CRLF2 fusions being more common than IGH-CRLF2 (approximately 80% vs. 20%).[111,113]

      IGH-CRLF2 and P2RY8-CRLF2 commonly occur as an early event in B-ALL development and show clonal prevalence.[115] However, in some cases they appear to be a late event and show subclonal prevalence.[115] Loss of the CRLF2 genomic abnormality in some cases at relapse confirms the subclonal nature of the alteration in these cases.[113,116]

      CRLF2 abnormalities are strongly associated with the presence of IKZF1 deletions. Other recurring genomic alterations found in association with CRLF2 alterations include deletions in genes associated with B-cell differentiation (e.g., PAX5, BTG1, EBF1, etc.) and cell cycle control (CDKN2A), as well as genomic alterations activating JAK-STAT pathway signaling (e.g., IL7R and JAK mutations).[4,107,108,111,117]

      Although the results of several retrospective studies suggest that CRLF2 abnormalities may have adverse prognostic significance in univariate analyses, most do not find this abnormality to be an independent predictor of outcome.[107,110,111,118,119] For example, in a large European study, increased expression of CRLF2 was not associated with unfavorable outcome in multivariate analysis, while IKZF1 deletion and Ph-like expression signatures were associated with unfavorable outcome.[104] Controversy exists about whether the prognostic significance of CRLF2 abnormalities should be analyzed on the basis of CRLF2 overexpression or on the presence of CRLF2 genomic alterations.[118,119]

    • IKZF1 deletions.

      IKZF1 deletions, including deletions of the entire gene and deletions of specific exons, are present in approximately 15% of B-ALL cases. Less commonly, IKZF1 can be inactivated by deleterious point mutations.[101]

      Cases with IKZF1 deletions tend to occur in older children, have a higher WBC count at diagnosis, and are therefore, more common in NCI high-risk patients than in NCI standard-risk patients.[2,101,117,120] A high proportion of Ph-like cases have a deletion of IKZF1,[3,117] and ALL arising in children with Down syndrome appears to have elevated rates of IKZF1 deletions.[121]IKZF1 deletions are also common in cases with CRLF2 genomic alterations and in Ph-like ALL.[77,100,117]

      Multiple reports have documented the adverse prognostic significance of an IKZF1 deletion, and most studies have reported that this deletion is an independent predictor of poor outcome in multivariate analyses.[77,100,101,104,117,122,123,124,125,126,127,128]; [129][Level of evidence: 2Di] However, the prognostic significance of IKZF1 may not apply equally across ALL biological subtypes, as illustrated by the apparent lack of prognostic significance in patients with ERG deletion.[77,78,79] Similarly, the prognostic significance of the IKZF1 deletion also appeared to be minimized in a cohort of COG patients with DUX4-rearranged ALL and with ERG transcriptional dysregulation that frequently occurred by ERG deletion.[6] The Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP)–Berlin-Frankfurt-Münster (BFM) group reported that IKZF1 deletions were significant adverse prognostic factors only in B-ALL patients with high end-induction MRD and in whom co-occurrence of deletions of CDKN2A, CDKN2B, PAX5, or PAR1 (in the absence of ERG deletion) were identified.[130]

      There are few published results of changing therapy on the basis of IKZF1 gene status. The Malaysia-Singapore group published results of two consecutive trials. In the first trial (MS2003), IKZF1 status was not considered in risk stratification, while in the subsequent trial (MS2010), IKZF1-deleted patients were excluded from the standard-risk group. Thus, more IKZF1-deleted patients in the MS2010 trial received intensified therapy. Patients with IKZF1-deleted ALL had improved outcomes in MS2010 compared with patients in MS2003, but interpretation of this observation is limited by other changes in risk stratification and therapeutic differences between the two trials.[131][Level of evidence: 2A]

T-ALL cytogenetics/genomics

T-ALL is characterized by genomic alterations leading to activation of transcriptional programs related to T-cell development and by a high frequency of cases (approximately 60%) with mutations in NOTCH1 and/or FBXW7 that result in activation of the NOTCH1 pathway.[132] In contrast to B-ALL, the prognostic significance of T-ALL genomic alterations is less well-defined. Cytogenetic abnormalities common in B-lineage ALL (e.g., hyperdiploidy, 51–65 chromosomes) are rare in T-ALL.[133,134]

  • Notch pathway signaling.

    Notch pathway signaling is commonly activated by NOTCH1 and FBXW7 gene mutations in T-ALL, and these are the most commonly mutated genes in pediatric T-ALL.[132,135]NOTCH1-activating gene mutations occur in approximately 50% to 60% of T-ALL cases, and FBXW7-inactivating gene mutations occur in approximately 15% of cases, with the result that approximately 60% of cases have Notch pathway activation by mutations in at least one of these genes.[136,137]

    The prognostic significance of NOTCH1/FBXW7 mutations may be modulated by genomic alterations in RAS and PTEN. The French Acute Lymphoblastic Leukaemia Study Group (FRALLE) and the Group for Research on Adult Acute Lymphoblastic Leukemia groups reported that patients having mutated NOTCH1/FBXW7 and wild-type PTEN/RAS constituted a favorable-risk group (i.e., low-risk group), while patients with PTEN or RAS mutations, regardless of NOTCH1/FBXW7 status, have a significantly higher risk of treatment failure (i.e., high-risk group).[138,139] In the FRALLE study, the 5-year disease-free survival (DFS) rate was 88% for the genetic low-risk group of patients and 60% for the genetic high-risk group of patients..[138] However, using the same criteria to define the genetic risk group, the Dana-Farber Cancer Institute consortium was unable to replicate these results. They reported a 5-year EFS rate of 86% for genetic low-risk patients and 79% for the genetic high-risk patients, a difference that was not statistically significant (P = .26).[137]

  • Chromosomal translocations.

    Multiple chromosomal translocations have been identified in T-ALL that lead to deregulated expression of the target genes. These chromosome rearrangements fuse genes encoding transcription factors (e.g., TAL1/TAL2, LMO1 and LMO2, LYL1, TLX1, TLX3, NKX2-I, HOXA, and MYB) to one of the T-cell receptor loci (or to other genes) and result in deregulated expression of these transcription factors in leukemia cells.[132,133,140,141,142,143,144] These translocations are often not apparent by examining a standard karyotype, but can be identified using more sensitive screening techniques, including FISH or PCR.[133] Mutations in a noncoding region near the TAL1 gene that produce a super-enhancer upstream of TAL1 represent nontranslocation genomic alterations that can also activate TAL1 transcription to induce T-ALL.[145]

    Translocations resulting in chimeric fusion proteins are also observed in T-ALL.[138]

    • A NUP214-ABL1 fusion has been noted in 4% to 6% of T-ALL cases and is observed in both adults and children, with a male predominance.[146,147,148] The fusion is cytogenetically cryptic and is seen in FISH on amplified episomes or, more rarely, as a small homogeneous staining region.[148] T-ALL may also uncommonly show ABL1 fusion proteins with other gene partners (e.g., ETV6, BCR, and EML1).[148]ABL tyrosine kinase inhibitors, such as imatinib or dasatinib, may demonstrate therapeutic benefits in this T-ALL subtype,[146,147,149] although clinical experience with this strategy is very limited.[150,151,152]
    • Gene fusions involving SPI1 (encoding the transcription factor PU.1) were reported in 4% of Japanese children with T-ALL.[153] Fusion partners included STMN1 and TCF7. T-ALL cases with SPI1 fusions had a particularly poor prognosis; six of seven affected individuals died within 3 years of diagnosis of early relapse.
    • Other recurring gene fusions in T-ALL patients include those involving MLLT10, KMT2A, and NUP98.[132]

Early T-cell precursor ALL cytogenetics/genomics

Detailed molecular characterization of early T-cell precursor ALL showed this entity to be highly heterogeneous at the molecular level, with no single gene affected by mutation or copy number alteration in more than one-third of cases.[154] Compared with other T-ALL cases, the early T-cell precursor group had a lower rate of NOTCH1 mutations and significantly higher frequencies of alterations in genes regulating cytokine receptors and RAS signaling, hematopoietic development, and histone modification. The transcriptional profile of early T-cell precursor ALL shows similarities to that of normal hematopoietic stem cells and myeloid leukemia stem cells.[154]

Studies have found that the absence of biallelic deletion of the TCR-gamma locus (ABD), as detected by comparative genomic hybridization and/or quantitative DNA-PCR, was associated with early treatment failure in patients with T-ALL.[155,156] ABD is characteristic of early thymic precursor cells, and many of the T-ALL patients with ABD have an immunophenotype consistent with the diagnosis of early T-cell precursor phenotype.

Mixed phenotype acute leukemia (MPAL) cytogenetics/genomics

For acute leukemias of ambiguous lineage, the WHO classification system is summarized in Table 3.[157,158] The criteria for lineage assignment for a diagnosis of MPAL are provided in Table 4.[17]

Table 3. Acute Leukemias of Ambiguous Lineage According to the World Health Organization Classification of Tumors of Hematopoietic and Lymphoid Tissuesa
Condition Definition
NOS = not otherwise specified.
a Adapted from Béné MC: Biphenotypic, bilineal, ambiguous or mixed lineage: strange leukemias! Haematologica 94 (7): 891-3, 2009.[157]Obtained from Haematologica/the Hematology Journal websitehttp://www.haematologica.org.
Acute undifferentiated leukemia Acute leukemia that does not express any marker considered specific for either lymphoid or myeloid lineage
Mixed phenotype acute leukemia with t(9;22)(q34;q11.2);BCR-ABL1(MPAL withBCR-ABL1) Acute leukemia meeting the diagnostic criteria for mixed phenotype acute leukemia in which the blasts also have the (9;22) translocation or theBCR-ABL1rearrangement
Mixed phenotype acute leukemia with t(v;11q23);KMT2A(MLL) rearranged (MPAL withKMT2A) Acute leukemia meeting the diagnostic criteria for mixed phenotype acute leukemia in which the blasts also have a translocation involving theKMT2Agene
Mixed phenotype acute leukemia, B/myeloid, NOS (B/M MPAL) Acute leukemia meeting the diagnostic criteria for assignment to both B and myeloid lineage, in which the blasts lack genetic abnormalities involvingBCR-ABL1orKMT2A
Mixed phenotype acute leukemia, T/myeloid, NOS (T/M MPAL) Acute leukemia meeting the diagnostic criteria for assignment to both T and myeloid lineage, in which the blasts lack genetic abnormalities involvingBCR-ABL1orKMT2A
Mixed phenotype acute leukemia, B/myeloid, NOS—rare types Acute leukemia meeting the diagnostic criteria for assignment to both B and T lineage
Other ambiguous lineage leukemias Natural killer–cell lymphoblastic leukemia/lymphoma
Table 4. Lineage Assignment Criteria for Mixed Phenotype Acute Leukemia According to the 2016 Revision to the World Health Organization Classification of Myeloid Neoplasms and Acute Leukemiaa
Lineage Criteria
a Adapted from Arber et al.[17]
b Strong defined as equal to or brighter than the normal B or T cells in the sample.
Myeloid lineage Myeloperoxidase (flow cytometry, immunohistochemistry, or cytochemistry);or monocytic differentiation (at least two of the following: nonspecific esterase cytochemistry, CD11c, CD14, CD64, lysozyme)
T lineage Strongb cytoplasmic CD3 (with antibodies to CD3 epsilon chain);or surface CD3
B lineage Strongb CD19 with at least one of the following strongly expressed: CD79a, cytoplasmic CD22, or CD10;or weak CD19 with at least two of the following strongly expressed: CD79a, cytoplasmic CD22, or CD10

The classification system for MPAL includes two entities that are defined by their primary molecular alteration: MPAL with BCR-ABL1 translocation and MPAL with KMT2A rearrangement. The genomic alterations associated with the MPAL, B/myeloid, NOS (B/M MPAL) and MPAL, T/myeloid, NOS (T/M MPAL) entities are distinctive, as described below:

  • B/M MPAL.
    • Among 115 MPAL cases for which genomic characterization was performed, 35 (30%) were B/M MPAL. There were an additional 16 MPAL cases (14%) with KMT2A rearrangements, 15 of whom showed a B/myeloid immunophenotype.
    • Approximately one-half of B/M MPAL cases had rearrangements of ZNF384 with recurrent fusion partners, including TCF3 and EP300. These cases had gene expression profiles indistinguishable from B-ALL cases with ZNF384 rearrangements.[88]
    • Approximately two-thirds of B/M MPAL cases had RAS pathway alterations, with NRAS and PTPN11 being the most commonly altered genes.[88]
    • Genes encoding epigenetic regulators (e.g., MLLT3, KDM6A, EP300, and CREBBP) are mutated in approximately two-thirds of B/M MPAL cases.[88]
  • T/M MPAL.
    • Among 115 MPAL cases for which genomic characterization was performed, 49 (43%) were T/M MPAL.[88] The genomic features of the T/M MPAL cases shared commonalities with those of early T-cell precursor (ETP) ALL, suggesting that T/M MPAL and ETP ALL are similar entities along the spectrum of immature leukemias.
    • Compared with T-ALL, T/M MPAL showed a lower rate of alterations in the core T-ALL transcription factors (TAL1, TAL2, TLX1, TLX3, LMO1, LMO2, NKX2-1, HOXA10, and LYL1) (63% vs. 16%, respectively).[88] A similar lower rate was also observed for ETP ALL.
    • CDKN2A/B and NOTCH1 mutations, which are present in approximately two-thirds of T-ALL cases, were much less common in T/M MPAL cases. By contrast, WT1 mutations occurred in approximately 40% of T/M MPAL, but in less than 10% of T-ALL cases.[88]
    • RAS and JAK-STAT pathway mutations were common in the T/M MPAL and ETP ALL cases, while the PI3K signaling pathway is more commonly altered in T-ALL.[88] For T/M MPAL, the most commonly mutated signaling pathway gene was FLT3 (43% of cases). FLT3 mutations tended to be mutually exclusive with RAS pathway mutations.
    • Genes encoding epigenetic regulators (e.g., EZH2 and PHF6) were mutated in approximately two-thirds of T/M MPAL cases.[88]

Gene polymorphisms in drug metabolic pathways

A number of polymorphisms of genes involved in the metabolism of chemotherapeutic agents have been reported to have prognostic significance in childhood ALL.[159,160,161]

  • TPMT.

    Patients with mutant phenotypes of TPMT (a gene involved in the metabolism of thiopurines such as mercaptopurine) appear to have more favorable outcomes,[162] although such patients may also be at higher risk of developing significant treatment-related toxicities, including myelosuppression and infection.[163,164] Patients with homozygosity for TPMT variants associated with low enzymatic activity tolerate only very low doses of mercaptopurine (approximately 10% of the standard dose) and are treated with reduced doses of mercaptopurine to avoid excessive toxicity. Patients who are heterozygous for this mutant enzyme gene generally tolerate mercaptopurine without serious toxicity, but they do require more frequent dose reductions for hematologic toxicity than do patients who are homozygous for the normal allele.[165,166]

  • NUDT15.

    Germline variants in NUDT15 that reduce or abolish activity of this enzyme also lead to diminished tolerance to thiopurines.[165,167] The NUDT15 variants are most common in East Asian and Hispanic patients, and they are rare in European and African patients. Patients homozygous for the risk variants tolerate only very low doses of mercaptopurine, while patients heterozygous for the risk alleles tolerate lower doses than do patients homozygous for the wild-type allele (approximately 25% dose reduction on average), but there is broad overlap in tolerated doses between the two groups.[165,168]

  • CEP72.

    Gene polymorphisms may also affect the expression of proteins that play central roles in the cellular effects of anticancer drugs. As an example, patients who are homozygous for a polymorphism in the promoter region of CEP72 (a centrosomal protein involved in microtubule formation) are at increased risk of vincristine neurotoxicity.[169]

  • Single nucleotide polymorphisms.

    Genome-wide polymorphism analysis has identified specific single nucleotide polymorphisms associated with high end-induction MRD and risk of relapse. Polymorphisms of interleukin-15, as well as genes associated with the metabolism of etoposide and methotrexate, were significantly associated with treatment response in two large cohorts of ALL patients treated on SJCRH and COG protocols.[170] Polymorphic variants involving the reduced folate carrier and methotrexate metabolism have been linked to toxicity and outcome.[171,172] While these associations suggest that individual variations in drug metabolism can affect outcome, few studies have attempted to adjust for these variations; it is unknown whether individualized dose modification on the basis of these findings will improve outcome.

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  168. Tanaka Y, Kato M, Hasegawa D, et al.: Susceptibility to 6-MP toxicity conferred by a NUDT15 variant in Japanese children with acute lymphoblastic leukaemia. Br J Haematol 171 (1): 109-15, 2015.
  169. Diouf B, Crews KR, Lew G, et al.: Association of an inherited genetic variant with vincristine-related peripheral neuropathy in children with acute lymphoblastic leukemia. JAMA 313 (8): 815-23, 2015.
  170. Yang JJ, Cheng C, Yang W, et al.: Genome-wide interrogation of germline genetic variation associated with treatment response in childhood acute lymphoblastic leukemia. JAMA 301 (4): 393-403, 2009.
  171. Gregers J, Christensen IJ, Dalhoff K, et al.: The association of reduced folate carrier 80G>A polymorphism to outcome in childhood acute lymphoblastic leukemia interacts with chromosome 21 copy number. Blood 115 (23): 4671-7, 2010.
  172. Radtke S, Zolk O, Renner B, et al.: Germline genetic variations in methotrexate candidate genes are associated with pharmacokinetics, toxicity, and outcome in childhood acute lymphoblastic leukemia. Blood 121 (26): 5145-53, 2013.

Risk-Based Treatment Assignment

Introduction to Risk-Based Treatment

Children with acute lymphoblastic leukemia (ALL) are usually treated according to risk groups defined by both clinical and laboratory features. The intensity of treatment required for cure varies substantially among subsets of children with ALL. Risk-based treatment assignment is utilized in children with ALL so that patients with favorable clinical and biological features who are likely to have a very good outcome with modest therapy can be spared more intensive and toxic treatment, while a more aggressive, and potentially more toxic, therapeutic approach can be provided for patients who have a lower probability of long-term survival.[1,2]

Certain ALL study groups, such as the Children's Oncology Group (COG), use a more- or less-intensive induction regimen based on a subset of pretreatment factors, while other groups give a similar induction regimen to all patients.

Factors used by the COG to determine the intensity of induction include the following:

  • Immunophenotype.
  • The presence or absence of extramedullary disease.
  • Steroid pretreatment.
  • The presence or absence of Down syndrome.
  • The National Cancer Institute (NCI) risk group classification.

The NCI risk group classification for B-ALL stratifies risk according to age and white blood cell (WBC) count, as follows:[3]

  • Standard risk: WBC count less than 50,000/μL and age 1 to younger than 10 years.
  • High risk: WBC count 50,000/μL or greater and/or age 10 years or older.

All study groups modify the intensity of postinduction therapy on the basis of a variety of prognostic factors, including NCI risk group, immunophenotype, early response determinations, and cytogenetics and genomic alterations.[4] Detection of the Philadelphia chromosome (i.e., Philadelphia chromosome–positive [Ph+] ALL) leads to immediate changes in induction therapy.[5]

Risk-based treatment assignment requires the availability of prognostic factors that reliably predict outcome. For children with ALL, a number of factors have demonstrated prognostic value, some of which are described below.[6] Factors affecting prognosis are grouped into the following three categories:

  • Patient and clinical disease characteristics.
  • Leukemic characteristics.
  • Response to initial treatment.

As in any discussion of prognostic factors, the relative order of significance and the interrelationship of the variables are often treatment dependent and require multivariate analysis to determine which factors operate independently as prognostic variables. Because prognostic factors are treatment dependent, improvements in therapy may diminish or abrogate the significance of any of these presumed prognostic factors.

A subset of the prognostic and clinical factors discussed below is used for the initial stratification of children with ALL for treatment assignment. (Refer to the Prognostic [risk] groups under clinical evaluation section of this summary for brief descriptions of the prognostic groupings currently applied in ongoing clinical trials in the United States.)

(Refer to the Prognostic Factors After First Relapse of Childhood ALL section of this summary for information about important prognostic factors at relapse.)

Prognostic Factors Affecting Risk-Based Treatment

Patient and clinical disease characteristics

Patient and clinical disease characteristics affecting prognosis include the following:

  1. Age at diagnosis.
  2. WBC count at diagnosis.
  3. Central nervous system (CNS) involvement at diagnosis.
  4. Testicular involvement at diagnosis.
  5. Down syndrome (trisomy 21).
  6. Sex.
  7. Race and ethnicity.
  8. Weight at diagnosis and during treatment.

Age at diagnosis

Age at diagnosis has strong prognostic significance, reflecting the different underlying biology of ALL in different age groups.[7]

  1. Infants (younger than 1 year).

    Infants with ALL have a particularly high risk of treatment failure. Treatment failure is most common in the following groups:

    • Infants younger than 6 months (with an even poorer prognosis for those aged ≤90 days).[8,9,10,11,12]
    • Infants with extremely high presenting leukocyte counts (>200,000–300,000 × 109 /L).[9]
    • Infants with a poor response to a prednisone prophase.[9]
    • Infants with a KMT2A (MLL) gene rearrangement.[8,9,10,11]

    Up to 80% of infants with ALL have a translocation of 11q23 with numerous chromosome partners generating a KMT2A gene rearrangement.[9,11,13,14] The most common rearrangement is KMT2A-AFF1 (t(4;11)(q21;q23)), but KMT2A rearrangements with many other translocation partners are observed.

    The rate of KMT2A gene rearrangements is extremely high in infants younger than 6 months; from 6 months to 1 year, the incidence of KMT2A rearrangements decreases but remains higher than that observed in older children.[9,15] Black infants with ALL are significantly less likely to have KMT2A rearrangements than are White infants.[15]

    Infants with leukemia and KMT2A rearrangements typically have very high WBC counts and an increased incidence of CNS involvement. Event-free survival (EFS) and overall survival (OS) are poor, with 5-year EFS and OS rates of only 35% to 40% for infants with KMT2A-rearranged ALL.[9,10,11] A comparison of the landscape of somatic mutations in infants and children with KMT2A-rearranged ALL revealed significant differences between the two groups, suggesting distinctive age-related biological behaviors for KMT2A-rearranged ALL that may relate to the significantly poorer outcome for infants.[16,17]

    Blasts from infants with KMT2A rearrangements are often CD10 negative and express high levels of FLT3.[9,10,14,18] Conversely, infants whose leukemic cells show a germline KMT2A gene configuration frequently present with CD10-positive precursor-B immunophenotype. These infants have a significantly better outcome than do infants with ALL characterized by KMT2A rearrangements.[9,10,14,19]

    (Refer to the Infants With ALL subsection in the Postinduction Treatment for Specific ALL Subgroups section of this summary for more information about infants with ALL.)

  2. Young children (aged 1 to <10 years).

    Young children (aged 1 to <10 years) have a better disease-free survival than older children, adolescents, and infants.[3,7,20,21,22] The improved prognosis in young children is at least partly explained by the more frequent occurrence of favorable cytogenetic features in the leukemic blasts, including hyperdiploidy with 51 to 65 chromosomes and/or favorable chromosome trisomies, or the ETV6-RUNX1 fusion (t(12;21)(p13;q22), also known as the TEL-AML1 translocation).[7,23,24]

  3. Adolescents and young adults (aged ≥10 years).

    In general, the outcome of patients aged 10 years and older is inferior to that of patients aged 1 to younger than 10 years. However, the outcome for older children, especially adolescents, has improved significantly over time.[25,26,27] Five-year survival rates for adolescents aged 15 to 19 years increased from 36% (1975–1984) to 72% (2003–2009).[28,29,30]

    Multiple retrospective studies have established that adolescents aged 16 to 21 years have a better outcome when treated on pediatric versus adult protocols.[31,32,33] (Refer to the Postinduction Treatment for Specific ALL Subgroups section of this summary for more information about adolescents with ALL.)

WBC count at diagnosis

A WBC count of 50,000/µL is generally used as an operational cut point between better and poorer prognosis,[3] although the relationship between WBC count and prognosis is a continuous function rather than a step function. Patients with B-ALL and high WBC counts at diagnosis have an increased risk of treatment failure compared with patients with low initial WBC counts.[34]

The median WBC count at diagnosis is much higher for T-ALL (>50,000/µL) than for B-ALL (<10,000/µL), and there is no consistent effect of WBC count at diagnosis on prognosis for T-ALL.[34,35,36,37,38,39,40,41,42]

CNS involvement at diagnosis

The presence or absence of CNS leukemia at diagnosis has prognostic significance. Patients who have a nontraumatic diagnostic lumbar puncture may be placed into one of three categories according to the number of WBC/µL and the presence or absence of blasts on cytospin as follows:

  • CNS1: Cerebrospinal fluid (CSF) that is cytospin negative for blasts regardless of WBC count.
  • CNS2: CSF with fewer than 5 WBC/µL and cytospin positive for blasts.
  • CNS3 (CNS disease): CSF with 5 or more WBC/µL and cytospin positive for blasts.

Children with ALL who present with CNS disease (CNS3) at diagnosis are at a higher risk of treatment failure (both within the CNS and systemically) than are patients who are classified as CNS1 or CNS2.[43,44] Some studies have reported increased risk of CNS relapse and/or inferior EFS in CNS2 patients, compared with CNS1 patients,[45,46] while others have not.[43,47,48,49]

A traumatic lumbar puncture (≥10 erythrocytes/µL) that includes blasts at diagnosis has also been associated with increased risk of CNS relapse and overall poorer outcome in some studies,[43,48,50] but not others.[46,47,51] Patients with CNS2, CNS3, or traumatic lumbar puncture have a higher frequency of unfavorable prognostic characteristics than do those with CNS1, including significantly higher WBC counts at diagnosis, older age at diagnosis, an increased frequency of the T-ALL phenotype, and KMT2A gene rearrangements.[43,47,48]

Most clinical trial groups have approached the treatment of CNS2 and traumatic lumbar puncture patients by utilizing more intensive therapy, primarily additional doses of intrathecal therapy during induction.[43,52,53]; [47][Level of evidence: 2A]; [54][Level of evidence: 1iiA]

To determine whether a patient with a traumatic lumbar puncture (with blasts) should be treated as CNS3, the COG uses an algorithm relating the WBC and red blood cell counts in the spinal fluid and the peripheral blood.[55]

Testicular involvement at diagnosis

Overt testicular involvement at the time of diagnosis occurs in approximately 2% of males,[56,57] with its frequency being higher in patients with T-ALL than in patients with B-ALL.[57]

In early ALL trials, testicular involvement at diagnosis was an adverse prognostic factor. With more aggressive initial therapy, however, it does not appear that testicular involvement at diagnosis has prognostic significance.[56,57] For example, the European Organization for Research and Treatment of Cancer (EORTC [EORTC-58881]) reported no adverse prognostic significance for overt testicular involvement at diagnosis.[57]

The role of radiation therapy for testicular involvement is unclear. A study from St. Jude Children's Research Hospital (SJCRH) suggests that a good outcome can be achieved with aggressive conventional chemotherapy without radiation.[56] The COG has also adopted this strategy for boys with testicular involvement that resolves completely by the end of induction therapy. The COG considers patients with testicular involvement to be high risk regardless of other presenting features, but most other large clinical trial groups in the United States and Europe do not consider testicular disease to be a high-risk feature.

Down syndrome (trisomy 21)

Outcomes in children with Down syndrome and ALL have often been reported as somewhat inferior to outcomes observed in children who do not have Down syndrome,[58,59,60,61,62] although on some studies, patients with Down syndrome appear to fare as well as patients without Down syndrome.[63,64] The lower EFS and OS of children with Down syndrome appear to be related to increased frequency of treatment-related mortality, as well as higher rates of induction failure and relapse.[58,59,60,61,65,66] The inferior anti-leukemic outcome may be due, in part, to the decreased prevalence of favorable biological features such as ETV6-RUNX1 or hyperdiploidy (51–65 chromosomes) with trisomies of chromosomes 4 and 10 in Down syndrome ALL patients.[65,66]

  • In a large retrospective study that included 653 patients with Down syndrome and ALL, Down syndrome patients had a lower CR rate (97% vs. 99%, P < .001), higher cumulative incidence of relapse (26% vs. 15%, P < .001) and higher treatment-related mortality (7% vs. < 1%, P < .001) compared with non-Down syndrome patients.[66] Among the patients with Down syndrome, age younger than 6 years, WBC count of less than 10,000/µL, and the presence of the ETV6-RUNX1 fusion (observed in 8% of patients) were independent predictors of favorable EFS.
  • In a report from the COG, among patients with B-ALL who lacked KMT2A rearrangements, BCR-ABL1, ETV6-RUNX1, and hyperdiploidy with trisomies of chromosomes 4 and 10, the EFS and OS rates were similar in children with and without Down syndrome.[65]
  • Certain genomic abnormalities, such as IKZF1 deletions, CRLF2 aberrations, and JAK mutations are seen more frequently in ALL arising in children with Down syndrome than in those without Down syndrome.[67,68,69,70,71] Studies of children with Down syndrome and ALL suggest that the presence of IKZF1 deletions (but not CRLF2 aberrations or JAK mutations) is associated with an inferior prognosis.[66,71,72]

Sex

In some studies, the prognosis for girls with ALL is slightly better than it is for boys with ALL.[73,74,75] One reason for the better prognosis for girls is the occurrence of testicular relapses among boys, but boys also appear to be at increased risk of bone marrow and CNS relapse for reasons that are not well understood.[73,74,75] While some reports describe outcomes for boys as closely approaching those of girls,[22,52,76] larger clinical trial experiences and national data continue to show somewhat lower survival rates for boys.[21,28,29,77]

Race and ethnicity

Over the last several decades in the United States, survival rates in Black and Hispanic children with ALL have been somewhat lower than the rates in White children with ALL.[78,79,80,81]

The following factors associated with race and ethnicity influence survival:

  • ALL subtype. The reason for better outcomes in White and Asian children than in Black and Hispanic children is at least partially explained by the different spectrum of ALL subtypes. For example, Black children have a higher relative incidence of T-ALL and lower rates of favorable genetic subtypes of B-ALL.
  • Treatment adherence. Differences in outcome may also be related to treatment adherence, as illustrated by a study of adherence to oral mercaptopurine (6-MP) in maintenance therapy. In the first report from the study, there was an increased risk of relapse in Hispanic children compared with non-Hispanic White children, depending on the level of adherence, even when adjusting for other known variables. However, even with adherence rates of 90% or more, Hispanic children continued to demonstrate increased rates of relapse.[82] In the second report from the study, adherence rates were shown to be significantly lower in Asian American and African American patients than in non-Hispanic White patients. A greater percentage of patients in these ethnic groups had adherence rates of less than 90%, which was associated with a 3.9-fold increased risk of relapse.[83]
  • Ancestry-related genomic variations. Ancestry-related genomic variations may also contribute to racial and ethnic disparities in both the incidence and outcome of ALL.[84] For example, the differential presence of specific host polymorphisms in different racial and ethnic groups may contribute to outcome disparities, as illustrated by the occurrence of single nucleotide polymorphisms in the ARID5B gene that occur more frequently among Hispanics and are linked to both ALL susceptibility and to relapse hazard.[85]

Weight at diagnosis and during treatment

Studies of the impact of obesity on the outcome of ALL have had variable results. In most of these studies, obesity is defined as weight above the 95th percentile for age and height.

  • Three studies did not demonstrate an independent effect of obesity on EFS.[86][Level of evidence: 2Dii]; [87,88][Level of evidence: 3iiDi]
  • Two studies showed obesity to be an independent prognostic factor only in patients older than 10 years or in patients with intermediate-risk or high-risk disease.[89,90][Level of evidence: 3iiDi]
  • The COG reported on the impact of obesity on outcome in 2,008 children, 14% of whom were obese, who were enrolled on a high-risk ALL trial (CCG-1961 [NCT00002812]).[91][Level of evidence: 2Di] Obesity was found to be an independent variable for inferior outcome compared with nonobese patients (5-year EFS rates, 64% vs. 74%; P = .002.) However, obese patients at diagnosis who then normalized their weight during the premaintenance period of treatment had outcomes similar to patients with normal weight at diagnosis.
  • In a retrospective study of patients treated at a single institution, obesity at diagnosis was linked to an increased risk of having minimal residual disease (MRD) at the end of induction and an inferior EFS.[92][Level of evidence: 3iiDi]
  • In a different retrospective study of 373 patients treated at a single institution, body mass index (BMI) at diagnosis was not associated with MRD at days 19 and 46, cumulative incidence of relapse, or EFS. OS was lower in patients with a high BMI, primarily resulting from treatment-related mortality and inferior salvage after relapse.[93][Level of evidence: 3iiA]

In a study of 762 pediatric patients with ALL (aged 2–17 years), the Dutch Childhood Oncology Group found that those who were underweight at diagnosis (8% of the population) had an almost twofold higher risk of relapse compared with patients who were not underweight (after adjusting for risk group and age), although this did not result in a difference in EFS or OS. Patients with a decrease in BMI during the first 32 weeks of treatment had similar rates of relapse as other patients, but had significantly worse OS, primarily because of poorer salvage rates after relapse.[94]

Leukemic characteristics

Leukemic cell characteristics affecting prognosis include the following:

  1. Immunophenotype.
  2. Cytogenetics/genomic alterations.

Immunophenotype

The 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia classifies ALL as either B-lymphoblastic leukemia or T-lymphoblastic leukemia, with further subdivisions based on molecular characteristics.[95,96] (Refer to the Diagnosis section of this summary for more information.)

Either B- or T-lymphoblastic leukemia can coexpress myeloid antigens. These cases need to be distinguished from leukemia of ambiguous lineage.

  1. B-ALL (WHO B-lymphoblastic leukemia).

    Before 2008, the WHO classified B-lymphoblastic leukemia as precursor B-lymphoblastic leukemia, and this terminology is still frequently used in the literature of childhood ALL to distinguish it from mature B-cell ALL. Mature B-cell ALL is now termed Burkitt leukemia and requires different treatment than has been given for B-ALL (precursor B-cell ALL).

    B-ALL, defined by the expression of CD19, HLA-DR, cytoplasmic CD79a, and other B-cell–associated antigens, accounts for 80% to 85% of childhood ALL. Approximately 90% of B-ALL cases express the CD10 surface antigen (formerly known as common ALL antigen [cALLa]). Absence of CD10 is usually associated with KMT2A rearrangements, particularly t(4;11)(q21;q23), and a poor outcome.[9,97] It is not clear whether CD10-negativity has any independent prognostic significance in the absence of a KMT2A gene rearrangement.[98]

    The major immunophenotypic subtypes of B-ALL are as follows:

    • Common B-ALL (CD10 positive and no surface or cytoplasmic immunoglobulin [Ig]).

      Approximately three-quarters of patients with B-ALL have the common precursor B-cell immunophenotype and have the best prognosis. Patients with favorable cytogenetics almost always show a common precursor B-cell immunophenotype.

    • Pro-B ALL (CD10 negative and no surface or cytoplasmic Ig).

      Approximately 5% of patients have the pro-B immunophenotype. Pro-B is the most common immunophenotype seen in infants and is often associated with KMT2A gene rearrangements.

    • Pre-B ALL (presence of cytoplasmic Ig).

      The leukemic cells of patients with pre-B ALL contain cytoplasmic Ig, and 25% of patients with pre-B ALL have the t(1;19)(q21;p13) translocation with the TCF3-PBX1 (previously known as E2A-PBX1) fusion.[99,100]

      Approximately 3% of patients have transitional pre-B ALL with expression of surface Ig heavy chain without expression of light chain, MYC gene involvement, or L3 morphology. Patients with this phenotype respond well to therapy used for B-ALL.[101]

    • Mature B-ALL (Burkitt lymphoma/leukemia).

      Approximately 2% of patients present with mature B-cell leukemia (surface Ig expression, generally with French-American-British criteria L3 morphology and an 8q24 translocation involving MYC), also called Burkitt leukemia. The treatment for mature B-cell ALL is based on therapy for non-Hodgkin lymphoma and is completely different from the treatment for B-ALL. Rare cases of mature B-cell leukemia that lack surface Ig but have L3 morphology with MYC gene translocations should also be treated as mature B-cell leukemia.[101] (Refer to the PDQ summary on Childhood Non-Hodgkin Lymphoma Treatment for more information about the treatment of children with mature B-cell lymphoma/leukemia and Burkitt lymphoma/leukemia.)

      A small number of cases of IG-MYC-translocated leukemias with precursor B-cell immunophenotype (e.g., absence of CD20 expression and surface Ig expression) have been reported.[102] These cases presented in both children and adults. Like Burkitt lymphoma/leukemia, they had a male predominance and most patients showed L3 morphology. The cases lacked mutations in genes recurrently altered in Burkitt lymphoma (e.g., ID3, CCND3, or MYC), whereas mutations in RAS genes (frequently altered in B-ALL) were common. The clinical significance of IG-MYC–translocated leukemias with precursor B-cell phenotype and molecular characteristics requires further study.

  2. T-ALL.

    T-ALL is defined by expression of the T-cell–associated antigens (cytoplasmic CD3, with CD7 plus CD2 or CD5) on leukemic blasts. T-ALL is frequently associated with a constellation of clinical features, including the following:[20,36,76]

    • Male sex.
    • Older age.
    • Leukocytosis.
    • Mediastinal mass.

    While not true historically, with appropriately intensive therapy, children with T-ALL now have an outcome approaching that of children with B-lineage ALL.[20,36,39,40,76,103]

    There are few commonly accepted prognostic factors for patients with T-ALL. Conflicting data exist regarding the prognostic significance of presenting leukocyte counts in T-ALL.[35,36,37,38,39,40,41,42,104] The presence or absence of a mediastinal mass at diagnosis has no prognostic significance. In patients with a mediastinal mass, the rate of regression of the mass lacks prognostic significance.[105]

    Early T-cell precursor (ETP) ALL

    ETP ALL, a distinct subset of childhood T-ALL, was initially defined by identifying T-ALL cases with gene expression profiles highly related to expression profiles for normal early T-cell precursors.[106] The subset of T-ALL cases, identified by these analyses represented 13% of all cases and they were characterized by a distinctive immunophenotype (CD1a and CD8 negativity, with weak expression of CD5 and coexpression of stem cell or myeloid markers).

    Initial reports describing ETP ALL suggested that this subset of patients has a poorer prognosis than other patients with T-ALL.[106,107,108] In addition, some studies have reported that these patients have a slower early response and higher frequency of induction failure than other patients with T-ALL.[42] Other studies have observed a more favorable outcome for patients with ETP ALL, including one study from the U.K. Medical Research Council that showed that the ETP ALL subgroup of patients had nonsignificantly inferior 5-year EFS rates compared with non–ETP patients (76% vs. 84%).[109] Similarly, in the COG AALL0434 [NCT00408005] trial, ETP status did not have a statistically significant impact on DFS (hazard ratio, 0.99; 95% CI, 0.59–1.67; P = .981) on multivariable analysis.[110,111] Further study in additional patient cohorts is needed to firmly establish the prognostic significance of early T-cell precursor ALL, but most ALL treatment groups do not change patient treatment on the basis of early T-cell precursor status.

  3. Myeloid antigen expression.

    Up to one-third of childhood ALL patients have leukemia cells that express myeloid-associated surface antigens. Myeloid-associated antigen expression appears to be associated with specific ALL subgroups, notably those with KMT2A rearrangements, ETV6-RUNX1, and BCR-ABL1.[112,113,114] Patients with B-ALL who have gene rearrangements involving ZNF384 also commonly show myeloid antigen expression.[115,116] No independent adverse prognostic significance exists for myeloid-surface antigen expression.[112,113]

    (Refer to the 2016 WHO Classification of Acute Leukemias of Ambiguous Lineage section of this summary for information about leukemia of ambiguous lineage.)

Cytogenetics/genomic alterations

(Refer to the Cytogenetics/Genomics of Childhood ALL section of this summary for information about B-ALL and T-ALL cytogenetics/genomics and gene polymorphisms in drug metabolic pathways.)

Response to initial treatment

The rapidity with which leukemia cells are eliminated after initiation of treatment and the level of residual disease at the end of induction are associated with long-term outcome. Because treatment response is influenced by the drug sensitivity of leukemic cells and host pharmacodynamics and pharmacogenomics,[117] early response has strong prognostic significance. Various ways of evaluating the leukemia cell response to treatment have been utilized, including the following:

  1. MRD determination.
  2. Day 7 and day 14 bone marrow responses.
  3. Peripheral blood response to steroid prophase.
  4. Peripheral blood response to multiagent induction therapy.
  5. Peripheral blood MRD before end of induction (day 8, day 15).
  6. Persistent leukemia at the end of induction (induction failure).

MRD determination

Morphologic assessment of residual leukemia in blood or bone marrow is often difficult and is relatively insensitive. Traditionally, a cutoff of 5% blasts in the bone marrow (detected by light microscopy) has been used to determine remission status. This corresponds to a level of 1 in 20 malignant cells. In order to detect lower levels of leukemic cells in either blood or marrow, specialized techniques are required; such techniques include polymerase chain reaction (PCR) assays, which determine unique Ig/T-cell receptor gene rearrangements and fusion transcripts produced by chromosome translocations, or flow cytometric assays, which detect leukemia-specific immunophenotypes. With these techniques, detection of as few as 1 leukemia cell in 100,000 normal cells is possible, and MRD at the level of 1 in 10,000 cells can be detected routinely.[118] Newer techniques involving high-throughput sequencing (HTS) of Ig/T-cell receptor gene rearrangements can increase sensitivity of MRD detection to 1 in 1 million cells (10-6 or 0.001%).[119]

Multiple studies have demonstrated that end-induction MRD is an important, independent predictor of outcome in children and adolescents with B-lineage ALL.[120,121,122] MRD response discriminates outcome in subsets of patients defined by age, leukocyte count, and cytogenetic abnormalities.[123] In general, patients with higher levels of end-induction MRD have a poorer prognosis than do those with lower or undetectable levels.[118,120,121,122] However, the absolute risk of relapse associated with specific MRD levels varies by genetic subtype. For example, at any given level of detectable end-induction MRD, patients with favorable cytogenetics, such as ETV6-RUNX1 or high hyperdiploidy, have a lower absolute risk of subsequent relapse than do other patients, while patients with high-risk cytogenetics have a higher absolute risk of subsequent relapse than do other patients.[124] This observation may have important implications when MRD is used to develop risk classification plans.

End-induction MRD is used by almost all groups as a factor in determining the intensity of postinduction treatment; patients found to have higher MRD levels (typically >0.1% to 0.01%) are allocated to more intensive therapies.[118,121,125]; [126][Level of evidence: 2A]

A study of 619 children with ALL compared the prognostic utility of MRD by flow cytometry with the more sensitive HTS assay. Using an end-induction MRD cutpoint level of 0.01%, high-throughput sequencing identified approximately 30% more cases as positive (i.e., >0.01%). Patients identified as positive by HTS, but negative by flow cytometry, had an intermediate prognosis compared with patients categorized as either positive or negative by both methods. Patients meeting the criteria for standard-risk ALL with undetectable MRD by HTS had an especially good prognosis (5-year EFS rate, 98.1%).[119]

MRD levels obtained 10 to 12 weeks after the start of treatment (end-consolidation) have also been shown to be prognostically important; patients with high levels of MRD at this time point have a significantly inferior EFS compared with other patients.[122,123]

  • B-ALL. For patients with B-ALL, evaluating MRD at two time points (end-induction and end-consolidation) can identify the following three prognostically distinct patient subsets:[123]
    1. Low or undetectable end-induction MRD: best prognosis.
    2. Detectable or high MRD at end-induction but low or negative end-consolidation MRD: intermediate prognosis.
    3. Detectable or high MRD at end-consolidation (week 12 of therapy): worst prognosis.
  • T-ALL. There are fewer studies documenting the prognostic significance of MRD in patients with T-ALL. The United Kingdom Acute Lymphoblastic Leukaemia (UKALL) group reported that T-ALL patients with nondetectable end-induction MRD had excellent outcomes, while those with very high MRD levels (>5%) at the end of induction had a poor prognosis; however, for all other T-ALL patients, an association between end-induction MRD level and relapse risk was not found.[124] The Dana-Farber Cancer Institute ALL consortium also reported that T-ALL patients with very low end-induction MRD (<10-4) had a very favorable outcome.[42]

    Another study also indicated that MRD at a later time point may be more prognostically significant in T-ALL.[127] In the Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP) ALL-BFM-2000 (NCT00430118) trial, MRD status at day 78 (week 12) was the most important predictor for relapse in patients with T-ALL.[127] Patients with detectable MRD at end-induction who had negative MRD by day 78 generally had a favorable prognosis, similar to that of patients who achieved MRD-negativity at the earlier end-induction time point.[127]

MRD measurements, in conjunction with other presenting features, have also been used to identify subsets of patients with an extremely low risk of relapse. The COG reported a very favorable prognosis (5-year EFS rate, 97% ± 1%) for patients with precursor B-cell phenotype, NCI standard risk age/leukocyte count, CNS1 status, and favorable cytogenetic abnormalities (either high hyperdiploidy with favorable trisomies or the ETV6-RUNX1 fusion) who had less than 0.01% MRD levels at both day 8 (from peripheral blood) and end-induction (from bone marrow).[121] The excellent outcomes in patients with low MRD at the end of induction were sustained for more than 10 years from diagnosis.[128]

Modifying therapy on the basis of MRD determination has been shown to improve outcome.

  • The UKALL2003 (NCT00222612) study demonstrated that reduction of therapy (i.e., one rather than two courses of delayed intensification) did not adversely impact outcome in non-high–risk patients with favorable end-induction MRD.[21][Level of evidence: 1iiDii] In a randomized controlled trial, the UKALL2003 study also demonstrated improved EFS for standard-risk and intermediate-risk patients who received augmented therapy if end-induction MRD was greater than 0.01% (5-year EFS rates, 89.6% for augmented therapy vs. 82.8% for standard therapy).[129]
  • The Dutch AAL10 trial stratified patients into the following three risk groups on the basis of MRD after the first month of treatment and after the second cycle of chemotherapy:[130][Level of evidence: 2A]
    • Standard risk (low MRD after the first month of treatment).
    • Moderate risk (high MRD after the first month of treatment, low MRD after the second cycle of chemotherapy).
    • High risk (high MRD after the second cycle of chemotherapy).

    Compared with previous trials conducted by the same group, therapy was less intensive for standard-risk patients but more intensive for moderate-risk and high-risk patients. The overall 5-year EFS rate (87%) and OS rate (92%) were superior to the previous Dutch studies.

Day 7 and day 14 bone marrow responses

Patients who have a rapid reduction in leukemia cells to less than 5% in their bone marrow within 7 or 14 days after the initiation of multiagent chemotherapy have a more favorable prognosis than do patients who have slower clearance of leukemia cells from the bone marrow.[131] MRD assessments at the end of induction therapy have generally replaced day 7 and day 14 morphological assessments as response to therapy prognostic indicators because the latter lose their prognostic significance in multivariate analysis once MRD is included in the analyses.[121,132]

Peripheral blood response to steroid prophase

Patients with a reduction in peripheral blast count to less than 1,000/µL after a 7-day induction prophase with prednisone and one dose of intrathecal methotrexate (a good prednisone response) have a more favorable prognosis than do patients whose peripheral blast counts remain above 1,000/µL (a poor prednisone response).[20] Poor prednisone response is observed in fewer than 10% of patients.[20,133] Treatment stratification for protocols of the Berlin-Frankfurt-Münster (BFM) clinical trials group is partially based on early response to the 7-day prednisone prophase (administered immediately before the initiation of multiagent remission induction).

Peripheral blood response to multiagent induction therapy

Patients with persistent circulating leukemia cells at 7 to 10 days after the initiation of multiagent chemotherapy are at increased risk of relapse compared with patients who have clearance of peripheral blasts within 1 week of therapy initiation.[134] Rate of clearance of peripheral blasts has been found to be of prognostic significance in both T-cell and B-lineage ALL.[134]

Peripheral blood MRD before end of induction (day 8, day 15)

MRD using peripheral blood obtained 1 week after the initiation of multiagent induction chemotherapy has also been evaluated as an early response-to-therapy prognostic factor.

  • In a COG study involving nearly 2,000 children with ALL, the presence of MRD in the peripheral blood at day 8 was associated with adverse prognosis; increasing MRD levels were associated with a progressively poorer outcome.[121]
  • In multivariate analysis, end-of-induction-therapy MRD was the most powerful prognostic factor, but day 8 peripheral blood MRD maintained its prognostic significance, as did NCI risk group and the presence of favorable trisomies. A smaller study assessed the prognostic significance of peripheral blood MRD at day 15 after 1 week of a steroid prophase and 1 week of multiagent induction therapy.[135] This study also observed multivariate significance for peripheral blood MRD levels after 1 week of multiagent induction therapy.

Both studies identified a group of patients who achieved low MRD levels after 1 week of multiagent induction therapy who had a low rate of subsequent treatment failure.

Persistent leukemia at the end of induction (induction failure)

The vast majority of children with ALL achieve complete morphologic remission by the end of the first month of treatment. The presence of greater than 5% lymphoblasts by morphological assessment at the end of the induction phase is observed in 1% to 2% of children with ALL.[21,22,136,137,138]

Features associated with a higher risk of induction failure include the following:[138,139,140]

  • T-cell phenotype.
  • Higher WBC at diagnosis for patients with B-ALL.
  • Older age.
  • Unfavorable biology.
    • KMT2A rearrangement.
    • BCR-ABL1 rearrangement (Ph+ ALL) (before the use of tyrosine kinase inhibitors).
    • Rearrangement of PDGFRB (most commonly EBF1-PDGFRB), commonly associated with the Ph-like subtype.[138,141] These patients represent less than 1% of B-ALL cases in children, but account for as much as 10% of induction failure cases.[138] Among 13 patients who were EBF1-PDGFRB positive, eight patients had end-of-induction MRD greater than 10%.[141]

In a large retrospective study, the OS rate of patients with induction failure was only 32%.[136] However, there was significant clinical and biological heterogeneity. A relatively favorable outcome was observed in patients with B-ALL between the ages of 1 and 5 years without adverse cytogenetics (KMT2A rearrangement or BCR-ABL1). This group had a 10-year survival exceeding 50%, and HSCT in first remission was not associated with a survival advantage compared with chemotherapy alone for this subset. Patients with the poorest outcomes (<20% 10-year survival) included those who were aged 14 to 18 years, or who had the Ph chromosome or KMT2A rearrangement. B-ALL patients younger than 6 years and T-ALL patients (regardless of age) appeared to have better outcomes if treated with allogeneic HSCT after achieving CR than those who received further treatment with chemotherapy alone.

Flow cytometry versus morphology

MRD is now being integrated with morphological assessment into the response to induction therapy, on the basis of studies that showed that patients with MRD levels above 5%, despite morphologic complete remission, had outcomes similar to patients with morphologic induction failure.

  1. In the UKALL2003 (NCT00222612) study, 59 of 3,113 patients (1.9%) had morphologic induction failure.[138]
    • The 5-year EFS rate was 51%, and the OS rate was 58%.
    • 2.3% of patients had a morphologic remission, but had MRD of ≥5% measured by real-time quantitative IgH–T-cell receptor (TCR) PCR; this group had a 5-year EFS rate of 47%, similar to those with morphologic induction failure.
    • The authors suggested that using both morphologic and MRD criteria to define induction failure would more precisely identify patients with poor outcomes.
  2. A study of 9,350 patients enrolled on COG clinical trials between 2004 and 2014 compared characteristics of patients and their outcomes categorized by morphology (M1 vs. M2/M3) and MRD status assessed by flow cytometry (<5% vs. ≥5%). Morphologic remission (M1 status) was achieved for 98.6% of B-ALL patients and 93.8% of T-ALL patients at the end of induction therapy.[142]
    • Morphology and MRD were concordant in 97.4% of children. However, only 87.3% of T-ALL patients were M1 with MRD of <5%, while 97.8% of B-ALL patients were in concordant remission.
    • Approximately 20% of patients (40 of 202) with M2/M3 morphology had MRD of <5%. B-ALL patients with M2/M3 morphology but MRD of <5% had a 5-year OS rate of 72.7%, which was inferior to that of patients concordantly in remission (5-year OS rate, 93.8%) but superior to that of patients with M3 marrow (5-year OS rate, 43.4%).
    • Among B-ALL and T-ALL patients with M1 marrow, 0.9% of B-ALL patients and 6.9% of T-ALL patients had MRD of ≥5%. Their outcome was compared with that of patients with M1 marrow and MRD of <5% and are shown in Table 5 below.
    • Table 5 shows that for children with B-ALL with M1 marrow and MRD of ≥5%, the 5-year EFS rate was significantly inferior to that of children concordantly in remission (59.1% vs. 87.1%) but was superior to that of children concordantly not in remission (M2 with MRD ≥5%: 5-year EFS rate, 39.1%).
    • The impact on EFS for MRD of ≥5% for children with B-ALL in morphologic remission was driven by NCI high-risk patients, as there was no significant difference in EFS between NCI standard-risk patients in morphologic remission with or without MRD of ≥5%.
    • Inferior EFS was also observed for patients with T-ALL with M1 marrow and MRD of ≥5% compared with those in concordant remission (87.6% vs. 80.3%); however, outcome for T-ALL patients not in remission (whether by morphology or MRD or both) was superior to that of comparable patients with B-ALL.
    • Factors predictive of discordant MRD (≥5%) for patients in morphologic remission at end of induction included: age 10 years and older, WBC count at presentation of 50,000/µL or higher, neutral or unfavorable cytogenetics, and ETP ALL (for patients with T-ALL).
Table 5. 5-Year Event-Free Survival and Overall Survival Among Patients With Concordant in Remission, Discordant, and Concordant Not in Remission End-of-Induction Bone Marrowsa
Outcome M1/MRD <5% P valueb M1/MRD ≥5% P valuec M2/MRD ≥5%
HR = high risk; MRD = minimal residual disease; SR = standard risk.
a Adapted from Gupta et al.[142]
b P value is comparing M1/MRD <5% with M1/MRD ≥5%.
c P value is comparing M1/MRD ≥5% with M2/MRD ≥5%.
Event-free survival rates:
B-ALL, overall 87.1% ± 0.4% (n = 7,682) <.0001 59.1% ± 6.5% (n = 66) .009 39.1% ± 7.9% (n = 40)
B-ALL, SR 90.8% ± 0.4% (n = 5,000) .25 85.9% ± 7.6% (n = 22) .45 76.2% ± 15.2% (n = 9)
B-ALL, HR 80% ± 0.9% (n = 2,682) <.0001 44.9% ± 8.3% (n = 44) .05 29% ± 8.2% (n = 31)
T-ALL 87.6% ± 1.5% (n = 1,303) .01 80.3% ± 7.3% (n = 97) .13 62.7% ± 13.5% (n = 40)
Overall survival rates:
B-ALL, overall 93.8% ± 0.3% (n = 7,682) <.0001 77.2% ± 5.6% (n = 66) .01 59% ± 8.9% (n = 40)
B-ALL, SR 96.6% ± 0.3% (n = 5,000) .24 95.5% ± 4.6% (n = 22 ) .75 88.9% ± 12.1% (n = 9)
B-ALL, HR 88.4% ± 0.7% (n = 2,682) <.0001 66.9% ± 8.3% (n = 44) .06 51.4% ± 10.4% (n = 31)
T-ALL 91.9% ± 1.3% (n = 1,303) .005 83.4% ± 6.8% (n = 97) .34 76.7% ± 12.3% (n = 40)

Prognostic (Risk) Groups

For decades, clinical trial groups studying childhood ALL have utilized risk classification schemes to assign patients to therapeutic regimens on the basis of their estimated risk of treatment failure. Initial risk classification systems utilized clinical factors such as age and presenting WBC count. Response to therapy measures were subsequently added, with some groups utilizing early morphologic bone marrow response (e.g., at day 8 or day 15) and with other groups utilizing response of circulating leukemia cells to single-agent prednisone. Modern risk classification systems continue to utilize clinical factors such as age and presenting WBC count, and in addition, incorporate cytogenetics and genomic lesions of leukemia cells at diagnosis (e.g., favorable and unfavorable translocations) and response to therapy based on detection of MRD at end of induction (and in some cases at later time points).[127] The risk classification systems of the COG and the BFM groups are briefly described below.

Children's Oncology Group (COG) risk groups

In COG protocols, children with ALL are initially stratified into treatment groups (with varying degrees of risk of treatment failure) on the basis of a subset of prognostic factors, including the following:

  • Age.
  • WBC count at diagnosis.
  • Immunophenotype.
  • Cytogenetics/genomic alterations.
  • Presence of extramedullary disease.
  • Down syndrome.
  • Steroid pretreatment.

EFS rates exceed 85% in children meeting good-risk criteria (aged 1 to <10 years, WBC count <50,000/μL, and precursor B-cell immunophenotype); in children meeting high-risk criteria, EFS rates are approximately 75%.[4,52,133,143,144] Additional factors, including cytogenetic abnormalities and measures of early response to therapy (e.g., MRD levels in peripheral blood on day 8 and in bone marrow samples at the end of induction), considered in conjunction with presenting age, WBC count, immunophenotype, the presence of extramedullary disease, and steroid pretreatment can identify patient groups for postinduction therapy with expected EFS rates ranging from less than 40% to more than 95%.[4,121]

Patients who are at very high risk of treatment failure include the following:[145,146,147,148]

  • Infants with KMT2A rearrangements.
  • Patients with hypodiploidy (<44 chromosomes).
  • Patients with initial induction failure.

Berlin-Frankfurt-Münster (BFM) risk groups

Since 2000, risk stratification on BFM protocols has been based almost solely on treatment response criteria. In addition to prednisone prophase response, treatment response is assessed via MRD measurements at two time points, end induction (week 5) and end consolidation (week 12).

The BFM risk groups include the following:[123]

  • Standard risk: Patients who are MRD negative (i.e., <0.01%) at both time points are classified as standard risk.
  • Intermediate risk: Patients who have positive MRD at week 5 and low MRD (<0.1%) at week 12 are considered intermediate risk.
  • High risk: Patients with high MRD (≥0.1%) at week 12 are high risk. Patients with a poor response to the prednisone prophase are also considered high risk, regardless of subsequent MRD.

Phenotype, leukemic cell mass estimate (also known as BFM risk factor) and CNS status at diagnosis do not factor into the current risk classification schema. Patients with either the t(9;22)(q34;q11.2) or the t(4;11)(q21;q23) are considered high risk, regardless of early response measures.

Prognostic (risk) groups under clinical evaluation

  1. COG AALL1731 (NCT03914625) standard-risk and AALL1732 (NCT03959085) high-risk clinical trials: The COG classifies patients into six risk groups for patients with B-ALL (standard-risk favorable, standard-risk average, standard-risk high, high-risk favorable, high risk, and very high risk) on the basis of the following:
    • Age and presenting leukocyte count (using NCI risk-group criteria).[3]
      • NCI standard (low) risk: Includes children aged 1 year to <10 years with WBC <50,000/µL at the time of diagnosis.
      • NCI high risk: Includes children aged ≥10 years and/or children who have WBC ≥50,000/µL at the time of diagnosis.
    • Extramedullary disease (presence or absence of CNS and/or testicular leukemia).
      • CNS1: Absence of blasts on CSF cytospin preparation, regardless of the number of WBCs.
      • CNS2: Presence of <5 WBC/μL in CSF and cytospin positive for blasts; or traumatic LP, ≥5 WBC/μL, cytospin positive for blasts but negative by Steinherz/Bleyer algorithm.
      • CNS3 is divided and defined as follows:
        • CNS3a: <10 RBC/μL; ≥5 WBC/μL and cytospin positive for blasts.
        • CNS3b: ≥10 RBC/μL; ≥5 WBC/μL and positive by Steinherz/Bleyer algorithm.
        • CNS3c: Clinical signs of CNS leukemia (such as facial nerve palsy, brain/eye involvement or hypothalamic syndrome).
    • Genomic alterations in leukemia cells.
    • Day 8 peripheral blood MRD.
    • Day 29 bone marrow morphologic response and MRD.
    • End of consolidation MRD.
    • Steroid pretreatment.

    Morphologic assessment of early response in the bone marrow is no longer performed on days 8 and 15 of induction as part of risk stratification. Patients with T-cell phenotype are treated on a separate study and are not risk classified in this way.

    For patients with B-ALL, the definitions of favorable, unfavorable, and neutral cytogenetics are as follows:

    • Favorable cytogenetic features include the following:
      • Hyperdiploidy with double trisomies of chromosomes 4 and 10 (double trisomy); or
      • ETV6-RUNX1 fusion.
    • Unfavorable cytogenetic features include the following:
      • Hypodiploidy (<44 chromosomes or DNA index <0.81).
      • KMT2A rearrangements.
      • t(17;19)(q21-q22;p13.3) or resultant E2A-HLF fusion transcript.
      • Intrachromosomal amplification of chromosome 21 (iAMP21); and
      • Ph+ ALL (BCR-ABL1 fusion transcript or t(9;22)(q34;q11)). Patients with Ph+ ALL are treated on a separate clinical trial.
    • Neutral cytogenetics: Lacking favorable and unfavorable cytogenetic features.

    NCI standard-risk patients are divided into a highly favorable group (standard-risk favorable; 5-year DFS rate, >95%), a group with favorable outcome (standard-risk average; 5-year DFS rate, 90%–95%), and a group with a 5-year DFS rate below 90% (standard-risk high). Patients classified as standard-risk high receive backbone chemotherapy as per high-risk B-ALL regimens with intensified consolidation, interim maintenance, and reinduction therapy. Criteria for these three groups are provided in Table 6, Table 7, and Table 8 below.

    Table 6. Standard-Risk (SR) Favorable B-ALL (Non-Down Syndrome and Down Syndrome)
    NCI Risk Group CNS Stage Steroid Pretreatmenta Favorable Genetics (ETV6-RUNX1or DT) PB MRD Day 8 BM MRD Day 29
    BM = bone marrow; CNS = central nervous system; DT = double trisomy; MRD = minimal residual disease; NCI = National Cancer Institute; PB = peripheral blood.
    a Within one month prior to diagnosis.
    SR 1, 2 None Yes <1% <0.01%
    Table 7. Standard-Risk (SR) Average B-ALL (Non-Down Syndrome and Down Syndrome)
    NCI Risk Group CNS Stage ETV6-RUNX1 DT Neutral Cytogenetics PB MRD Day 8 BM MRD Day 29
    BM = bone marrow; CNS = central nervous system; DT = double trisomy; MRD = minimal residual disease; NCI = National Cancer Institute; PB = peripheral blood.
    SR 1, 2 Yes to either No ≥1% <0.01%
    SR 1, 2 No Yes No Any ≥0.01 to <0.1%
    SR 1 No No Yes Any <0.01%
    Table 8. Standard-Risk (SR) High B-ALL
    NCI Risk Group CNS Stage ETV6-RUNX1 DT Neutral Cytogenetics Unfavorable Cytogenetics PB MRD Day 8 BM MRD Day 29
    BM = bone marrow; CNS = central nervous system; DT = double trisomy; MRD = minimal residual disease; NCI = National Cancer Institute; PB = peripheral blood.
    SR 1, 2 Yes No No No Any ≥0.01%
    SR 1, 2 No Yes No No Any ≥0.1%
    SR 1 No No Yes No Any ≥0.01%
    SR 2 No No Yes No Any Any
    SR 1, 2 No No No Yes Any Any

    High-risk favorable B-ALL is defined by the characteristics in Table 9. These patients have an EFS rate higher than 90% on past COG clinical trials for high-risk patients.

    Table 9. Characteristics of High-Risk (HR) Favorable B-ALL Patients
    NCI Risk Group Age (y) CNS Status Testicular Leukemia Steroid Pretreatment Favorable Genetics (ETV6-RUNX1or DT) Bone marrow MRD EOI
    HR <10 1 None ≤24 hoursa Yes <0.01%
    CNS = central nervous system; DT = double trisomy; EOI = end of induction; MRD = minimal residual disease; NCI = National Cancer Institute.
    a Within two weeks of diagnosis.

    High-risk B-ALL is defined by the characteristics in Table 10. NCI standard-risk patients are elevated to high-risk status based on steroid pretreatment and CNS and/or testicular involvement.

    Table 10. Characteristics of High-Risk (HR) B-ALL Patients
    NCI Risk Group Age (y) CNS and/or Testicular Leukemia Steroid Pretreatment Cytogenetics Bone marrow MRD EOI Bone marrow MRD EOC
    CNS = central nervous system; EOC = end of consolidation; EOI = end of induction; MRD = minimal residual disease; N/A = not applicable; NCI = National Cancer Institute; SR = standard risk.
    a CNS3.
    b Philadelphia chromosome–positive (Ph+) ALL is excluded.
    c Only subjects with EOI bone marrow MRD ≥0.01% will have a bone marrow MRD assessment at EOC.
    d Within 2 weeks of diagnosis.
    e CNS2 or CNS3.
    SR <10 Yesa Any Anyb Any <1%c
    SR <10 No >24 hoursd Anyb Any <1%c
    HR ≥10 Any Any Anyb <0.01% N/A
    HR <10 Yese Any Anyb <0.01% N/A
    HR <10 No >24 hoursd Anyb <0.01% N/A
    HR <10 No ≤24 hoursd Neutral/unfavorableb <0.01% N/A
    HR Any Any Any Anyb ≥0.01% <0.01%

    NCI high-risk patients with end-of-consolidation marrow MRD ≥0.01% are classified as very high risk and are eligible for a chimeric antigen receptor (CAR) T-cell clinical trial in first remission (NCT03792633).

    Patients with B-ALL and Down syndrome are classified into risk groups similar to other children, but Down syndrome patients classified as high risk receive a treatment regimen that is modified to reduce toxicity.

  2. NCI-2014-00712; AALL1231 (NCT02112916)(Combination Chemotherapy With or Without Bortezomib in Treating Younger Patients With Newly Diagnosed T-ALL or Stage II-IV T-Cell Lymphoblastic Lymphoma): For patients with T-ALL, COG uses the following criteria to assign risk category:

    Standard risk.

    • M1 marrow with MRD <0.01% on day 29.
    • CNS1 status and no testicular disease at diagnosis.
    • No steroid therapy pretreatment.

    Intermediate risk.

    • M1 or M2 marrow at day 29 with MRD ≥0.01%.
    • MRD <0.1% at end of consolidation.
    • Any CNS status at diagnosis.

    Very high risk.

    • M3 marrow at day 29 or MRD ≥0.1% at end of consolidation.
    • Any CNS status.
  3. SJCRH Total 17 study (NCT03117751) (Total Therapy XVII for Newly Diagnosed Patients With ALL and Lymphoma): The overarching objective of this study is to use novel precision medicine strategies based on inherited and leukemia-specific genomic features and targeted treatment approaches to improve the cure rate and quality of life of children with ALL and acute lymphoblastic lymphoma.

    Criteria for low-risk (approximately 42% of patients).

    • B-ALL with DNA index ≥1.16, ETV6-RUNX1 fusion, OR age 1 to 9.9 years and presenting WBC count <50 × 109 /L.
    • Patients must not have the following:
      • CNS3 status (≥5 WBC/μL of CSF with leukemic blasts or cranial nerve palsy).
      • Overt testicular leukemia (evidenced by ultrasonography).
      • Adverse genetic features: BCR-ABL1 fusion; TCF3-PBX1 fusion; rearranged KMT2A (by FISH, PCR, and/or transcriptome or whole-genome sequencing); hypodiploidy (defined by <0.95 DNA index, <44 chromosomes, or genome-wide DNA copy-number alterations and gene expression); iAMP21; or MEF2D fusion.
      • Poor early response (≥1% lymphoblasts on Day 15 of remission induction or ≥0.01% lymphoblasts on remission date [end of remission induction] by immunologic or molecular methods).

    Criteria for standard-risk (approximately 48% of patients).

    • Patients with T-ALL or B-ALL who do not meet the criteria for low-risk or high-risk ALL.

    Criteria for high-risk (approximately 10% of patients).

    • MRD ≥1% at the end of remission induction.
    • MRD ≥0.1% at the end of early intensification and inadequate decrease in MRD levels after 1 to 2 courses of consolidation treatment.
    • Increasing MRD level at ≥0.01% after remission induction.
    • Hypodiploid (defined by <0.95 DNA index, <44 chromosomes or genome-wide analysis) and MRD ≥0.01% at the end of remission induction.
    • Re-emergence of leukemic lymphoblasts by MRD at ≥0.01% in patients previously MRD negative.
    • Persistently detectable MRD at ≥0.01% after reinduction II (week 17 of continuation).
  4. DFCI ALL 16-001 (NCT03020030) (Risk Classification Schemes in Identifying Better Treatment Options for Children and Adolescents with ALL): Patients are assigned an initial risk group by day 10 of therapy on the basis of presenting features and leukemia biology:
    • Initial low risk: All of the following criteria are met: B-cell ALL, age 1 to younger than 15 years, WBC count less than 50 × 109 /L, CNS1 or CNS2, no iAMP21, no very high-risk features.
    • Initial high risk: Any of the following criteria are met: Aged 15 years or older, WBC count greater than 50 × 109 /L, T-ALL, CNS3, presence of iAMP21. Very high-risk features must be absent.
    • Initial very high risk: Any of the following criteria are met: IKZF1 deletion, MLL gene-rearrangement, low hypodiploidy (<40 chromosomes).

    Patients with BCR-ABL1 are removed from protocol therapy at day 15. The final risk group is based on the initial risk group and MRD (assessed by next-generation sequencing) at the end of induction (day 32; first time point) and week 10 of therapy (second time point):

    • Final low risk: Initial low risk and MRD less than 0.01% at the first time point.
    • Final high risk: Initial low risk with MRD greater than 0.01% at the first time point and less than 0.1% at the second time point or initial high risk with MRD less than 0.1% at the second time point.
    • Final very high risk: Initial very high-risk patients or any patient with MRD greater than 0.1% at the second time point.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

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Treatment Option Overview for Childhood ALL

Phases of Therapy

Treatment for children with ALL is typically divided into the following phases:

  1. Remission induction chemotherapy (at the time of diagnosis).
  2. Postinduction therapy (after achieving complete remission).
    • Consolidation/intensification therapy.
    • Maintenance therapy.

Sanctuary Sites

Historically, certain extramedullary sites have been considered sanctuary sites (i.e., anatomic spaces that are poorly penetrated by many of the orally and intravenously administered chemotherapy agents typically used to treat ALL). The two most important sanctuary sites in childhood ALL are the central nervous system (CNS) and the testes. Successful treatment of ALL requires therapy that effectively addresses clinical or subclinical involvement of leukemia in these extramedullary sanctuary sites.

Central nervous system (CNS)

At diagnosis, approximately 3% of patients have CNS3 disease (defined as cerebrospinal fluid specimen with ≥5 white blood cells/μL with lymphoblasts and/or the presence of cranial nerve palsies). However, unless specific therapy is directed toward the CNS, most children will eventually develop overt CNS leukemia whether or not lymphoblasts were detected in the spinal fluid at initial diagnosis. CNS-directed treatments include intrathecal chemotherapy, CNS-directed systemic chemotherapy, and cranial radiation; some or all of these are included in current regimens for ALL. (Refer to the CNS-Directed Therapy for Childhood ALL section of this summary for more information.)

Testes

Overt testicular involvement at the time of diagnosis occurs in approximately 2% of males. In early ALL trials, testicular involvement at diagnosis was an adverse prognostic factor. With more aggressive initial therapy, however, the prognostic significance of initial testicular involvement is unclear.[1,2] The role of radiation therapy for testicular involvement is also unclear. A study from St. Jude Children's Research Hospital suggests that a good outcome can be achieved with aggressive conventional chemotherapy without radiation.[1] The Children's Oncology Group has also adopted this strategy for boys with testicular involvement that resolves completely during induction chemotherapy.

References:

  1. Hijiya N, Liu W, Sandlund JT, et al.: Overt testicular disease at diagnosis of childhood acute lymphoblastic leukemia: lack of therapeutic role of local irradiation. Leukemia 19 (8): 1399-403, 2005.
  2. Sirvent N, Suciu S, Bertrand Y, et al.: Overt testicular disease (OTD) at diagnosis is not associated with a poor prognosis in childhood acute lymphoblastic leukemia: results of the EORTC CLG Study 58881. Pediatr Blood Cancer 49 (3): 344-8, 2007.

Special Considerations for the Treatment of Children With Cancer

Because treatment of children with acute lymphoblastic leukemia (ALL) entails complicated risk assignment and therapies and the need for intensive supportive care (e.g., transfusions; management of infectious complications; and emotional, financial, and developmental support), evaluation and treatment are best coordinated by a multidisciplinary team in cancer centers or hospitals with all of the necessary pediatric supportive care facilities.[1] A multidisciplinary team approach incorporates the skills of the following health care professionals and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life:

  • Primary care physicians.
  • Pediatric medical oncologists/hematologists.
  • Pediatric surgical subspecialists.
  • Radiation oncologists.
  • Pediatric intensivists.
  • Rehabilitation specialists.
  • Pediatric nurse specialists.
  • Social workers.
  • Child life professionals.
  • Psychologists.

The American Academy of Pediatrics has outlined guidelines for cancer centers and their role in the treatment of pediatric patients with cancer.[1] Treatment of childhood ALL typically involves chemotherapy given for 2 to 3 years. Because myelosuppression and generalized immunosuppression are anticipated consequences of leukemia and chemotherapy treatment, adequate facilities must be immediately available both for hematologic support and for the treatment of infections and other complications throughout all phases of therapy. Approximately 1% to 3% of patients die during the remission induction phase and another 1% to 3% die after having achieved complete remission from treatment-related complications.[2,3,4,5,6] It is important that the clinical centers and the specialists directing the patient's care maintain contact with the referring physician in the community. Strong lines of communication optimize any urgent or interim care required when the child is at home.

Clinical trials are generally available for children with ALL, with specific protocols designed for children at standard (low) risk of treatment failure and for children at higher risk of treatment failure. Clinical trials for children with ALL are generally designed to compare therapy that is currently accepted as standard for a particular risk group with a potentially better treatment approach that may improve survival outcome and/or diminish toxicities associated with the standard treatment regimen. Many of the therapeutic innovations that produced increased survival rates in children with ALL were established through clinical trials, and it is appropriate for children and adolescents with ALL to be offered participation in a clinical trial.

Risk-based treatment assignment is an important therapeutic strategy utilized for children with ALL. This approach allows children who historically have a very good outcome to be treated with less intensive therapy and to be spared more toxic treatments, while allowing children with a historically lower probability of long-term survival to receive more intensive therapy that may increase their chance of cure. (Refer to the Risk-Based Treatment Assignment section of this summary for more information about a number of clinical and laboratory features that have demonstrated prognostic value.)

References:

  1. American Academy of Pediatrics: Standards for pediatric cancer centers. Pediatrics 134 (2): 410-4, 2014. Also available online. Last accessed August 18, 2021.
  2. Rubnitz JE, Lensing S, Zhou Y, et al.: Death during induction therapy and first remission of acute leukemia in childhood: the St. Jude experience. Cancer 101 (7): 1677-84, 2004.
  3. Christensen MS, Heyman M, Möttönen M, et al.: Treatment-related death in childhood acute lymphoblastic leukaemia in the Nordic countries: 1992-2001. Br J Haematol 131 (1): 50-8, 2005.
  4. Vrooman LM, Stevenson KE, Supko JG, et al.: Postinduction dexamethasone and individualized dosing of Escherichia Coli L-asparaginase each improve outcome of children and adolescents with newly diagnosed acute lymphoblastic leukemia: results from a randomized study--Dana-Farber Cancer Institute ALL Consortium Protocol 00-01. J Clin Oncol 31 (9): 1202-10, 2013.
  5. Lund B, Åsberg A, Heyman M, et al.: Risk factors for treatment related mortality in childhood acute lymphoblastic leukaemia. Pediatr Blood Cancer 56 (4): 551-9, 2011.
  6. Alvarez EM, Malogolowkin M, Li Q, et al.: Decreased Early Mortality in Young Adult Patients With Acute Lymphoblastic Leukemia Treated at Specialized Cancer Centers in California. J Oncol Pract 15 (4): e316-e327, 2019.

Treatment of Newly Diagnosed Childhood ALL

Standard Induction Treatment Options for Newly Diagnosed ALL

Standard treatment options for newly diagnosed childhood acute lymphoblastic leukemia (ALL) include the following:

  1. Chemotherapy.

Remission induction chemotherapy

The goal of the first phase of therapy (remission induction) is to induce a complete remission (CR). This induction phase typically lasts 4 weeks. Overall, approximately 98% of patients with newly diagnosed B-ALL achieve CR by the end of this phase, with somewhat lower rates in infants and in noninfant patients with T-ALL or high presenting leukocyte counts.[1,2,3,4,5]

Induction chemotherapy typically consists of the following drugs, with or without an anthracycline (either doxorubicin or daunorubicin):

  • Vincristine.
  • Corticosteroid (either prednisone or dexamethasone).
  • L-asparaginase.
  • Intrathecal chemotherapy.

The Children's Oncology Group (COG) protocols administer a three-drug induction (vincristine, corticosteroid, and pegaspargase) to National Cancer Institute (NCI) standard-risk B-ALL patients and a four-drug induction (vincristine, corticosteroid, and pegaspargase plus anthracycline) to NCI high-risk B-ALL and all T-ALL patients. Other groups use a four-drug induction for all patients.[1,2,3]

Corticosteroid therapy

Many current regimens utilize dexamethasone instead of prednisone during remission induction and later phases of therapy, although controversy exists as to whether dexamethasone benefits all subsets of patients. Some trials also suggest that dexamethasone during induction may be associated with more toxicity than prednisone, including higher rates of infection, myopathy, and behavioral changes.[1,6,7,8] The COG reported that dexamethasone during induction was associated with a higher risk of osteonecrosis in older children (aged >10 years),[8] although this finding has not been confirmed in other randomized studies.[1,7]

Evidence (dexamethasone vs. prednisone during induction):

  1. The Children's Cancer Group conducted a randomized trial that compared dexamethasone and prednisone in standard-risk B-ALL patients receiving a three-drug induction without an anthracycline.[6]
    • Dexamethasone was associated with a superior event-free survival (EFS).
    • Dexamethasone was associated with a higher frequency of reversible steroid myopathy and hyperglycemia. No significant differences in rates of infection during induction were observed between the two randomized arms.
  2. Another randomized trial that included both standard-risk and high-risk patients was conducted by the United Kingdom Medical Research Council.[7]
    • The trial demonstrated that dexamethasone was associated with a more favorable outcome than prednisolone in all patient subgroups.
    • Patients who received dexamethasone had a significantly lower incidence of both central nervous system (CNS) and non-CNS relapses than did patients who received prednisolone.
    • Dexamethasone was associated with a higher incidence of steroid-associated behavioral problems and myopathy, but an excess risk of osteonecrosis was not observed. There was no difference in induction death rates between the randomized groups.
  3. The Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP) ALL-BFM-2000 (NCT00430118) trial randomly assigned 3,720 patients to receive either dexamethasone (10 mg/m2 /d) or prednisone (60 mg/m2 /d) during multiagent remission induction (including an anthracycline for all patients) after a 7-day prednisone prophase.[9]
    • Dexamethasone was associated with higher incidence of life-threatening events (primarily infections), resulting in a significantly higher induction death rate (2.5% for dexamethasone vs. 0.9% for prednisone; P = .00013).
    • There was no difference in rates of osteonecrosis between the randomized groups.
    • The 5-year cumulative incidence of relapse was significantly lower with dexamethasone (11% vs. 16%; P < .0001), resulting in superior 5-year EFS rates (84% for dexamethasone vs. 81% for prednisone, P = .024) despite the increased induction death rate.
    • No difference in overall survival (OS) was observed based on steroid randomization, although the study was not sufficiently powered to detect small differences in OS.
    • In a predefined subgroup analysis, a survival benefit was observed with dexamethasone treatment in patients with T-ALL and a good response to the prednisone prophase (5-year OS rates, 91% with dexamethasone vs. 83% with prednisone, P = .036).
  4. The COG conducted a randomized trial of dexamethasone and prednisone in NCI high-risk B-ALL patients.[8] Patients were randomly assigned to receive 14 days of dexamethasone or 28 days of prednisone during a four-drug induction (with an anthracycline). This trial also included a randomized comparison of high-dose and escalating-dose methotrexate during the interim maintenance phase.
    • Dexamethasone was associated with a higher rate of infection, but there was no difference in the induction death rate when comparing dexamethasone and prednisone.
    • For patients who were younger than 10 years at diagnosis, there was a significant interaction between the corticosteroid and methotrexate randomizations; however, the best outcome for this group of patients was observed in those who received both dexamethasone during induction and high-dose methotrexate during interim maintenance.
    • The corticosteroid randomization was closed early for patients aged 10 years or older at diagnosis because of excessive rates of osteonecrosis in patients randomly assigned to dexamethasone; however, it did not appear that there was any EFS benefit associated with dexamethasone in these older patients (5-year EFS rates of 73.1% with dexamethasone and 73.9% with prednisone; P = .78)

The ratio of dexamethasone to prednisone dose used may influence outcome. Studies in which the dexamethasone to prednisone ratio was 1:5 to 1:7 have shown a better result for dexamethasone, while studies that used a 1:10 ratio have shown similar outcomes.[10]

L-asparaginase

Several forms of L-asparaginase have been used in the treatment of children with ALL, including the following:

  • Pegaspargase (PEG-asparaginase).
  • Asparaginase Erwinia chrysanthemi (Erwinia L-asparaginase).
  • Native Escherichia coli (E. coli) L-asparaginase (unavailable in the United States, but still available in other countries).

Pegaspargase (PEG-asparaginase)

Pegaspargase is a form of L-asparaginase in which the E. coli–derived enzyme is modified by the covalent attachment of polyethylene glycol. It is the most common preparation used during both induction and postinduction phases of treatment in newly diagnosed patients treated in the United States and Western Europe.

Pegaspargase may be given either intramuscularly (IM) or intravenously (IV).[11] Pharmacokinetics and toxicity profiles are similar for IM and IV pegaspargase administration.[11] There is no evidence that IV administration of pegaspargase is more toxic than IM administration.[11,12,13]

Pegaspargase has a much longer serum half-life than native E. coli L-asparaginase, producing prolonged asparagine depletion after a single injection.[14]

Serum asparaginase enzyme activity levels of more than 0.1 IU/mL have been associated with serum asparagine depletion. Studies have shown that a single dose of pegaspargase given either IM or IV as part of multiagent induction results in serum enzyme activity of more than 0.1 IU/mL in nearly all patients for at least 2 to 3 weeks.[11,12,15,16] In one study of 54 NCI high-risk patients conducted by the COG, plasma asparaginase activity as low as 0.02 IU/mL was associated with serum asparagine depletion; using that cut-off value, it was estimated that 96% of patients maintained the therapeutic effect (plasma asparagine depletion) for 22 to 29 days after a single pegaspargase dose of 2,500 IU/m2.[17] In one randomized study, higher doses of pegaspargase (3,500 IU/m2) did not improve outcome when compared with standard doses (2,500 IU/m2).[18][Level of evidence: 1iiA]

In another study, doses of pegaspargase were reduced in an attempt to decrease toxicity.[19] While lower doses were successful in maintaining appropriate asparaginase levels of more than 0.1 IU/mL, the frequency of asparaginase-related toxicities was similar to the frequency of toxicities reported in previous studies that used higher doses of pegaspargase. This study did not report on the impact of lower doses of pegaspargase on EFS.

Evidence (use of pegaspargase versus native E. coli L-asparaginase):

  1. A randomized comparison of IV pegaspargase versus IM native E. coli asparaginase was conducted. Each agent was administered for a 30-week period after the achievement of CR.[13][Level of evidence: 1iiC]
    • Serum asparaginase activity (SAA) levels were significantly higher with IV pegaspargase and exceeded goal therapeutic levels (>0.1 IU/mL) in nearly all patients throughout the 30-week period.
    • There was no significant difference in EFS and OS between the randomized arms.
    • There was no difference in rates of asparaginase-related toxicities, including hypersensitivity, pancreatitis, and thromboembolic complications.
    • Similar outcome and similar rates of asparaginase-related toxicities were observed for both groups of patients.
    • IV pegaspargase was associated with less treatment-related anxiety, as assessed by patient and parent surveys.
  2. Another randomized trial of patients with standard-risk ALL assigned patients to receive either pegaspargase or native E. coli asparaginase during induction and in each of two delayed intensification courses.[15]
    • A single dose of pegaspargase given in conjunction with vincristine and prednisone during induction therapy appeared to have similar activity and toxicity as nine doses of IM E. coli L-asparaginase (3 times a week for 3 weeks).[15]
    • The use of pegaspargase was associated with more rapid blast clearance and a lower incidence of neutralizing antibodies.

Patients with an allergic reaction to pegaspargase are typically switched to Erwinia L-asparaginase. A COG analysis investigated the deleterious effect on disease-free survival (DFS) of early discontinuation of treatment with pegaspargase in patients with high-risk B-ALL. The study found that the adverse effect on outcome could be reversed with the use of Erwinia L-asparaginase to complete the planned course of asparaginase therapy.[20][Level of evidence: 3iiiDii] Measurement of SAA levels after a mild or questionable reaction to pegaspargase may help to differentiate patients for whom the switch to Erwinia is indicated (because of inadequate SAA) versus those for whom a change in preparation may not be necessary.[21,22]

Evidence (adverse prognostic impact of early discontinuation of pegaspargase or silent inactivation of asparaginase):

  1. Several studies have identified a subset of patients who experience silent inactivation of asparaginase, which is defined as the absence of therapeutic SAA levels without overt allergy.[23,24]
    • In a trial conducted by the Dana-Farber Cancer Institute (DFCI) Consortium, 12% of patients who were initially treated with native E.coli L-asparaginase demonstrated silent inactivation; these patients had a superior EFS if their asparaginase preparation was changed.[24]
    • Patients who were treated with pegaspargase appear to have lower levels of silent inactivation (<10%).[13,23,25]

    Determination of the optimal frequency of pharmacokinetic monitoring for pegaspargase-treated patients, and whether such screening impacts outcome, awaits further investigation.

  2. A report from the COG included 8,196 patients with newly diagnosed B-ALL who were enrolled between 2004 to 2011.[20][Level of evidence: 3iiiDii]
    • The cumulative incidence of pegaspargase discontinuation (because of toxicity) was 12.2% in NCI standard-risk patients and 25.4% in NCI high-risk patients.
    • In multivariable analysis, NCI high-risk patients who discontinued pegaspargase early had inferior DFS (hazard ratio [HR], 1.5; P = .002) than did those who received all prescribed doses; for NCI standard-risk patients, there was no impact of pegaspargase discontinuation on DFS, except in patients with slow-early response who received intensified postinduction therapy (HR, 1.7; P = .03).
    • NCI high-risk patients who discontinued pegaspargase but then switched to Erwinia asparaginase and received all subsequent intended doses, did not have an increased risk of relapse (HR, 1.1; P = .69).
  3. An analysis of 1,115 non–high-risk ALL patients from the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol reported the following:[25]
    • 255 patients received a truncated asparaginase course because of toxicity, and 46 patients had evidence of silent inactivation on therapeutic drug monitoring.
    • The 7-year cumulative incidence of relapse was 11.1% in the 301 patients who received a truncated asparaginase course, compared with 6.7% in the remaining 814 patients who received the planned courses (HR, 1.73; P = .03).
    • In a Cox model, suboptimal asparaginase treatment (because of either truncated pegaspargase or silent inactivation) was significantly associated with a higher relapse risk (HR, 1.69; P = 0.03).

Another formulation of pegylated asparaginase, calaspargase pegol, is also available for the treatment of children and adolescents with ALL.[26] This formulation is similar in structure to pegaspargase, except with a different linker between the L-asparaginase enzyme and the PEG moiety, resulting in a longer half-life.[27,28]

AsparaginaseErwinia chrysanthemi(ErwiniaL-asparaginase)

Erwinia L-asparaginase is typically used in patients who have experienced an allergy to native E. coli or pegaspargase.

The half-life of Erwinia L-asparaginase (0.65 days) is much shorter than that of native E. coli (1.2 days) or pegaspargase (5.7 days).[14] If Erwinia L-asparaginase is utilized, the shorter half-life of the Erwinia preparation requires more frequent administration to achieve adequate asparagine depletion.

Evidence (increased dose frequency of Erwinia L-asparaginase needed to achieve goal therapeutic effect):

  1. A COG trial demonstrated that IM Erwinia L-asparaginase given three times a week to patients with an allergy to pegaspargase leads to therapeutic serum asparaginase enzyme activity levels (defined as a level ≥0.1 IU/mL).[29]
    • On this trial, 96% of children achieved a level of 0.1 IU/mL or more at 2 days after a dose of Erwinia L-asparaginase and 85% did so at 3 days after a dose.
  2. A trial of IV Erwinia L-asparaginase given on a Monday-Wednesday-Friday schedule to patients with an allergy to pegaspargase demonstrated therapeutic serum asparaginase enzyme activity (defined as ≥0.1 IU/mL) in 83% of patients 48 hours after a dose but in only 43% of patients 72 hours after a dose.[30]
    • If IV Erwinia is given on a Monday-Wednesday-Friday schedule, the authors suggest that 72-hour nadir enzyme activity levels be monitored to ensure therapeutic levels.

Anthracycline use during induction

The COG protocols administer a three-drug induction (vincristine, corticosteroid, and pegaspargase) to NCI standard-risk B-ALL patients and a four-drug induction (vincristine, corticosteroid, and pegaspargase plus an anthracycline) to NCI high-risk B-ALL and all T-ALL patients. Other groups use a four-drug induction for all patients.[1,2,3]

In induction regimens that include an anthracycline, either daunorubicin or doxorubicin are typically used. In a randomized trial comparing the two agents during induction, there were no differences in early response measures, including reduction in peripheral blood blast counts during the first week of therapy, day 15 marrow morphology, and end-induction minimal residual disease (MRD) levels.[31][Level of evidence: 1iiDiv]

Response to remission induction chemotherapy

More than 95% of children with newly diagnosed ALL will achieve a CR within the first 4 weeks of treatment. Of those who fail to achieve CR within the first 4 weeks, approximately one-half will experience a toxic death during the induction phase (usually caused by infection) and the other half will have resistant disease (persistent morphologic leukemia).[32,33,34]; [35][Level of evidence: 3iA]

Most patients with persistence of morphologically detectable leukemia at the end of the 4-week induction phase have a poor prognosis and may benefit from an allogeneic hematopoietic stem cell transplant (HSCT) once CR is achieved.[4,36,37] In a large retrospective series, the 10-year OS rate for such patients was 32%.[38] A trend for superior outcome with allogeneic HSCT compared with chemotherapy alone was observed in patients with T-cell phenotype (any age) and B-ALL patients older than 6 years. B-ALL patients who were aged 1 to 5 years at diagnosis and did not have any adverse cytogenetic abnormalities (KMT2A [MLL] rearrangement, BCR-ABL1) had a relatively favorable prognosis, without any advantage in outcome with the utilization of HSCT compared with chemotherapy alone.[38]

For patients who achieve CR, measures of the rapidity of blast clearance and MRD determinations have important prognostic significance, particularly the following:

  • The percentage of morphologically detectable marrow blasts at 7 and 14 days after starting multiagent remission induction therapy has been correlated with relapse risk,[39] and has been used in the past by the COG to risk-stratify patients. However, in multivariate analyses, when end-induction MRD is included, these early marrow findings lose their prognostic significance.[40,41]
  • End-induction levels of submicroscopic MRD, assessed by multiparameter flow cytometry, polymerase chain reaction, or next-generation sequencing assays strongly correlates with long-term outcome.[40,42,43,44,45] Intensification of postinduction therapy for patients with high levels of end-induction MRD is a common component of most ALL treatment regimens. In a randomized trial conducted by the United Kingdom Acute Lymphoblastic Leukaemia (UKALL) group, augmented postinduction therapy was shown to improve outcome for standard-risk and intermediate-risk patients with high end-induction MRD.[46]
  • MRD levels earlier in induction (e.g., days 8 and 15) and at later postinduction time points (e.g., week 12 after starting therapy) have also been shown to have prognostic significance in both B-ALL and T-ALL.[40,41,44,47,48,49,50]

(Refer to the Response to initial treatment section of this summary for more information.)

(Refer to the CNS-Directed Therapy for Childhood ALL section of this summary for specific information about CNS therapy to prevent CNS relapse in children with newly diagnosed ALL.)

Standard Postinduction Treatment Options for Childhood ALL

Standard treatment options for consolidation/intensification and maintenance therapy (postinduction therapy) include the following:

  1. Chemotherapy.

Central nervous system (CNS)-directed therapy is provided during premaintenance chemotherapy by all groups. Some protocols (Children's Oncology Group [COG], St. Jude Children's Research Hospital [SJCRH], and Dana-Farber Cancer Institute [DFCI]) provide ongoing intrathecal chemotherapy during maintenance, while others (Berlin-Frankfurt-Münster [BFM]) do not. (Refer to the CNS-Directed Therapy for Childhood ALL section of this summary for specific information about CNS therapy to prevent CNS relapse in children with acute lymphoblastic leukemia [ALL] who are receiving postinduction therapy.)

Consolidation/intensification therapy

Once complete remission (CR) has been achieved, systemic treatment in conjunction with CNS-directed therapy follows. The intensity of the postinduction chemotherapy varies considerably depending on risk group assignment, but all patients receive some form of intensification after the achievement of CR and before beginning maintenance therapy.

The most commonly used intensification schema is the BFM backbone. This therapeutic backbone, first introduced by the BFM clinical trials group, includes the following:[1]

  1. An initial consolidation (referred to as induction IB) immediately after the initial induction phase. This phase includes cyclophosphamide, low-dose cytarabine, and mercaptopurine.

    An interim maintenance phase, which includes four doses of high-dose methotrexate (typically 5 g/m2) with leucovorin rescue.

  2. Reinduction (or delayed intensification), which typically includes agents and schedules similar to those used during the induction and initial consolidation phases.
  3. Maintenance, typically consisting of daily mercaptopurine (6-MP), weekly low-dose methotrexate, and sometimes, administration of vincristine and a corticosteroid, as well as continued intrathecal therapy.

This backbone has been adopted by many groups, including the COG. Variation of this backbone includes the following:

  • Intensification for higher-risk patients by including additional doses of vincristine and pegaspargase, as well as repeated interim maintenance and delayed intensification phases.[51,52]
  • The use of escalating doses of methotrexate (starting at a dose of 100 mg/m2) without leucovorin rescue instead of high-dose methotrexate during interim maintenance phases.
  • Elimination or truncation of some of the phases for lower-risk patients to minimize acute and long-term toxicity.

Other clinical trial groups utilize a different therapeutic backbone during postinduction treatment phases, as follows:

  • DFCI: The DFCI ALL Consortium protocols include 30 weeks of pegaspargase therapy beginning at week 7 of therapy, given in conjunction with maintenance regimen (vincristine/dexamethasone pulses, weekly low-dose methotrexate, daily mercaptopurine).[3] These protocols also do not include a delayed intensification phase, but high-risk patients receive additional doses of doxorubicin (instead of low-dose methotrexate) during the first six months of postinduction therapy.
  • SJCRH: SJCRH follows a BFM backbone but augments the reinduction and maintenance phases for some patients by including intensified dosing of pegaspargase, frequent vincristine/corticosteroid pulses, and rotating drug pairs during maintenance.[53]

Standard-risk ALL

In children with standard-risk B-ALL, there has been an attempt to limit exposure to drugs such as anthracyclines and alkylating agents that may be associated with an increased risk of late toxic effects.[54,55,56] For regimens utilizing a BFM backbone (such as COG), a single reinduction/delayed intensification phase, given with interim maintenance phases consisting of escalating doses of methotrexate (without leucovorin rescue) and vincristine, have been associated with favorable outcomes.[57] Favorable outcomes for standard-risk patients were also reported in trials that utilized a limited number of courses of intermediate-dose or high-dose methotrexate as consolidation followed by maintenance therapy (without a reinduction phase).[55,58,59] The DFCI ALL Consortium study utilized multiple doses of pegaspargase (30 weeks) as consolidation, without postinduction exposure to alkylating agents or anthracyclines.[60,61]

However, the prognostic impact of end-induction and/or consolidation minimal residual disease (MRD) has influenced the treatment of patients originally diagnosed as National Cancer Institute (NCI) standard risk. Multiple studies have demonstrated that higher levels of end-induction MRD are associated with poorer prognosis.[40,42,43,62,63] Augmenting therapy has been shown to improve the outcome in standard-risk patients with elevated MRD levels at the end of induction.[46] Therefore, standard-risk patients with higher levels of end-induction MRD are not treated with the approaches described for standard-risk patients who have low end-induction MRD, but are usually treated with high-risk regimens.

Evidence (intensification for standard-risk ALL):

  1. Clinical trials conducted in the 1980s and early 1990s demonstrated that the use of a delayed intensification phase improved outcome for children with standard-risk ALL treated with regimens using a BFM backbone.[64,65,66] The delayed intensification phase on such regimens, including those of the COG, consists of an 8-week phase of reinduction (including an anthracycline) and reconsolidation containing cyclophosphamide, cytarabine, and 6-thioguanine given approximately 4 to 6 months after remission is achieved.[33,64,67]
  2. The former Children's Cancer Group (CCG) study (CCG-1991/COG-1991) for standard-risk ALL utilized dexamethasone in a three-drug induction phase and tested the utility of a second delayed intensification phase. This study also compared escalating intravenous (IV) methotrexate (without leucovorin rescue) in conjunction with vincristine versus a standard maintenance combination with oral methotrexate given during two interim maintenance phases.[57][Level of evidence: 1iiDi]
    • A second delayed intensification phase provided no benefit in patients who were rapid early responders (M1 or M2 marrow by day 14 of induction).
    • Escalating IV methotrexate during the interim maintenance phases, compared with oral methotrexate during these phases, produced a significant improvement in event-free survival (EFS), which was because of a decreased incidence of isolated extramedullary relapses, particularly those involving the CNS.
  3. The COG AALL0331 (NCT00103285) study stratified intensity of therapy for NCI standard-risk patients on the basis of biology and early response. Rapid early response was defined as less than 5% bone marrow blasts by day 15 based on local morphologic interpretation and an M1 bone marrow with MRD levels of less than 0.1% at day 29. Standard-risk low patients were those with favorable biology (ETV6-RUNX1 or high hyperdiploidy with triple trisomy), CNS1 status, and a rapid early response. Standard-risk average patients were those lacking favorable or unfavorable biology who also had a rapid early response. Standard-risk high patients were those with slow early response and/or CNS3 status, or KMT2A-rearranged patients with rapid early response. All patients received a three-drug induction (no anthracycline). Standard-risk average patients were randomly assigned to either intensified consolidation (augmented BFM) or standard consolidation. Standard-risk high patients were nonrandomly assigned to the full augmented BFM therapy used for NCI high-risk patients, including two delayed intensification phases.[68]
    • The 6-year EFS rate for all patients was 89%, and the overall survival (OS) rate was 96%.
    • For standard-risk average patients, the augmented consolidation regimen did not improve rates of continuous complete remission (CCR) or OS. The 6-year rates of CCR and OS for the standard-risk average cohort were 88% to 89% and 95% to 96%, respectively.
    • Standard-risk average patients with end-induction MRD levels of 0.01% to <0.1% had an inferior outcome compared with those with MRD levels of <0.01% (6-year CCR rates, 77% vs. 91%, respectively). Augmented consolidation was not associated with a better outcome in standard-risk average patients with higher levels of MRD.
    • The standard-risk high cohort achieved a relatively favorable 6-year CCR rate of 86% and an OS rate of 93%.
  4. In a randomized study conducted in the United Kingdom, children and young adults with ALL who lacked high-risk features (including adverse cytogenetics, and/or M3 marrow morphology at day 8 or day 15 of induction) were risk-stratified on the basis of MRD level at the end of induction (week 4) and at week 11 of therapy. Patients with undetectable MRD at week 4 (or with low MRD at week 4 and undetectable by week 11) were considered low risk, and were eligible to be randomly assigned to therapy with either one or two delayed intensification phases.[69][Level of evidence: 1iiDi]
    • There was no significant difference in EFS between patients who received one and those who received two delayed intensification phases.
    • There was no significant difference in treatment-related deaths between the two arms; however, the second delayed intensification phase was associated with grade 3 or 4 toxic events in 17% of the 261 patients randomly assigned to that arm, and one patient experienced a treatment-related death during that phase.
  5. In the Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP) ALL-BFM-2000 (NCT00430118) trial, standard-risk patients (defined as those with undetectable MRD at days 33 and 78 and absence of high-risk cytogenetics) were randomly assigned to receive treatment with a single delayed-intensification phase of either standard intensity or reduced intensity (shorter duration, with reduced total dosages of dexamethasone, vincristine, doxorubicin, and cyclophosphamide).[70]
    • Reduced-intensity delayed intensification was associated with an inferior 8-year DFS rate (89% vs. 92%, P = .04), resulting from an increased risk of relapse.
    • In a subset analysis, for patients with the ETV6-RUNX1 fusion, no difference in outcome between the two treatment arms was observed (8-year DFS rate, approximately 94% for both arms).
  6. Patients who are standard or intermediate risk at diagnosis, but have high levels of end-induction MRD, have been shown to have a poorer prognosis and should be treated as high-risk patients. The UKALL2003 (NCT00222612) trial used augmented postinduction therapy (extra doses of pegaspargase and vincristine and an escalated-dose of IV methotrexate without leucovorin rescue) to treat standard- or intermediate-risk patients with high levels of end-induction MRD.[46][Level of evidence: 1iiDi]
    • Augmented postinduction therapy resulted in an increased EFS that was comparable to that of patients with low levels of end-induction MRD.

High-risk ALL

In high-risk patients, a number of different approaches have been used with comparable efficacy.[60,71]; [67][Level of evidence: 2Di] Treatment for high-risk patients is generally more intensive than that for standard-risk patients and typically includes higher cumulative doses of multiple agents, including anthracyclines and/or alkylating agents. Higher doses of these agents increase the risk of both short-term and long-term toxicities, and many clinical trials have focused on reducing the side effects of these intensified regimens.

Evidence (intensification for high-risk ALL):

  1. The former CCG developed an augmented BFM treatment regimen that included a second interim maintenance and delayed intensification phase. This regimen featured repeated courses of escalating-dose IV methotrexate (without leucovorin rescue) given with vincristine and pegaspargase during interim maintenance and additional vincristine and pegaspargase pulses during initial consolidation and delayed intensification. In the CCG-1882 trial, NCI high-risk patients with slow early response (M3 marrow on day 7 of induction) were randomly assigned to receive either standard- or augmented-BFM therapy.[51]
    • The augmented-therapy regimen in the CCG-1882 trial produced a significantly better EFS than did the standard CCG modified-BFM therapy.
    • There was a significantly higher incidence of osteonecrosis in patients older than 10 years who received the augmented therapy (which included two 21-day postinduction dexamethasone courses), compared with those who were treated on the standard arm (one 21-day postinduction dexamethasone course).[72]
  2. In an Italian study, investigators showed that two applications of delayed intensification therapy (protocol II) significantly improved outcome for patients with a poor response to a prednisone prophase.[73]
  3. The CCG-1961 study used a 2 × 2 factorial design to compare both standard- versus augmented-intensity therapies and therapies of standard duration (one interim maintenance and delayed intensification phase) versus increased duration (two interim maintenance and delayed intensification phases) among NCI high-risk patients with a rapid early response. This trial also tested whether continuous versus alternate-week dexamethasone during delayed intensification phases affected rates of osteonecrosis.
    • Augmented therapy was associated with an improvement in EFS; there was no EFS benefit associated with the administration of the second interim maintenance and delayed intensification phases.[52,74][Level of evidence: 1iiA]
    • The cumulative incidence of osteonecrosis at 5 years was 9.9% for patients aged 10 to 15 years and 20.0% for patients aged 16 to 21 years, compared with 1.0% for patients aged 1 to 9 years (P = .0001). For patients aged 10 to 21 years, alternate-week dosing of dexamethasone during delayed intensification phases was associated with a significantly lower cumulative incidence of osteonecrosis, compared with continuous dosing (8.7% vs. 17.0%, P = .0005).[75][Level of evidence: 1iiC]
  4. In the COG AALL0232 (NCT00075725) study (2004–2011), patients with high-risk B-ALL received an augmented BFM backbone with one interim maintenance and delayed intensification phase; only patients with end-induction MRD greater than 0.1% or M2/M3 marrow at day 15 received two interim maintenance/delayed intensification phases. Patients were randomly assigned to receive either high-dose methotrexate or escalating dose IV methotrexate (Capizzi methotrexate) during the interim maintenance phase (the first phase only for those receiving two of these phases).[8,41]
    • The methotrexate randomization was terminated early when planned interim monitoring indicated that high-dose methotrexate was associated with superior outcome. The 5-year EFS rate of patients randomly assigned to high-dose methotrexate was 79.6%, compared with 75% for those randomly assigned to the Capizzi methotrexate arm. High-dose methotrexate was also associated with a superior 5-year OS (P = .025).[8]
    • Patients with MRD less than 0.01% at end of induction had a 5-year EFS rate of 87%, compared with 74% for those with MRD 0.01% to 0.1%. Those with MRD levels greater than 0.1% fared worse.[41]
    • High-dose methotrexate was associated with a superior EFS rate in patients with end-induction MRD greater than 0.01% (high-dose methotrexate, 68%; Capizzi methotrexate, 58%; P = .008).[41]

Because treatment for high-risk ALL involves more intensive therapy, leading to a higher risk of acute and long-term toxicities, a number of clinical trials have tested interventions to prevent side effects without adversely impacting EFS. Interventions that have been investigated include the use of the cardioprotectant dexrazoxane to prevent anthracycline-related cardiac toxic effects and alternative scheduling of corticosteroids to reduce the risk of osteonecrosis.

Evidence (cardioprotective effect of dexrazoxane):

  1. In a DFCI ALL Consortium trial, children with high-risk ALL were randomly assigned to receive doxorubicin alone (30 mg/m2 /dose to a cumulative dose of 300 mg/m2) or with dexrazoxane during the induction and intensification phases of multiagent chemotherapy.[76,77]
    • The use of the cardioprotectant dexrazoxane before doxorubicin resulted in better left ventricular fractional shortening and improved end-systolic dimension Z-scores without any adverse effect on EFS or increase in second malignancy risk, compared with the use of doxorubicin alone 5 years posttreatment.
    • A greater long-term protective effect was noted in girls than in boys.
  2. On the POG-9404 trial, patients with T-ALL were randomly assigned to receive dexrazoxane or not before each dose of doxorubicin (cumulative dose 360 mg/m2).[78]
    • There was no difference in EFS between patients with T-ALL who were treated with dexrazoxane and patients who were not treated with dexrazoxane (cumulative doxorubicin dose, 360 mg/m2).
    • Three years after initial diagnosis, left ventricular shortening fraction and left ventricular wall thickness were both significantly worse in patients who received doxorubicin alone than in patients who received dexrazoxane, indicating that dexrazoxane was cardioprotective. The frequency of grade 3 and 4 toxicities that occurred during therapy was similar between the randomized groups, and there was no difference in cumulative incidence of second malignant neoplasms.

Evidence (reducing risk of osteonecrosis):

  1. In the CCG-1961 study, alternate-week dosing of dexamethasone during delayed intensification was studied with the goal of reducing the frequency of osteonecrosis.[75] Patients with high-risk B-ALL and a rapid early morphologic response to induction therapy were randomly assigned to receive either one or two delayed intensification phases. Patients randomly assigned to one delayed intensification phase received daily dosing of dexamethasone (21 consecutive days), while those randomly assigned to two delayed intensification phases received alternate-week dosing of dexamethasone (days 0–6 and 14–21) during each delayed intensification phase.
    • For patients aged 10 years or older at diagnosis, those who received two delayed intensification phases (alternate-week dosing of dexamethasone) had a significantly lower risk of symptomatic osteonecrosis (5-year cumulative incidence of 8.7%, compared with 17% for patients receiving one delayed intensification phase with continuous dexamethasone dosing; P = .001).
    • The greatest impact was seen in females aged 16 to 21 years, who showed the highest incidence of osteonecrosis with standard therapy containing continuous dexamethasone; the incidence of osteonecrosis with alternative-week dexamethasone was 5.6%, compared with 57.6% for those receiving continuous dosing.

(Refer to the Osteonecrosis section of this summary for more information.)

Very high-risk ALL

Approximately 10% to 20% of patients with ALL are classified as very high risk, including the following:[67,79]

  • Infants younger than 1 year, especially if there is a KMT2A (MLL) gene rearrangement present. (Refer to the Infants With ALL subsection in the Postinduction Treatment for Specific ALL Subgroups section of this summary for more information about infants with ALL.)
  • Patients with adverse cytogenetic abnormalities, including BCR-ABL1 (t(9;22)(q34;q11.2)), TCF3-HLF (t(17;19)), KMT2A gene rearrangements, and low hypodiploidy (<44 chromosomes).
  • Patients who achieve CR but have a slow early response to initial therapy, including those with a high absolute blast count after a 7-day steroid prophase, and patients with high MRD levels at the end of induction (week 4) or later time points (e.g., week 12).
  • Patients who have morphologically persistent disease after the first 4 weeks of therapy (induction failure), even if they later achieve CR.

Patients with very high-risk features have been treated with multiple cycles of intensive chemotherapy during the consolidation phase (usually in addition to the typical BFM backbone intensification phases). These additional cycles often include agents not typically used in frontline ALL regimens for standard-risk and high-risk patients, such as high-dose cytarabine, ifosfamide, and etoposide.[67] However, even with this intensified approach, reported long-term EFS rates range from 30% to 50% for this patient subset.[36,67]

On some clinical trials, very high-risk patients have also been considered candidates for allogeneic hematopoietic stem cell transplantation (HSCT) in first CR.[36,80,81,82] However, there are limited data regarding the outcome of very high-risk patients treated with allogeneic HSCT in first CR. Controversy exists regarding which subpopulations could potentially benefit from HSCT.

Evidence (allogeneic HSCT in first remission for very high-risk patients):

  1. In a European cooperative group study conducted between 1995 and 2000, very high-risk patients were defined as one of the following: morphologically persistent disease after a four-drug induction, t(9;22)(q34;q11.2) or t(4;11)(q21;q23), or poor response to prednisone prophase in patients with either T-cell phenotype or presenting white blood cells (WBC) >100,000/μL. These patients were assigned to receive either an allogeneic HSCT in first CR (based on the availability of a human lymphocyte antigen–matched related donor) or intensive chemotherapy.[36]
    • Using an intent-to-treat analysis, patients assigned to allogeneic HSCT (on the basis of donor availability) had a superior 5-year DFS rate compared with patients assigned to intensive chemotherapy (57% ± 7% for transplant vs. 41% ± 3% for chemotherapy, P = .02).
    • There was no significant difference in OS rates (56% ± 6% for transplant vs. 50% ± 3% for chemotherapy; P = .12).
    • For patients with T-ALL and a poor response to prednisone prophase, both DFS and OS rates were significantly better with allogeneic HSCT.[80]
  2. In a large retrospective series of patients with initial induction failure, the 10-year OS rate for patients with persistent leukemia was 32%.[38]
    • A trend for superior outcome with allogeneic HSCT, compared with chemotherapy alone, was observed in patients with T-cell phenotype (any age) and with B-ALL who were older than 6 years.
    • Patients with B-ALL who were aged 1 to 5 years at diagnosis and did not have any adverse cytogenetic abnormalities (KMT2A rearrangement, BCR-ABL1) had a relatively favorable prognosis, without any advantage in outcome with the utilization of HSCT compared with chemotherapy alone.
  3. The AIEOP ALL-BFM-2000 (NCT00430118) study (2000–2006) classified patients as high risk if they met any of the following criteria: poor response to prednisone prophase, failure to achieve CR at the end of the first month of treatment, high MRD levels after induction IB (day 78 of therapy), and t(4;11)(q21;q23). These patients were allocated to allogeneic HSCT in first CR per protocol on the basis of donor availability and investigator preference.[83][Level of evidence: 2Dii]
    • The overall 5-year EFS rate of patients meeting high-risk criteria was 58.9%.
    • The 5-year EFS rate was 74% for patients whose only high-risk feature was prednisone-poor response; there was no significant difference in DFS (P = .31) or OS (P = .91) when comparing HSCT and chemotherapy for patients with poor prednisone response in whom HSCT was allowed per protocol (those with T-ALL and/or WBC ≥100,000/mm3).
    • All other high-risk patients (i.e., those with initial induction failure, high day 78 MRD and/or t(4;11)(q21;q23)) had EFS rates less than 50%. For these patients, there was no statistically significant difference in DFS between those who received HSCT (n = 66) and those who received chemotherapy only (n = 88), after adjusting for waiting time to HSCT (5.7 months).
  4. On the Nordic Society for Pediatric Hematology and Oncology (NOPHO) ALL2008 (NCT00819351) protocol, patients were allocated to HSCT in first CR if they had MRD levels of 5% or greater at the end of induction or MRD levels of 0.1% or greater at end of consolidation. All patients allocated to HSCT received at least three blocks of intensive chemotherapy before HSCT to reduce levels of MRD.[84]
    • In the intent-to-treat analysis of 69 patients who met HSCT criteria (10 of whom did not undergo HSCT), the 5-year DFS rate was 78%.
    • Comparing the patients in this cohort who did and did not receive HSCT, receipt of HSCT was not significantly associated with survival (hazard ratio [HR], 1.4; P = .69).
    • For patients who underwent HSCT, superior outcomes (better DFS and lower cumulative incidence of relapse) were observed in patients who had nondetectable MRD before HSCT.
  5. Two retrospective analyses investigated the role of HSCT in first CR for patients with hypodiploid ALL. The studies showed no clear evidence that HSCT improved outcomes when 1) transplanting all patients with hypodiploid ALL, or 2) transplanting hypodiploid patients deemed at high risk on the basis of high MRD after induction. The studies did not examine the strategy of HSCT for persistent MRD after consolidation, nor did they analyze the status of MRD at the time of HSCT.
    1. In a study of 306 hypodiploid patients from 16 ALL cooperative groups treated between 1997 and 2013, a subgroup of 228 patients (42 who underwent HSCT) with 44 or fewer chromosomes who achieved remission were analyzed.[85][Level of evidence: 3iDiii]
      • Favorable prognostic factors included a chromosome number of 44 (compared with 43 or fewer), MRD less than 0.01% after induction, and treatment on an MRD-stratified protocol that intensified therapy for patients with higher MRD after induction.
      • After correction for median time to transplant, patients with low MRD who underwent HSCT had a DFS rate of 73.6%, compared with a DFS rate of 70% for those treated with chemotherapy alone (P = .81); patients with higher MRD after induction who underwent HSCT had a DFS rate of 55.9%, compared with a DFS rate of 40.3% for those treated with chemotherapy (P = .29).
    2. The COG published an analysis of 113 evaluable patients with hypodiploid ALL who were treated between 2003 and 2011; 61 of those patients underwent HSCT in first CR.[86][Level of evidence: 3iA]
      • The 5-year EFS rate was 57.4% for patients who underwent HSCT and 47.8% for patients in the chemotherapy cohorts (P = .49). The OS rate was 66.2% for patients who underwent HSCT and 53.8% for patients in the chemotherapy cohorts (P = .34).
      • Patients with high MRD after induction (≥0.01%) had a very poor EFS rate of 26.7% at 5 years, with no difference between the patients who received HSCT and the patients who received chemotherapy.

Maintenance therapy

Backbone of maintenance therapy

The backbone of maintenance therapy in most protocols includes daily oral mercaptopurine and weekly oral or parenteral methotrexate. On many protocols, intrathecal chemotherapy for CNS sanctuary therapy is continued during maintenance therapy. It is imperative to carefully monitor children on maintenance therapy for both drug-related toxicity and for compliance with the oral chemotherapy agents used during maintenance therapy.[87] Studies conducted by the COG have demonstrated significant differences in compliance with mercaptopurine among various racial and socioeconomic groups. Importantly, nonadherence to treatment with mercaptopurine in the maintenance phase has been associated with a significant increase in the risk of relapse.[87,88]

In the past, clinical practice generally called for the administration of oral mercaptopurine in the evening, on the basis of evidence from older studies that this practice may improve EFS.[89] However, in a study conducted by the NOPHO group, in which details of oral intake were prospectively captured, timing of mercaptopurine administration (nighttime vs. other times of day) was not of prognostic significance.[90] In a COG study, taking mercaptopurine at varying times of day rather than consistently at nighttime was associated with higher rates of nonadherence; however, among adherent patients (i.e., those who took >95% of prescribed doses), there was no association between timing of mercaptopurine ingestion and relapse risk.[91]

Some patients may develop severe hematologic toxicity when receiving conventional dosages of mercaptopurine because of an inherited deficiency (homozygous mutant) of thiopurine S-methyltransferase, an enzyme that inactivates mercaptopurine.[92,93] These patients are able to tolerate mercaptopurine only in much lower dosages than those conventionally used.[92,93] Patients who are heterozygous for the mutation generally tolerate mercaptopurine without serious toxicity, but they do require more frequent dose reductions for hematologic toxicity than do patients who are homozygous for the normal allele.[92] Polymorphisms of the NUDT15 gene, observed most frequently in East Asian and Hispanic patients, have also been linked to extreme sensitivity to the myelosuppressive effects of mercaptopurine.[94,95,96]

Evidence (maintenance therapy):

  1. A meta-analysis of randomized trials compared thiopurines and found the following:
    • Thioguanine did not improve the overall EFS, although particular subgroups may benefit from its use.[97]
    • The use of continuous thioguanine instead of mercaptopurine during the maintenance phase is associated with an increased risk of hepatic complications, including veno-occlusive disease and portal hypertension.[98,99,100,101,102]
    • Because of the increased toxicity of thioguanine, mercaptopurine remains the standard drug of choice.
  2. In the COG AALL0932 (NCT01190930) trial, NCI standard-risk patients with average-risk features were randomly assigned to receive weekly oral methotrexate during maintenance at one of two starting doses: 20 mg/m2 (standard) or 40 mg/m2 (investigational).[103][Level of evidence: 1iiA]
    • There was no significant difference in 5-year DFS from the start of maintenance therapy between the two treatment arms (5-year DFS rate, 95.1% for patients who received the standard dose vs. 94.2% for patients who received the investigational dose; P = .92), indicating no advantage for the higher dose of oral methotrexate.
  3. An intensified maintenance regimen, consisting of rotating pairs of agents, including cyclophosphamide and epipodophyllotoxins along with more standard maintenance agents, has been evaluated in several clinical trials conducted by SJCRH and other groups.[2]
    • The intensified maintenance with rotating pairs of agents was associated with more episodes of febrile neutropenia [104] and a higher risk of secondary acute myelogenous leukemia,[105,106] especially when epipodophyllotoxins were included.[104]

      On the basis of these findings, SJCRH modified the agents used in the rotating pair schedule during the maintenance phase. On the Total XV study, standard-risk and high-risk patients received three rotating pairs (mercaptopurine plus methotrexate, cyclophosphamide plus cytarabine, and dexamethasone plus vincristine) throughout this treatment phase; low-risk patients received more standard maintenance (without cyclophosphamide and cytarabine).[53]

    • A randomized study from Argentina demonstrated no benefit from this intensified approach compared with a more standard maintenance regimen for patients who receive induction and consolidation phases based on a BFM backbone.[104]

Vincristine/corticosteroid pulses

Pulses of vincristine and corticosteroid are often added to the standard maintenance backbone, although the benefit of these pulses within the context of contemporary multiagent chemotherapy regimens remains controversial.

Evidence (vincristine/corticosteroid pulses):

  1. A CCG randomized trial conducted in the 1980s demonstrated improved outcome in patients who received monthly vincristine/prednisone pulses.[107]
  2. A meta-analysis combining data from six clinical trials from the same treatment era showed an EFS advantage for vincristine/prednisone pulses.[108,109] However, overall EFS from these trials was lower than is observed with more contemporary regimens.
  3. A systematic review of the impact of vincristine plus steroid pulses from more recent clinical trials raised the question of whether such pulses are of value in current ALL treatment, which includes more intensive early therapy and risk stratification incorporating early response (MRD) and biologic factors.[109]
  4. In a multicenter randomized trial in children with intermediate-risk ALL being treated on a BFM regimen, there was no benefit associated with the addition of six pulses of vincristine/dexamethasone during the continuation phase, although the pulses were administered less frequently than in other trials in which a benefit had been demonstrated.[110]
  5. A small multicenter trial of average-risk patients demonstrated superior EFS in patients receiving vincristine plus corticosteroid pulses. In this study, there was no difference in outcome based on type of steroid (prednisone vs. dexamethasone).[111][Level of evidence: 1iiA]
  6. In the COG AALL0932 (NCT01190930) trial, standard-risk patients were randomly assigned during maintenance to receive vincristine/dexamethasone pulses every 4 weeks or every 12 weeks.[103][Level of evidence: 1iiA]
    • For the randomly assigned standard-risk patients, the 5-year DFS rate from the start of maintenance was 94.6%; there was no significant difference between the every-4-week group and the every-12-week group.

For regimens that include vincristine/steroid pulses, a number of studies have addressed which steroid (dexamethasone or prednisone) should be used. From these studies, it appears that dexamethasone is associated with superior EFS, but also may lead to a greater frequency of steroid-associated complications, including bone toxicity and infections, especially in older children and adolescents.[6,7,24,64,112] Compared with prednisone, dexamethasone has also been associated with a higher frequency of behavioral problems.[7] In a randomized study of 50 patients aged 3 to 16 years who received maintenance chemotherapy, concurrent administration of hydrocortisone (at physiologic dosing) during dexamethasone pulses reduced the frequency of behavioral difficulties, emotional lability, and sleep disturbances.[113]

Evidence (dexamethasone vs. prednisone):

  1. In a CCG study, dexamethasone was compared with prednisone during the induction and maintenance phases for children aged 1 to younger than 10 years with lower-risk ALL.[6,64]
    • Patients randomly assigned to receive dexamethasone had significantly fewer CNS relapses and a significantly better EFS rate.
  2. In a Medical Research Council (MRC) United Kingdom Acute Lymphoblastic Leukaemia (UKALL) trial, dexamethasone was compared with prednisolone during the induction and maintenance phases in both standard-risk and high-risk patients.[7]
    • The EFS and incidence of both CNS and non-CNS relapses improved with the use of dexamethasone.
    • Dexamethasone was associated with an increased risk of steroid-associated toxicities, including behavioral problems, myopathy, and osteopenia.
  3. In a DFCI ALL Consortium trial, patients were randomly assigned to receive either dexamethasone or prednisone during all postinduction treatment phases.[24]
    • Dexamethasone was associated with a superior EFS, but also with a higher frequency of infections (primarily episodes of bacteremia) and, in patients aged 10 years or older, an increased incidence of osteonecrosis and fracture.

The benefit of using dexamethasone in children aged 10 to 18 years requires further investigation because of the increased risk of steroid-induced osteonecrosis in this age group.[72,112]

Duration of maintenance therapy

Maintenance chemotherapy generally continues for 2 to 3 years of continuous CR. On some studies, boys are treated longer than girls;[64] on others, there is no difference in the duration of treatment based on sex.[60,67] It is not clear whether longer duration of maintenance therapy reduces relapse in boys, especially in the context of current therapies.[67][Level of evidence: 2Di] Extending the duration of maintenance therapy beyond 3 years does not improve outcome.[108]

Adherence to oral medications during maintenance therapy

Nonadherence to treatment with mercaptopurine during maintenance therapy is associated with a significant risk of relapse.[87]

Evidence (adherence to treatment):

  1. The COG studied the impact of nonadherence to mercaptopurine during maintenance therapy in 327 children and adolescents (169 Hispanic patients and 158 non-Hispanic White patients).[87]
    • A progressive increase in relapse was observed with decreasing adherence to mercaptopurine, with HRs ranging between 4.0% to 5.7% for adherence rates ranging from 94.9% to 90%, 89.9% to 85%, and less than 85%. After adjusting for other prognostic factors (including NCI risk group and chromosomal abnormalities), a progressive increase in relapse was observed with decreasing adherence to mercaptopurine. MRD data were unavailable in this study population, so they were not included in the analysis of prognostic factors.
    • Adherence was significantly lower among Hispanics, patients older than 12 years, and patients from single-mother households. Among adherent patients, Hispanic ethnicity remained an independent predictor of adverse outcome.
  2. A second study of adherence was conducted in 298 children with ALL (71 Asian American patients, 68 African American patients, and 159 non-Hispanic White patients).[88]
    • Using an adherence rate of less than 90% to define nonadherence, 20.5% of the participants were nonadherers.
    • An adherence rate of less than 90% was associated with increased relapse risk (HR, 3.9).
    • Adherence rates were significantly lower in Asian American and African American patients than in non-Hispanic White patients.
  3. In a third study of 742 children, the following key observations were made:[114]
    • Patients with mercaptopurine nonadherence (defined as mean adherence rate of <95%) were at a 2.7-fold increased risk of relapse compared with adherers.
    • Amongst adherers, high intra-individual variability in thioguanine levels (due to varying dose-intensity and drug treatment interruptions) was associated with increased risk of relapse.
  4. The authors of the above studies also found that self-reporting was not a reliable measure of adherence, with 84% of patients overreporting compliance with taking mercaptopurine at least some of the time.[115] The data suggest that additional measures of adherence besides self-reporting are needed.
  5. In a follow-up study, the above authors explored mercaptopurine ingestion habits, red cell thioguanine nucleotide (TGN) levels, adherence, and relapse risk.[91][Level of evidence: 2Diii]
    • The findings showed that certain ingestion habits (e.g., taking with dairy and taking at varying times throughout the day) were associated with nonadherence. However, after adjusting for adherence and other prognostic factors, ingestion habits were not associated with relapse risk.
    • For adherent patients, there was no association between TGN levels and ingestion habits.
    • The authors conclude that commonly practiced restrictions surrounding mercaptopurine ingestion do not appear to impact outcome but may hinder adherence.

Treatment options under clinical evaluation

Risk-based treatment assignment is a key therapeutic strategy utilized for children with ALL, and protocols are designed for specific patient populations that have varying degrees of risk of treatment failure. The Risk-Based Treatment Assignment section of this summary describes the clinical and laboratory features used for the initial stratification of children with ALL into risk-based treatment groups.

Information about NCI-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following are examples of national and/or institutional clinical trials that are currently being conducted:

COG studies for B-ALL

Standard-risk ALL

  1. COG-AALL1731 (NCT03914625) (A Study to Determine the Outcomes of Patients With Localized B-Cell Lymphoblastic Lymphoma When Treated With Standard-Risk B-ALL Therapy): This protocol is open for NCI standard-risk B-ALL non-Down syndrome patients and all B-ALL patients with Down syndrome (age <31 years) regardless of presenting WBC. The protocol is testing whether the addition of the bispecific T-cell engaging antibody blinatumomab can improve outcome and whether reducing duration of treatment in boys (from 3 years from the start of interim maintenance 1 phase to 2 years from the start of that phase) does not adversely impact DFS.

    All patients receive a three-drug induction (no anthracycline). After completion of induction, patients are classified into one of three groups on the basis of biology and early response measures:

    • Standard-risk favorable: Presence of either ETV6-RUNX1 or double trisomy (chromosomes 4 and 10), day 8 peripheral blood MRD of <1% and day 29 marrow MRD of <0.01%.
    • Standard-risk average: Favorable biology but day 8 peripheral blood MRD of >1% (but day 29 marrow MRD of <0.01%); or presence of double trisomy and day 29 marrow MRD of ≥0.01% but <0.1%; or neutral cytogenetics with day 29 marrow MRD of <0.01%.
    • Standard-risk high: Presence of ETV6-RUNX1 or neutral cytogenetics and day 29 marrow MRD of ≥0.01%; or presence of double trisomy and day 29 MRD of ≥0.1%; or presence of neutral cytogenetics and CNS2 at diagnosis, regardless of early response measures; or presence of unfavorable cytogenetics (iAMP21, KMT2A rearrangement, hypodiploidy (<44 chromosomes), or TCF3-HLF (t(17;19)).

    Standard-risk favorable patients will be treated with standard therapy.

    All standard-risk average patients will have MRD evaluated at day 29 of induction using high-throughput sequencing (HTS)-MRD assay. HTS-MRD undetectable patients will be treated with standard therapy, while patients with HTS-MRD detectable disease (or if HTS-MRD is indeterminate or unavailable), as well as those with double trisomies and day 29 marrow MRD of ≥0.01% to <0.1% will be eligible to participate in a randomization of standard therapy or standard therapy plus the addition of two cycles of blinatumomab.

    Standard-risk high patients will be treated with the augmented BFM (NCI high risk) backbone. Any patients with end-consolidation MRD of >1% are removed from protocol therapy. Those with end-consolidation MRD of <0.1% will be eligible to participate in a randomization of either the NCI high-risk backbone alone or this therapy plus two cycles of blinatumomab. Those with end-consolidation MRD of ≥0.1% and <1% will be directly assigned to receive NCI high-risk backbone therapy plus two cycles of blinatumomab.

    NCI standard-risk Down syndrome patients who meet definition of standard-risk average will be treated in the same way as non-Down syndrome standard-risk average patients, as detailed above. All other Down syndrome patients, including NCI high-risk Down syndrome patients, those with unfavorable biology, and those with high day 29 MRD will be considered Down syndrome-high, and will be nonrandomly assigned to receive two cycles of blinatumomab added to a deintensified chemotherapy regimen that omits intensive elements of the augmented BFM treatment backbone. Omitted elements include anthracyclines during induction and cyclophosphamide/cytarabine-based chemotherapy during the second half of delayed intensification.

    All patients, regardless of risk group, will receive the same duration of therapy (2 years from the start of interim maintenance 1 phase). This represents a reduction in treatment duration by 1 year for boys compared with standard treatment.

High-risk and very high-risk ALL

  1. COG-AALL1521 (NCT02723994) (A Phase II Study of Ruxolitinib With Chemotherapy in Children With ALL): This nonrandomized study is testing the addition of ruxolitinib (JAK inhibitor) in combination with the modified augmented BFM regimen (similar to AALL1131) for the treatment of NCI high-risk B-ALL patients (aged 1–21 years) with any of the following genetic abnormalities: 1) rearranged CRLF2; 2) mutations in JAK1 or JAK2; or 3) other alterations involving the JAK pathway (e.g., JAK2 fusions, EPO-R fusions, SH2B3 deletions, IL7RA mutations). Patients enter the study after completing the induction phase. Ruxolitinib will be administered in conjunction with all postinduction treatment phases. The primary objective is to evaluate the safety, tolerability, and efficacy of the combination.
  2. COG-AALL1721 (NCT03876769) (Study of Efficacy and Safety of Tisagenlecleucel in High-Risk B-ALL End-of-Consolidation MRD-Positive Patients): This protocol is open to patients with NCI high-risk B-ALL who are aged 1 to 25 years, were in morphologic CR at end of induction and have end-consolidation MRD of ≥0.01%. The primary objective of the trial is to evaluate the efficacy of tisagenlecleucel (a CD19-directed chimeric antigen receptor [CAR] T cell) as definitive therapy in this patient population, specifically to determine whether the 5-year DFS rate with tisagenlecleucel therapy exceeds 55%.

    Patients enrolled on this trial will undergo leukapheresis to collect autologous T cells, which will then be sent for manufacturing of tisagenlecleucel. While awaiting completion of manufacturing, patients will proceed with interim maintenance phase 1 (high-dose methotrexate); this phase may be interrupted as soon as product is available. Once available, patients will then receive lymphodepleting chemotherapy and infusion of tisagenlecleucel. No further anti-leukemic treatment is to be administered after tisagenlecleucel. Marrow samples will be obtained at regular intervals postinfusion, beginning at day 29 after tisagenlecleucel administration to assess disease status; tests of peripheral blood will also be sent to screen for evidence of B-cell aplasia.

    Patients must have evidence of CD19-positivity at diagnosis to enroll on trial. Patients with M3 marrow at end of induction, M2/M3 marrow at end of consolidation, hypodiploidy (<44 chromosomes), Ph+ ALL, or previous treatment with tyrosine kinase inhibitors are excluded from enrollment.

  3. COG-AALL1732 (NCT03959085) (A Phase III Randomized Trial of Inotuzumab Ozogamicin for Newly Diagnosed High-Risk B-ALL; Risk-Adapted Postinduction Therapy for High-Risk B-ALL, Mixed Phenotype Acute Leukemia [MPAL], and Disseminated B-Lymphoblastic Lymphoma): This protocol is open for patients with NCI high-risk non-Down syndrome ALL, any patient with MPAL, and patients with disseminated B-lymphoblastic lymphoma. Patients with NCI standard-risk B-ALL who had steroid pretreatment, CNS3 status, or testicular disease at diagnosis are also eligible for this study.

    For patients with B-ALL, the protocol is testing whether the addition of two blocks of inotuzumab ozogamicin to a modified-BFM backbone will improve DFS and whether reducing duration of treatment in boys (from 3 years from the start of interim maintenance 1 phase to 2 years from the start of that phase) does not adversely impact DFS. The study also aims to determine the EFS of patients with MPAL and disseminated B-lymphoblastic lymphoma who are treated with a standard high-risk ALL chemotherapy regimen.

    All patients receive a four-drug induction (including daunorubicin). After completion of induction, subsequent therapy depends on age, biology, and response to therapy.

    • High-risk favorable: Patients who are younger than 10 years with ETV6-RUNX1 fusions or high hyperdiploidy with trisomies of chromosomes 4 and 10 and who achieve an MRD of <0.01% at end of induction will receive a modified-BFM regimen with one interim maintenance phase (high-dose methotrexate), but are not eligible for randomization.
    • Other high-risk B-ALL patients who do not meet high-risk favorable criteria but who achieve an MRD of <0.01% (for NCI high risk) or <1% (for NCI standard risk) by the end of consolidation (EOC) will be eligible for randomization to modified-BFM therapy with or without two blocks of inotuzumab. Patients who are CD22 negative at diagnosis (or have unknown CD22 status) are not eligible to be randomized, and they are removed from protocol therapy.
    • Patients with MPAL and disseminated B-lymphoblastic lymphoma will receive a standard high-risk modified-BFM backbone with two interim maintenance phases, but are not eligible for randomization.

    All patients will receive the same duration of therapy (2 years from the start of interim maintenance 1 phase). This represents a reduction in treatment duration by 1 year for boys, compared with standard treatment. NCI high-risk B-ALL patients with EOC MRD of ≥0.01% are removed from protocol therapy and are eligible to enroll on the COG-AALL1721 trial (see above). NCI standard-risk patients with EOC MRD of ≥1% are removed from protocol therapy and are not eligible for enrollment on the COG-AALL1721 trial.

Other studies

  1. St. Jude Total 17 study (TOT17, NCT03117751) (Combination Chemotherapy in Treating Patients With ALL or Lymphoma):

    This trial has the following four main objectives:

    1. To improve the EFS of provisional standard-risk or high-risk patients with genetically or immunologically targetable lesions or MRD of ≥5% at day 15 or ≥1% at the end of remission induction, by the addition of molecular and immunotherapeutic approaches including tyrosine kinase inhibitors or CAR T cells/blinatumomab for refractory B-ALL patients, and the proteasome inhibitor bortezomib for those lacking targetable lesions.
    2. To improve overall treatment outcome of patients with T-ALL by optimizing pegaspargase and cyclophosphamide treatment, by the addition of new agents in patients with targetable genomic abnormalities (e.g., activated tyrosine kinases or JAK/STAT mutations) or by the addition of bortezomib for those who have a poor early response to treatment but no targetable lesions, and by administering nelarabine to T-ALL patients with leukemia cells in cerebrospinal fluid at diagnosis or MRD of ≥0.01% at the end of induction.
    3. To examine in a randomized study design whether the administration of two doses of rituximab to children with B-ALL during early remission induction therapy decreases allergic reactions to pegaspargase.
    4. To determine in a randomized study design whether the incidence and/or severity of acute vincristine-induced peripheral neuropathy can be reduced by decreasing the dosage of vincristine in patients with the high-risk CEP72 TT genotype or by shortening the duration of vincristine therapy in patients with the CEP72 CC or CT genotype.
  2. DFCI ALL Consortium 16-001 (NCT03020030) (Risk Classification Schemes in Identifying Better Treatment Options for Children and Adolescents with ALL):

    This trial has the following two main objectives:

    1. To test a novel risk classification scheme for children and adolescents with ALL.
    2. To test the feasibility of administering pegaspargase at a reduced dose during postinduction treatment phases (adjusting doses based on serum asparaginase activity levels), with the goal of maintaining therapeutic serum asparaginase activity levels while potentially reducing nonallergic asparaginase-related toxicities.

    Patients are assigned an initial risk group by day 10 of therapy. Patients are considered initial very high risk if any of the following are present: IKZF1 deletion, KMT2A gene rearrangement, TCF3-HLF fusion (t(17;19)), or low hypodiploidy (<40 chromosomes). Patients are considered initial low risk if they meet all of the following criteria: B-cell ALL, aged 1 year to younger than 15 years, WBC count less than 50 × 109, CNS1 or CNS2, absence of iAMP21, and absence of very high-risk features. Initial high-risk patients include all other patients lacking very high-risk features, including all patients with T-ALL.

    Intensity of induction depends on initial risk group. Initial low-risk patients receive a three-drug induction (no anthracycline). All other patients receive a four-drug induction (with an anthracycline).

    Final risk group, which determines the intensity of postinduction therapy, is assigned on the basis of MRD (assessed by next-generation sequencing) at the end of induction (day 32; first time point) and week 10 (second time point).

    • Initial low-risk patients with low MRD (<0.01%) at the first time point are considered final low risk. They continue treatment per DFCI standard-risk backbone, including 30 weeks of pegaspargase, without any anthracycline.
    • Initial low-risk patients with high MRD (≥0.01%) at the first time point but low MRD (<0.1%) at the second time point and all initial high-risk patients with low MRD (<0.1%) at the second time point continue treatment per DFCI high-risk backbone, including doxorubicin, but with a reduced dose of dexamethasone compared with previous trials.
    • All patients with very high-risk biology and any initial low-risk/high-risk patient with high MRD (≥0.1%) at the second time point are considered very high risk and receive an intensified consolidation phase followed by the DFCI high-risk backbone. Any very high-risk patients identified as having Ph-like ALL (BCR-ABL1–like ALL) with a gene fusion involving a kinase that is sensitive to dasatinib (e.g., ABL1, ABL2, CSF1F, and PDGFRB) will receive dasatinib during all postinduction treatment phases.

    Treatment for all risk groups includes 30 weeks of pegaspargase (15 doses given every 2 weeks) during postinduction therapy. All final low-risk/high-risk patients are eligible to participate in a randomized comparison of postinduction pegaspargase dosing: standard dose (2,500 IU/m2 /dose) or pharmacokinetic-adjusted reduced dose (starting dose: 2,000 IU/m2). In all patients, nadir serum asparaginase activity (NSAA) is checked before each pegaspargase dose; any patient found to have a nondetectable NSAA is switched to Erwinia asparaginase. On the pharmacokinetic-adjusted reduced-dose arm, the dose may be decreased further to 1,750 IU/m2 if NSAA is found to be extremely high (>1.0 IU/mL) after the fourth pegaspargase dose; the dose will be increased up to standard dose (2,500 IU/m2) if NSAA is low but detectable (<0.4 IU/mL) at any time point. The trial is also piloting a strategy to rechallenge patients with grade 2 hypersensitivity reactions to pegaspargase with pharmacokinetic-monitoring to determine whether such patients will switch to Erwinia or may continue to receive pegaspargase with premedication.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

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  83. Conter V, Valsecchi MG, Parasole R, et al.: Childhood high-risk acute lymphoblastic leukemia in first remission: results after chemotherapy or transplant from the AIEOP ALL 2000 study. Blood 123 (10): 1470-8, 2014.
  84. Ifversen M, Turkiewicz D, Marquart HV, et al.: Low burden of minimal residual disease prior to transplantation in children with very high risk acute lymphoblastic leukaemia: The NOPHO ALL2008 experience. Br J Haematol 184 (6): 982-993, 2019.
  85. Pui CH, Rebora P, Schrappe M, et al.: Outcome of Children With Hypodiploid Acute Lymphoblastic Leukemia: A Retrospective Multinational Study. J Clin Oncol 37 (10): 770-779, 2019.
  86. McNeer JL, Devidas M, Dai Y, et al.: Hematopoietic Stem-Cell Transplantation Does Not Improve the Poor Outcome of Children With Hypodiploid Acute Lymphoblastic Leukemia: A Report From Children's Oncology Group. J Clin Oncol 37 (10): 780-789, 2019.
  87. Bhatia S, Landier W, Shangguan M, et al.: Nonadherence to oral mercaptopurine and risk of relapse in Hispanic and non-Hispanic white children with acute lymphoblastic leukemia: a report from the children's oncology group. J Clin Oncol 30 (17): 2094-101, 2012.
  88. Bhatia S, Landier W, Hageman L, et al.: 6MP adherence in a multiracial cohort of children with acute lymphoblastic leukemia: a Children's Oncology Group study. Blood 124 (15): 2345-53, 2014.
  89. Schmiegelow K, Glomstein A, Kristinsson J, et al.: Impact of morning versus evening schedule for oral methotrexate and 6-mercaptopurine on relapse risk for children with acute lymphoblastic leukemia. Nordic Society for Pediatric Hematology and Oncology (NOPHO). J Pediatr Hematol Oncol 19 (2): 102-9, 1997 Mar-Apr.
  90. Clemmensen KK, Christensen RH, Shabaneh DN, et al.: The circadian schedule for childhood acute lymphoblastic leukemia maintenance therapy does not influence event-free survival in the NOPHO ALL92 protocol. Pediatr Blood Cancer 61 (4): 653-8, 2014.
  91. Landier W, Hageman L, Chen Y, et al.: Mercaptopurine Ingestion Habits, Red Cell Thioguanine Nucleotide Levels, and Relapse Risk in Children With Acute Lymphoblastic Leukemia: A Report From the Children's Oncology Group Study AALL03N1. J Clin Oncol 35 (15): 1730-1736, 2017.
  92. Relling MV, Hancock ML, Rivera GK, et al.: Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. J Natl Cancer Inst 91 (23): 2001-8, 1999.
  93. Andersen JB, Szumlanski C, Weinshilboum RM, et al.: Pharmacokinetics, dose adjustments, and 6-mercaptopurine/methotrexate drug interactions in two patients with thiopurine methyltransferase deficiency. Acta Paediatr 87 (1): 108-11, 1998.
  94. Yang JJ, Landier W, Yang W, et al.: Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia. J Clin Oncol 33 (11): 1235-42, 2015.
  95. Moriyama T, Nishii R, Perez-Andreu V, et al.: NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity. Nat Genet 48 (4): 367-73, 2016.
  96. Zhou H, Li L, Yang P, et al.: Optimal predictor for 6-mercaptopurine intolerance in Chinese children with acute lymphoblastic leukemia: NUDT15, TPMT, or ITPA genetic variants? BMC Cancer 18 (1): 516, 2018.
  97. Escherich G, Richards S, Stork LC, et al.: Meta-analysis of randomised trials comparing thiopurines in childhood acute lymphoblastic leukaemia. Leukemia 25 (6): 953-9, 2011.
  98. Broxson EH, Dole M, Wong R, et al.: Portal hypertension develops in a subset of children with standard risk acute lymphoblastic leukemia treated with oral 6-thioguanine during maintenance therapy. Pediatr Blood Cancer 44 (3): 226-31, 2005.
  99. De Bruyne R, Portmann B, Samyn M, et al.: Chronic liver disease related to 6-thioguanine in children with acute lymphoblastic leukaemia. J Hepatol 44 (2): 407-10, 2006.
  100. Vora A, Mitchell CD, Lennard L, et al.: Toxicity and efficacy of 6-thioguanine versus 6-mercaptopurine in childhood lymphoblastic leukaemia: a randomised trial. Lancet 368 (9544): 1339-48, 2006.
  101. Jacobs SS, Stork LC, Bostrom BC, et al.: Substitution of oral and intravenous thioguanine for mercaptopurine in a treatment regimen for children with standard risk acute lymphoblastic leukemia: a collaborative Children's Oncology Group/National Cancer Institute pilot trial (CCG-1942). Pediatr Blood Cancer 49 (3): 250-5, 2007.
  102. Stork LC, Matloub Y, Broxson E, et al.: Oral 6-mercaptopurine versus oral 6-thioguanine and veno-occlusive disease in children with standard-risk acute lymphoblastic leukemia: report of the Children's Oncology Group CCG-1952 clinical trial. Blood 115 (14): 2740-8, 2010.
  103. Angiolillo AL, Schore RJ, Kairalla JA, et al.: Excellent Outcomes With Reduced Frequency of Vincristine and Dexamethasone Pulses in Standard-Risk B-Lymphoblastic Leukemia: Results From Children's Oncology Group AALL0932. J Clin Oncol 39 (13): 1437-1447, 2021.
  104. Felice MS, Rossi JG, Gallego MS, et al.: No advantage of a rotational continuation phase in acute lymphoblastic leukemia in childhood treated with a BFM back-bone therapy. Pediatr Blood Cancer 57 (1): 47-55, 2011.
  105. Hijiya N, Hudson MM, Lensing S, et al.: Cumulative incidence of secondary neoplasms as a first event after childhood acute lymphoblastic leukemia. JAMA 297 (11): 1207-15, 2007.
  106. Pui CH, Ribeiro RC, Hancock ML, et al.: Acute myeloid leukemia in children treated with epipodophyllotoxins for acute lymphoblastic leukemia. N Engl J Med 325 (24): 1682-7, 1991.
  107. Bleyer WA, Sather HN, Nickerson HJ, et al.: Monthly pulses of vincristine and prednisone prevent bone marrow and testicular relapse in low-risk childhood acute lymphoblastic leukemia: a report of the CCG-161 study by the Childrens Cancer Study Group. J Clin Oncol 9 (6): 1012-21, 1991.
  108. Duration and intensity of maintenance chemotherapy in acute lymphoblastic leukaemia: overview of 42 trials involving 12 000 randomised children. Childhood ALL Collaborative Group. Lancet 347 (9018): 1783-8, 1996.
  109. Eden TO, Pieters R, Richards S, et al.: Systematic review of the addition of vincristine plus steroid pulses in maintenance treatment for childhood acute lymphoblastic leukaemia - an individual patient data meta-analysis involving 5,659 children. Br J Haematol 149 (5): 722-33, 2010.
  110. Conter V, Valsecchi MG, Silvestri D, et al.: Pulses of vincristine and dexamethasone in addition to intensive chemotherapy for children with intermediate-risk acute lymphoblastic leukaemia: a multicentre randomised trial. Lancet 369 (9556): 123-31, 2007.
  111. De Moerloose B, Suciu S, Bertrand Y, et al.: Improved outcome with pulses of vincristine and corticosteroids in continuation therapy of children with average risk acute lymphoblastic leukemia (ALL) and lymphoblastic non-Hodgkin lymphoma (NHL): report of the EORTC randomized phase 3 trial 58951. Blood 116 (1): 36-44, 2010.
  112. Strauss AJ, Su JT, Dalton VM, et al.: Bony morbidity in children treated for acute lymphoblastic leukemia. J Clin Oncol 19 (12): 3066-72, 2001.
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CNS-Directed Therapy for Childhood ALL

Overview of CNS-Directed Treatment Regimens

At diagnosis, approximately 3% of patients have central nervous system 3 (CNS3) disease (defined as cerebrospinal fluid [CSF] specimen with ≥5 white blood cells [WBC]/μL with lymphoblasts and/or the presence of cranial nerve palsies). However, unless specific therapy is directed toward the CNS, most children will eventually develop overt CNS leukemia whether or not lymphoblasts were detected in the spinal fluid at initial diagnosis. Therefore, all children with acute lymphoblastic leukemia (ALL) should receive systemic combination chemotherapy together with some form of CNS prophylaxis.

Because the CNS is a sanctuary site (i.e., an anatomic space that is poorly penetrated by many of the systemically administered chemotherapy agents typically used to treat ALL), specific CNS-directed therapies must be instituted early in treatment to eliminate clinically evident CNS disease at diagnosis and to prevent CNS relapse in all patients. Historically, survival rates for children with ALL improved dramatically after CNS-directed therapies were added to treatment regimens.

Standard treatment options for CNS-directed therapy include the following:

  1. Intrathecal chemotherapy.
  2. CNS-directed systemic chemotherapy.
  3. Cranial radiation therapy.

All of these treatment modalities have a role in the treatment and prevention of CNS leukemia. The combination of intrathecal chemotherapy plus CNS-directed systemic chemotherapy is standard; cranial radiation is reserved for select situations.[1]

The type of CNS-therapy that is used is based on a patient's risk of CNS-relapse, with higher-risk patients receiving more intensive treatments. Data suggest that the following groups of patients are at increased risk of CNS relapse:

  • Patients with 5 or more WBC/µL and blasts in the CSF (CNS3), obtained at diagnosis.
  • Patients with blasts in the CSF but fewer than 5 WBC/µL (CNS2) may be at increased risk of CNS relapse,[2] although this risk appears to be nearly fully abrogated if they receive more doses of intrathecal chemotherapy, especially during the induction phase.[3]
  • Patients with T-ALL, especially those with high presenting peripheral blood leukocyte counts.
  • Patients who have a traumatic lumbar puncture showing blasts at the time of diagnosis may have an increased risk of CNS relapse. These patients receive more intensive CNS-directed therapy on some treatment protocols.[3,4]

CNS-directed treatment regimens for newly diagnosed childhood ALL are presented in Table 11.

Table 11. CNS-Directed Treatment Regimens for Newly Diagnosed Childhood ALL
Disease Status Standard Treatment Options
ALL = acute lymphoblastic leukemia; CNS = central nervous system; CNS3 = cerebrospinal fluid with ≥5 white blood cells/µL, cytospin positive for blasts, or cranial nerve palsies.
a The drug itself is not CNS-penetrant, but leads to cerebrospinal fluid asparagine depletion.
Standard-risk ALL Intrathecal chemotherapy
Methotrexate alone
Methotrexate with cytarabine and hydrocortisone
CNS-directed systemic chemotherapy
Dexamethasone
L-asparaginasea
High-dose methotrexate with leucovorin rescue
Escalating-dose intravenous methotrexate (no leucovorin rescue)
High-risk and very high-risk ALL Intrathecal chemotherapy
Methotrexate alone
Methotrexate with cytarabine and hydrocortisone
CNS-directed systemic chemotherapy
Dexamethasone
L-asparaginasea
High-dose methotrexate with leucovorin rescue
Cranial radiation therapy

A major goal of current ALL clinical trials is to provide effective CNS therapy while minimizing neurologic toxic effects and other late effects.

Intrathecal Chemotherapy

All therapeutic regimens for childhood ALL include intrathecal chemotherapy. Intrathecal chemotherapy is usually started at the beginning of induction, intensified during consolidation and, in many protocols, continued throughout the maintenance phase.

Intrathecal chemotherapy typically consists of one of the following:[5]

  1. Methotrexate alone.
  2. Methotrexate with cytarabine and hydrocortisone (triple intrathecal chemotherapy).

Unlike intrathecal cytarabine, intrathecal methotrexate has a significant systemic effect, which may contribute to prevention of marrow relapse.[6]

CNS-Directed Systemic Chemotherapy

In addition to therapy delivered directly to the brain and spinal fluid, systemically administered agents are also an important component of effective CNS prophylaxis. The following systemically administered drugs provide some degree of CNS prophylaxis:

  • Dexamethasone.
  • L-asparaginase (does not penetrate into CSF itself, but leads to CSF asparagine depletion).[7]
  • High-dose methotrexate with leucovorin rescue.
  • Escalating dose intravenous (IV) methotrexate without leucovorin rescue.

Evidence (CNS-directed systemic chemotherapy):

  1. In a randomized Children's Cancer Group (CCG) study of standard-risk patients who all received the same dose and schedule of intrathecal methotrexate without cranial irradiation, oral dexamethasone was associated with a 50% decrease in the rate of CNS relapse compared with oral prednisone.[8]
  2. In another standard-risk ALL trial (COG-1991), escalating dose IV methotrexate without leucovorin rescue significantly reduced the CNS relapse rate compared with standard, low-dose, oral methotrexate given during each of two interim maintenance phases.[9]
  3. In a randomized clinical trial conducted by the former Pediatric Oncology Group, T-ALL patients who received high-dose methotrexate experienced a significantly lower CNS relapse rate than did patients who did not receive high-dose methotrexate.[10]

Cranial Radiation Therapy

The proportion of patients receiving cranial radiation therapy has decreased significantly over time. At present, most newly diagnosed children with ALL are treated without cranial radiation therapy. Many groups administer cranial radiation therapy only to those patients considered to be at highest risk of subsequent CNS relapse, such as those with documented CNS leukemia at diagnosis (as defined above) (≥5 WBC/μL with blasts; CNS3) and/or T-cell phenotype with high presenting WBC count.[11] In patients who do receive radiation therapy, the cranial radiation dose has been significantly reduced and administration of spinal irradiation is not standard.

Ongoing trials seek to determine whether radiation therapy can be eliminated from the treatment of all children with newly diagnosed ALL without compromising survival or leading to increased rate of toxicities from upfront and salvage therapies.[12,13] A meta-analysis of randomized trials of CNS-directed therapy has confirmed that radiation therapy can be replaced by intrathecal chemotherapy in most patients with newly diagnosed ALL. Additional systemic therapy may be required depending on the agents and intensity used.[14]; [1][Level of evidence: 1iDi]

CNS Therapy for Standard-risk Patients

Intrathecal chemotherapy without cranial radiation therapy, given in the context of appropriate systemic chemotherapy, results in CNS relapse rates of less than 5% for children with standard-risk ALL.[12,13,15,16,17,18]

The use of cranial radiation therapy is not a necessary component of CNS-directed therapy for these patients.[19,20] Some regimens use triple intrathecal chemotherapy (methotrexate, cytarabine, and hydrocortisone), while others use intrathecal methotrexate alone throughout therapy.

Evidence (triple intrathecal chemotherapy vs. intrathecal methotrexate):

  1. The CCG-1952 study for National Cancer Institute (NCI) standard-risk patients compared the relative efficacy and toxicity of triple intrathecal chemotherapy (methotrexate, cytarabine, and hydrocortisone) with methotrexate as the sole intrathecal agent in nonirradiated patients.[21]
    1. There was no significant difference in either CNS or non-CNS toxicities.
    2. Although triple intrathecal chemotherapy was associated with a lower rate of isolated CNS relapse (3.4% ± 1.0% compared with 5.9% ± 1.2% for intrathecal methotrexate; P = .004), there was no difference in event-free survival (EFS).
      • The reduction in CNS relapse rate was especially notable in patients with CNS2 status at diagnosis (lymphoblasts seen in CSF cytospin, but with <5 WBC/high-power field on CSF cell count); the isolated CNS relapse rate was 7.7% (± 5.3%) for CNS2 patients who received triple intrathecal chemotherapy compared with 23.0% (± 9.5%) for those who received intrathecal methotrexate alone (P = .04).
      • There were more bone marrow relapses in the group that received the triple intrathecal chemotherapy, leading to a worse overall survival (OS) rate (90.3% ± 1.5%) compared with the intrathecal methotrexate group (94.4% ± 1.1%; P = .01).
      • When the analysis was restricted to patients with B-ALL and rapid early response (M1 marrow on day 14), there was no difference between triple and single intrathecal chemotherapy in terms of rates of CNS relapse, OS, or EFS.
      • The findings of this trial need to be interpreted within the context of other therapy administered to patients. Dexamethasone, which has been associated with lower CNS relapse rates and improved EFS in standard-risk patients in other trials,[8,22] was not used in CCG-1952 (prednisone was the only steroid administered to patients).[23] It is not clear whether the results of the CCG-1952 trial are generalizable to protocols that include the use of dexamethasone and/or other CNS-directed systemic therapies.
    3. In a follow-up study of neurocognitive functioning in the two groups, there were no clinically significant differences.[24][Level of evidence: 1iiC]

CNS Therapy for High-risk and Very High-risk Patients Without CNS Involvement

Intrathecal chemotherapy

Approaches to intrathecal therapy have also been studied in high-risk patients.

Evidence (triple intrathecal chemotherapy vs. intrathecal methotrexate):

  1. The COG AALL1131 (NCT02883049) study for National Cancer Institute (NCI) high-risk patients and NCI standard-risk B-ALL patients with slow early response (defined by day 8 peripheral blood MRD and/or day 29 marrow MRD) randomly assigned patients aged 1 to 30 years to receive either postinduction intrathecal methotrexate or triple intrathecal chemotherapy (methotrexate, cytarabine, and hydrocortisone). Patients with CNS3 disease were not eligible, and patients on this trial did not receive cranial radiation. Postinduction intrathecal therapy was administered for a total of 21 to 26 doses. Neurocognitive assessments were performed in a subset of patients aged 6 to 12 years at initial diagnosis.[25]
    • The 5-year postinduction disease-free survival (DFS) rates were 93.2% (± 2.1%) for patients randomly assigned to intrathecal methotrexate and 90.6% (± 2.3%) (P = .85) for patients assigned to triple intrathecal chemotherapy.
    • The OS rates were 96.3% (± 1.5%) for patients who received intrathecal methotrexate and 96.7% (± 1.4%) (P = .77) for patients who received triple intrathecal chemotherapy.
    • There were no differences in the cumulative incidence of isolated bone marrow relapse, isolated CNS relapse, or combined bone marrow and CNS relapse between the two arms.
    • There were no significant differences in neurologic toxicities or in assessments of neurocognitive functioning during treatment for patients who received intrathecal methotrexate compared with patients who received triple intrathecal chemotherapy.

Cranial radiation therapy

Controversy exists as to whether high-risk and very high-risk patients should be treated with cranial radiation therapy, although there is a growing consensus that cranial radiation therapy may not be necessary for most of these patients.[14] Indications for cranial radiation therapy on some treatment regimens have included the following:[11]

  • Patients with T-cell phenotype and high initial WBC count.
  • Patients with high-risk B-ALL and extremely high presenting leukocyte counts and/or adverse cytogenetic abnormalities.

Both the proportion of patients receiving radiation therapy and the dose of radiation administered have decreased over the last two decades.

Evidence (cranial radiation therapy):

  1. In a trial conducted between 1990 and 1995, the Berlin-Frankfurt-Münster (BFM) group demonstrated that a reduced dose of prophylactic radiation (12 Gy instead of 18 Gy) provided effective CNS prophylaxis in high-risk patients.[26]
  2. In the follow-up trial conducted by the BFM group between 1995 and 2000 (BFM-95), cranial radiation therapy was administered to approximately 20% of patients (compared with 70% on the previous trial), including patients with T-cell phenotype, a slow early response (as measured by peripheral blood blast count after a 1-week steroid prophase), and/or adverse cytogenetic abnormalities.[18]
    • While the rate of isolated CNS relapses was higher in the nonirradiated higher-risk patients compared with historic (irradiated) cohorts, their overall EFS rates were not significantly different.
  3. Several groups, including the St. Jude Children's Research Hospital (SJCRH), the Dutch Childhood Oncology Group (DCOG), and the European Organization for Research and Treatment of Cancer (EORTC), have published results of trials that omitted cranial radiation therapy for all patients, including high-risk subsets.[12,13,27] Most of these trials have included at least four doses of high-dose methotrexate during postinduction consolidation and an increased frequency of intrathecal chemotherapy. The SJCRH and DCOG studies also included frequent vincristine/dexamethasone pulses and intensified dosing of pegaspargase,[12,13] while the EORTC trials included additional high-dose methotrexate and multiple doses of high-dose cytarabine during postinduction treatment phases for patients with CNS3 status (CSF with ≥5 WBC/µL and cytospin positive for blasts).[27]
    • The 5-year cumulative incidence of isolated CNS relapse on those trials was between 2% and 4%, although some patient subsets had a significantly higher rate of CNS relapse. On the SJCRH study, clinical features associated with a significantly higher risk of isolated CNS relapse included T-cell phenotype, the t(1;19) translocation, and the presence of blasts in the CSF at diagnosis.[12]
    • The overall EFS rate was 85.6% for the SJCRH study and 81% for the DCOG study—both in line with outcomes achieved by contemporaneously conducted clinical trials on which some patients received prophylactic radiation therapy—but was lower on the EORTC trial (8-year EFS rate, 69.6%).[27]
    • On the SJCRH study, 33 of 498 patients (6.6%) in first remission with high-risk features (including 26 patients with high minimal residual disease [MRD], 6 with Philadelphia chromosome-positive ALL, and 1 with near haploidy) received an allogeneic hematopoietic stem cell transplant, which included total-body irradiation.[12]
  4. In a meta-analysis of aggregated data from more than 16,000 patients treated between 1996 and 2007 by ten cooperative groups, the use of cranial radiation therapy did not appear to impact 5-year OS or cumulative incidence of any event.[14]
    • In subgroup analyses of high-risk subsets, only those with CNS3 status at diagnosis appeared to benefit from cranial radiation, with a significantly lower rate of CNS relapses (isolated/any) in irradiated patients; however, even within this subgroup, OS was similar with or without the use of radiation therapy.
    • This study suggests that cranial radiation therapy may not be an essential component of treatment, even for high-risk patients; however, interpretation is limited by the considerable variation in treatment administered to patients by the different cooperative groups.
  5. The EORTC-58832 trial that was conducted between 1983 and 1989 included patients with medium-risk and high-risk ALL. Patients were randomly assigned to receive or not to receive cranial radiation after intensification and before maintenance therapy.[28][Level of evidence: 1iiA]
    • The 25-year EFS and OS rates in the two arms of the trial were similar: the EFS rate was 59.5% and the OS rate was 78.1% for patients who did not receive cranial radiation; the EFS rate was 60.5% and the OS rate was 78.5% for patients who received cranial radiation.
    • There was a dramatic decrease in the rate of late CNS adverse events in the patients who did not receive cranial radiation therapy.
    • The incidence of second neoplasms was also decreased in patients who did not receive radiation (7.3%) compared with patients who did receive radiation (13%) (HR, 0.43). Meningiomas accounted for the increased incidence of second neoplasms in the cranial radiation group.

CNS Therapy for Patients With CNS3 Disease at Diagnosis

Therapy for ALL patients with clinically evident CNS disease (≥5 WBC/high-power field with blasts on cytospin; CNS3) at diagnosis typically includes intrathecal chemotherapy and cranial radiation therapy (usual dose is 18 Gy).[18,20] Spinal radiation is no longer used.

Evidence (cranial radiation therapy):

  1. The SJCRH, DCOG, and the EORTC have published results of trials that omitted cranial radiation therapy for all patients, including high-risk subsets.[12,27] These trials have included at least four doses of high-dose methotrexate during postinduction consolidation and an increased frequency of intrathecal chemotherapy. The SJCRH study also included higher cumulative doses of anthracycline than on Children's Oncology Group (COG) trials, and frequent vincristine/dexamethasone pulses and intensified dosing of pegaspargase,[12] while the EORTC trials included additional high-dose methotrexate and multiple doses of high-dose cytarabine, during postinduction treatment phases for CNS3 (CSF with ≥5 WBC/µL and cytospin positive for blasts) patients.[27]
    • On the SJCRH Total XV (TOTXV) study, patients with CNS3 status (N = 9) were treated without cranial radiation therapy (observed 5-year EFS rate, 43% ± 23%; OS rate, 71% ± 22%).[12] On this study, CNS leukemia at diagnosis (defined as CNS3 status or traumatic lumbar puncture with blasts) was an independent predictor of inferior EFS.
    • On the DCOG-9 trial, the 5-year EFS rate of CNS3 patients (n = 21) treated without cranial radiation therapy was 67% (± 10%).[13]
    • On the EORTC trial, the 8-year EFS rate of CNS3 patients (n = 49) treated without cranial radiation therapy was 68%. The cumulative incidence of isolated CNS relapse for those patients was 9.4%.[27][Level of evidence: 2A]
  2. A meta-analysis of aggregated data from more than 16,000 patients treated between 1996 and 2007 by ten cooperative groups evaluated whether the use of cranial radiation therapy affected outcome in high-risk patient subsets.[14]
    • In subgroup analyses of high-risk subsets, only those with CNS3 status at diagnosis appeared to benefit from cranial radiation therapy, with a significantly lower rate of CNS relapses (isolated/any) in irradiated patients; however, even within this subgroup, OS was similar with or without the use of radiation therapy.

Larger prospective studies will be necessary to fully elucidate the safety of omitting cranial radiation therapy in CNS3 patients.

CNS Therapy Options Under Clinical Evaluation

Information about NCI-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following are examples of national and/or institutional clinical trials that are currently being conducted:

  1. SJCRH Total XVII study (TOT17; NCT03117751) (Combination Chemotherapy in Treating Patients With ALL or Lymphoma): Patients receive both intrathecal chemotherapy and high-dose methotrexate without radiation therapy. Certain patients with high-risk features receive intensified intrathecal therapy.
  2. DFCI ALL 16-001 (NCT03020030) (Risk Classification Schemes in Identifying Better Treatment Options for Children and Adolescents With ALL): Only patients with CNS3 status at diagnosis (<5% of patients) receive cranial radiation therapy (18 Gy). All other patients receive intrathecal chemotherapy and high-dose methotrexate without radiation therapy. T-ALL patients receive extra doses of intrathecal chemotherapy during the continuation phase.

Toxicity of CNS-Directed Therapy

Toxic effects of CNS-directed therapy for childhood ALL can be acute and subacute or late developing. (Refer to the Late Effects of the Central Nervous System section in the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.)

Acute and subacute toxicities

The most common acute side effect associated with intrathecal chemotherapy alone is seizures. Up to 5% of nonirradiated patients with ALL treated with frequent doses of intrathecal chemotherapy will have at least one seizure during therapy.[12] Higher rates of seizure were observed with consolidation regimens that included 12 courses of intermediate-dose intravenous (IV) methotrexate (1 g/m2) given every 2 weeks with intrathecal chemotherapy.[29] Intrathecal and high-dose IV methotrexate have also been associated with a stroke-like syndrome, which, in most cases, appears to be reversible.[30]

Patients with ALL who develop seizures during the course of treatment and who receive anticonvulsant therapy should not receive phenobarbital or phenytoin as anticonvulsant treatment, as these drugs may increase the clearance of some chemotherapeutic drugs and adversely affect treatment outcome.[31] Gabapentin or valproic acid are alternative anticonvulsants with less enzyme-inducing capabilities.[31]

Late-developing toxicities

Late effects associated with CNS-directed therapies include subsequent neoplasms, neuroendocrine disturbances, leukoencephalopathy, and neurocognitive impairments.

Subsequent neoplasms are observed primarily in survivors who received cranial radiation therapy. Meningiomas are common and typically of low malignant potential, but high-grade lesions also occur. In a SJCRH retrospective study of more than 1,290 patients with ALL who had never relapsed, the 30-year cumulative incidence of a subsequent neoplasm occurring in the CNS was 3%; excluding meningiomas, the 30-year cumulative incidence was 1.17%.[32] Nearly all of these CNS subsequent neoplasms occurred in previously irradiated patients.

Neurocognitive impairments, which can range in severity and functional consequences, have been documented in long-term ALL survivors treated both with and without radiation therapy. In general, patients treated without cranial radiation therapy have less severe neurocognitive sequelae than irradiated patients, and the deficits that do develop represent relatively modest declines in a limited number of domains of neuropsychological functioning.[33,34,35,36] For patients who receive cranial radiation therapy, the frequency and severity of toxicities appear dose-related; patients treated with 18 Gy of cranial radiation therapy appear to be at lower risk of severe impairments compared with those treated with doses of 24 Gy or higher. Younger age at diagnosis and female sex have been reported in many studies to be associated with a higher risk of neurocognitive late effects.[37]

Several studies have also evaluated the impact of other components of treatment on the development of late neurocognitive impairments. A comparison of neurocognitive outcomes of patients treated with methotrexate versus triple intrathecal chemotherapy showed no clinically meaningful difference.[24][Level of evidence: 3iiiC] Controversy exists about whether patients who receive dexamethasone have a higher risk of neurocognitive disturbances.[38] In a SJCRH study of nonirradiated long-term survivors, treatment with dexamethasone was associated with increased risk of impairments in attention and executive function.[39] Conversely, long-term neurocognitive testing in 92 children with a history of standard-risk ALL who had received either dexamethasone or prednisone during treatment did not demonstrate any meaningful differences in cognitive functioning based on corticosteroid randomization.[40]

Evidence (neurocognitive late effects of cranial radiation):

  1. A SJCRH study of 567 adult long-term survivors of childhood ALL underwent neurocognitive testing (mean time from diagnosis, 26 years).[39]
    • Patients treated with 24 Gy of cranial radiation therapy showed the highest rates of impairment. Up to one-third of these patients demonstrated impairments (defined as test scores 2 or more standard deviations below age-adjusted national norms) in attention, memory, processing speed, and executive function.
    • Significantly fewer patients who had received 18 Gy of cranial radiation therapy demonstrated severe impairments compared with those who had received 24 Gy. In general, there was no significant difference in rates of impairment between nonirradiated survivors and those who received 18 Gy of cranial radiation therapy; however, the 18-Gy group was at increased risk of academic problems.
    • In addition to being dose-related, the neurocognitive impact of cranial radiation therapy was also dependent on age at diagnosis, with higher frequency of impairments in patients diagnosed at a younger age.
  2. A study compared memory impairment in patients who received 18 Gy of cranial radiation therapy (n = 127) versus 24 Gy of cranial radiation therapy (n = 138).[41]
    • Long-term survivors who received 24 Gy, but not 18 Gy, of cranial radiation therapy demonstrated significant impairments in immediate and delayed memory.
  3. In a randomized trial comparing irradiated (at a dose of 18 Gy) and nonirradiated standard-risk ALL patients, the following was observed: [33][Level of evidence: 1iiC]
    • Cognitive function for both groups (assessed at a median of 6 years postdiagnosis) was in the average range, with only subtle differences noted between the groups in cognitive skills.
  4. In a randomized trial, hyperfractionated radiation therapy (at a dose of 18 Gy) did not decrease neurologic late effects when compared with conventionally fractionated radiation therapy; cognitive function for both groups was not significantly impaired.[42]

Evidence (neurocognitive late effects in nonirradiated patients):

  1. In the SJCRH long-term follow-up study of 567 adult long-term survivors, some nonirradiated patients also demonstrated neurocognitive impairments.[39]
    • The age-adjusted mean test scores for nonirradiated patients were very similar to that of expected national norms; however, approximately 15% of the nonirradiated survivors participating in this study demonstrated impairments in some domains, including attention, memory, processing speed, and executive function.
    • Despite the impairments noted on neurocognitive testing, overall, the educational attainment and employment status of the tested ALL survivors were similar to age- and sex-adjusted expected proportions using census data for the U.S. population.
  2. In a second study from SJCRH, patients enrolled on Total Study XV (which omitted cranial radiation therapy in all patients) underwent comprehensive neuropsychological assessments at induction, end of maintenance, and 2 years after completion of therapy.[43]
    • Neurocognitive function was largely age appropriate 2 years after completing therapy, without evidence of excess impairment on measures of intellectual functioning, academic abilities, learning, and memory. Problems with sustained attention were observed at an increased frequency in this population compared with normative expectations.
    • High-risk patients who received more intensive CNS-directed chemotherapy (including high-dose methotrexate and more doses of intrathecal chemotherapy) were at greater risk of difficulties in attention, processing speed, and academics.

References:

  1. Richards S, Pui CH, Gayon P, et al.: Systematic review and meta-analysis of randomized trials of central nervous system directed therapy for childhood acute lymphoblastic leukemia. Pediatr Blood Cancer 60 (2): 185-95, 2013.
  2. Mahmoud HH, Rivera GK, Hancock ML, et al.: Low leukocyte counts with blast cells in cerebrospinal fluid of children with newly diagnosed acute lymphoblastic leukemia. N Engl J Med 329 (5): 314-9, 1993.
  3. Bürger B, Zimmermann M, Mann G, et al.: Diagnostic cerebrospinal fluid examination in children with acute lymphoblastic leukemia: significance of low leukocyte counts with blasts or traumatic lumbar puncture. J Clin Oncol 21 (2): 184-8, 2003.
  4. Gajjar A, Harrison PL, Sandlund JT, et al.: Traumatic lumbar puncture at diagnosis adversely affects outcome in childhood acute lymphoblastic leukemia. Blood 96 (10): 3381-4, 2000.
  5. Pullen J, Boyett J, Shuster J, et al.: Extended triple intrathecal chemotherapy trial for prevention of CNS relapse in good-risk and poor-risk patients with B-progenitor acute lymphoblastic leukemia: a Pediatric Oncology Group study. J Clin Oncol 11 (5): 839-49, 1993.
  6. Thyss A, Suciu S, Bertrand Y, et al.: Systemic effect of intrathecal methotrexate during the initial phase of treatment of childhood acute lymphoblastic leukemia. The European Organization for Research and Treatment of Cancer Children's Leukemia Cooperative Group. J Clin Oncol 15 (5): 1824-30, 1997.
  7. Rizzari C, Lanvers-Kaminsky C, Valsecchi MG, et al.: Asparagine levels in the cerebrospinal fluid of children with acute lymphoblastic leukemia treated with pegylated-asparaginase in the induction phase of the AIEOP-BFM ALL 2009 study. Haematologica 104 (9): 1812-1821, 2019.
  8. Bostrom BC, Sensel MR, Sather HN, et al.: Dexamethasone versus prednisone and daily oral versus weekly intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the Children's Cancer Group. Blood 101 (10): 3809-17, 2003.
  9. Matloub Y, Bostrom BC, Hunger SP, et al.: Escalating intravenous methotrexate improves event-free survival in children with standard-risk acute lymphoblastic leukemia: a report from the Children's Oncology Group. Blood 118 (2): 243-51, 2011.
  10. Asselin BL, Devidas M, Wang C, et al.: Effectiveness of high-dose methotrexate in T-cell lymphoblastic leukemia and advanced-stage lymphoblastic lymphoma: a randomized study by the Children's Oncology Group (POG 9404). Blood 118 (4): 874-83, 2011.
  11. Pui CH, Howard SC: Current management and challenges of malignant disease in the CNS in paediatric leukaemia. Lancet Oncol 9 (3): 257-68, 2008.
  12. Pui CH, Campana D, Pei D, et al.: Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med 360 (26): 2730-41, 2009.
  13. Veerman AJ, Kamps WA, van den Berg H, et al.: Dexamethasone-based therapy for childhood acute lymphoblastic leukaemia: results of the prospective Dutch Childhood Oncology Group (DCOG) protocol ALL-9 (1997-2004). Lancet Oncol 10 (10): 957-66, 2009.
  14. Vora A, Andreano A, Pui CH, et al.: Influence of Cranial Radiotherapy on Outcome in Children With Acute Lymphoblastic Leukemia Treated With Contemporary Therapy. J Clin Oncol 34 (9): 919-26, 2016.
  15. Pui CH, Sandlund JT, Pei D, et al.: Improved outcome for children with acute lymphoblastic leukemia: results of Total Therapy Study XIIIB at St Jude Children's Research Hospital. Blood 104 (9): 2690-6, 2004.
  16. Tubergen DG, Gilchrist GS, O'Brien RT, et al.: Prevention of CNS disease in intermediate-risk acute lymphoblastic leukemia: comparison of cranial radiation and intrathecal methotrexate and the importance of systemic therapy: a Childrens Cancer Group report. J Clin Oncol 11 (3): 520-6, 1993.
  17. Conter V, Aricò M, Valsecchi MG, et al.: Extended intrathecal methotrexate may replace cranial irradiation for prevention of CNS relapse in children with intermediate-risk acute lymphoblastic leukemia treated with Berlin-Frankfurt-Münster-based intensive chemotherapy. The Associazione Italiana di Ematologia ed Oncologia Pediatrica. J Clin Oncol 13 (10): 2497-502, 1995.
  18. Möricke A, Reiter A, Zimmermann M, et al.: Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95. Blood 111 (9): 4477-89, 2008.
  19. Clarke M, Gaynon P, Hann I, et al.: CNS-directed therapy for childhood acute lymphoblastic leukemia: Childhood ALL Collaborative Group overview of 43 randomized trials. J Clin Oncol 21 (9): 1798-809, 2003.
  20. Moghrabi A, Levy DE, Asselin B, et al.: Results of the Dana-Farber Cancer Institute ALL Consortium Protocol 95-01 for children with acute lymphoblastic leukemia. Blood 109 (3): 896-904, 2007.
  21. Matloub Y, Lindemulder S, Gaynon PS, et al.: Intrathecal triple therapy decreases central nervous system relapse but fails to improve event-free survival when compared with intrathecal methotrexate: results of the Children's Cancer Group (CCG) 1952 study for standard-risk acute lymphoblastic leukemia, reported by the Children's Oncology Group. Blood 108 (4): 1165-73, 2006.
  22. Mitchell CD, Richards SM, Kinsey SE, et al.: Benefit of dexamethasone compared with prednisolone for childhood acute lymphoblastic leukaemia: results of the UK Medical Research Council ALL97 randomized trial. Br J Haematol 129 (6): 734-45, 2005.
  23. Vrooman LM, Stevenson KE, Supko JG, et al.: Postinduction dexamethasone and individualized dosing of Escherichia Coli L-asparaginase each improve outcome of children and adolescents with newly diagnosed acute lymphoblastic leukemia: results from a randomized study--Dana-Farber Cancer Institute ALL Consortium Protocol 00-01. J Clin Oncol 31 (9): 1202-10, 2013.
  24. Kadan-Lottick NS, Brouwers P, Breiger D, et al.: Comparison of neurocognitive functioning in children previously randomly assigned to intrathecal methotrexate compared with triple intrathecal therapy for the treatment of childhood acute lymphoblastic leukemia. J Clin Oncol 27 (35): 5986-92, 2009.
  25. Salzer WL, Burke MJ, Devidas M, et al.: Impact of Intrathecal Triple Therapy Versus Intrathecal Methotrexate on Disease-Free Survival for High-Risk B-Lymphoblastic Leukemia: Children's Oncology Group Study AALL1131. J Clin Oncol 38 (23): 2628-2638, 2020.
  26. Schrappe M, Reiter A, Ludwig WD, et al.: Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: results of trial ALL-BFM 90. German-Austrian-Swiss ALL-BFM Study Group. Blood 95 (11): 3310-22, 2000.
  27. Sirvent N, Suciu S, Rialland X, et al.: Prognostic significance of the initial cerebro-spinal fluid (CSF) involvement of children with acute lymphoblastic leukaemia (ALL) treated without cranial irradiation: results of European Organization for Research and Treatment of Cancer (EORTC) Children Leukemia Group study 58881. Eur J Cancer 47 (2): 239-47, 2011.
  28. Piette C, Suciu S, Bertrand Y, et al.: Long-term outcome evaluation of medium/high risk acute lymphoblastic leukaemia children treated with or without cranial radiotherapy in the EORTC 58832 randomized study. Br J Haematol 189 (2): 351-362, 2020.
  29. Mahoney DH, Shuster JJ, Nitschke R, et al.: Acute neurotoxicity in children with B-precursor acute lymphoid leukemia: an association with intermediate-dose intravenous methotrexate and intrathecal triple therapy--a Pediatric Oncology Group study. J Clin Oncol 16 (5): 1712-22, 1998.
  30. Bhojwani D, Sabin ND, Pei D, et al.: Methotrexate-induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia. J Clin Oncol 32 (9): 949-59, 2014.
  31. Relling MV, Pui CH, Sandlund JT, et al.: Adverse effect of anticonvulsants on efficacy of chemotherapy for acute lymphoblastic leukaemia. Lancet 356 (9226): 285-90, 2000.
  32. Hijiya N, Hudson MM, Lensing S, et al.: Cumulative incidence of secondary neoplasms as a first event after childhood acute lymphoblastic leukemia. JAMA 297 (11): 1207-15, 2007.
  33. Waber DP, Turek J, Catania L, et al.: Neuropsychological outcomes from a randomized trial of triple intrathecal chemotherapy compared with 18 Gy cranial radiation as CNS treatment in acute lymphoblastic leukemia: findings from Dana-Farber Cancer Institute ALL Consortium Protocol 95-01. J Clin Oncol 25 (31): 4914-21, 2007.
  34. Jansen NC, Kingma A, Schuitema A, et al.: Neuropsychological outcome in chemotherapy-only-treated children with acute lymphoblastic leukemia. J Clin Oncol 26 (18): 3025-30, 2008.
  35. Espy KA, Moore IM, Kaufmann PM, et al.: Chemotherapeutic CNS prophylaxis and neuropsychologic change in children with acute lymphoblastic leukemia: a prospective study. J Pediatr Psychol 26 (1): 1-9, 2001 Jan-Feb.
  36. Copeland DR, Moore BD, Francis DJ, et al.: Neuropsychologic effects of chemotherapy on children with cancer: a longitudinal study. J Clin Oncol 14 (10): 2826-35, 1996.
  37. von der Weid N, Mosimann I, Hirt A, et al.: Intellectual outcome in children and adolescents with acute lymphoblastic leukaemia treated with chemotherapy alone: age- and sex-related differences. Eur J Cancer 39 (3): 359-65, 2003.
  38. Waber DP, Carpentieri SC, Klar N, et al.: Cognitive sequelae in children treated for acute lymphoblastic leukemia with dexamethasone or prednisone. J Pediatr Hematol Oncol 22 (3): 206-13, 2000 May-Jun.
  39. Krull KR, Brinkman TM, Li C, et al.: Neurocognitive outcomes decades after treatment for childhood acute lymphoblastic leukemia: a report from the St Jude lifetime cohort study. J Clin Oncol 31 (35): 4407-15, 2013.
  40. Kadan-Lottick NS, Brouwers P, Breiger D, et al.: A comparison of neurocognitive functioning in children previously randomized to dexamethasone or prednisone in the treatment of childhood acute lymphoblastic leukemia. Blood 114 (9): 1746-52, 2009.
  41. Armstrong GT, Reddick WE, Petersen RC, et al.: Evaluation of memory impairment in aging adult survivors of childhood acute lymphoblastic leukemia treated with cranial radiotherapy. J Natl Cancer Inst 105 (12): 899-907, 2013.
  42. Waber DP, Silverman LB, Catania L, et al.: Outcomes of a randomized trial of hyperfractionated cranial radiation therapy for treatment of high-risk acute lymphoblastic leukemia: therapeutic efficacy and neurotoxicity. J Clin Oncol 22 (13): 2701-7, 2004.
  43. Jacola LM, Krull KR, Pui CH, et al.: Longitudinal Assessment of Neurocognitive Outcomes in Survivors of Childhood Acute Lymphoblastic Leukemia Treated on a Contemporary Chemotherapy Protocol. J Clin Oncol 34 (11): 1239-47, 2016.

Postinduction Treatment for Specific ALL Subgroups

T-ALL

Historically, patients with T-acute lymphoblastic leukemia (ALL) have had a worse prognosis than children with B-ALL. In a review of a large number of patients treated on Children's Oncology Group (COG) trials over a 15-year period, T-cell immunophenotype still proved to be a negative prognostic factor on multivariate analysis.[1] However, with current treatment regimens, outcomes for children with T-ALL are now approaching those achieved for children with B-ALL. For example, the Dana-Farber Cancer Institute ALL Consortium reported a 5-year event-free survival (EFS) rate of 81% and an OS rate of 90% for patients with T-ALL who were treated on two consecutive clinical trials between 2005 and 2015.[2] Another example is the COG trial for T-ALL (AALL0434 [NCT00408005]) that resulted in a 5-year EFS rate of 83.8% and an OS rate of 89.5%.[3]

Treatment options for T-ALL

Treatment options for T-ALL include the following:

  1. Chemotherapy and prophylactic cranial radiation therapy.

Evidence (chemotherapy and prophylactic cranial radiation therapy):

  1. Protocols of the former Pediatric Oncology Group (POG) treated children with T-ALL differently from children with B-ALL. The POG-9404 protocol for patients with T-ALL was designed to evaluate the role of high-dose methotrexate. The multiagent chemotherapy regimen for this protocol was based on the DFCI-87001 regimen.[4]
    • This POG study was the first clinical trial to provide evidence that high-dose methotrexate can improve outcome for children with T-ALL (10-year EFS rates, 78% with high-dose methotrexate vs. 68% without high-dose methotrexate). High-dose asparaginase, doxorubicin, and prophylactic cranial irradiation were also important components of this regimen.[5,6]
  2. In the POG-9404 study, patients were randomly assigned to receive doxorubicin with or without dexrazoxane to determine the efficacy of dexrazoxane in preventing late cardiac mortality.[7][Level of evidence: 1iiDi]
    • There was no difference in EFS between patients with T-ALL who were treated with dexrazoxane and patients who were not treated with dexrazoxane (cumulative doxorubicin dose, 360 mg/m2).[7]
    • The frequency of grade 3 and grade 4 toxicities that occurred during therapy was similar between the randomized groups, and there was no difference in cumulative incidence of second malignant neoplasms. Three years after initial diagnosis, left ventricular shortening fraction and left ventricular wall thickness were both significantly worse in patients who received doxorubicin alone than in patients who received dexrazoxane, indicating that dexrazoxane was cardioprotective.[7]
    • With combined data from three COG trials that randomized dexrazoxane with doxorubicin therapy (P9404, P9425, and P9426) and had a median follow-up of 12.6 years, dexrazoxane did not appear to compromise long-term survival.[8][Level of evidence: 1iiA]
  3. On protocols of the former Children's Cancer Group (CCG), children with T-ALL received the same treatment regimens as did children with B-ALL; protocol and treatment assignment were based on the patients' clinical characteristics (e.g., age and white blood cell [WBC] count) and the disease response to initial therapy. Most children with T-ALL met National Cancer Institute (NCI) high-risk criteria.
    • Results from the CCG-1961 trial for high-risk ALL, which included patients with T-ALL, showed that an augmented Berlin-Frankfurt-Münster (BFM) regimen with a single delayed intensification course produced the best results for patients with morphologic rapid response to initial induction therapy (estimated 5-year EFS rate, 83%).[9,10] With this approach, patients with a presenting WBC count greater than 200,000 had similar outcomes to those with a WBC count of less than 200,000.[11][Level of evidence: 1iiDi]
    • Overall results from POG-9404 and CCG-1961 were similar, although POG-9404 used a higher cumulative dose of anthracyclines and cranial radiation therapy for every patient, while CCG-1961 used cranial radiation therapy only for patients with slow morphologic response.[10,5]
    • Among children with NCI standard-risk T-ALL, the 7-year EFS rates for those treated on CCG-1952, COG-1991, and POG-9404 were comparable with the CCG regimens that used significantly less anthracycline in a less intensive chemotherapy backbone without the prophylactic cranial irradiation included in POG-9404.[12]
  4. In the COG, children with T-ALL are not treated on the same protocols as children with B-ALL.
    1. Pilot studies from the COG have demonstrated the feasibility of incorporating nelarabine (a nucleoside analog with demonstrated activity in patients with relapsed and refractory T-cell lymphoblastic disease) in the context of a BFM regimen for patients with newly diagnosed T-ALL.[13,14,15]
      • The pilot study showed a 5-year EFS rate of 73% for all patients who received nelarabine and 69% for those patients with a slow early response.[16]
    2. The COG AALL0434 (NCT00408005) trial enrolled 1,562 evaluable patients aged 1 to 31 years with T-ALL. Patients received an augmented BFM regimen and were randomly assigned to receive either high-dose methotrexate with leucovorin rescue or escalating methotrexate without leucovorin (Capizzi).[3] Intermediate-risk and high-risk patients were also randomly assigned to receive either six courses of nelarabine during postinduction treatment or no nelarabine.[17] Nearly all patients received either prophylactic (12 Gy) or therapeutic (18 Gy) cranial irradiation; only 10% of patients considered to be low risk were not irradiated. Patients assigned to the Capizzi methotrexate arm received cranial radiation therapy earlier than did patients assigned to the high-dose methotrexate arm (week 8 vs. week 26). Patients on the Capizzi methotrexate arm also received two additional doses of pegaspargase. Results were as follows:[3,17]
      • The overall 5-year EFS rate was 83.8%, and the OS rate was 89.5%.
      • Results indicated a better DFS for patients who were randomly assigned to the Capizzi arm (5-year DFS rate, 91.5%) than for patients randomly assigned to the high-dose methotrexate arm (5-year DFS rate, 85.3%; P = .005).
      • For intermediate-risk and high-risk patients, treatment with nelarabine was associated with a superior outcome (5-year DFS rate, 88.2% with nelarabine vs. 82.1% without nelarabine; P = .029). The 5-year cumulative incidence of central nervous system (CNS) relapse was significantly lower for patients treated with nelarabine (1.3% vs. 6.9% in the no-nelarabine arm).
      • The best outcome for intermediate-risk and high-risk patients was observed in those randomly assigned to both the Capizzi and nelarabine arms (5-year DFS rate, 91.4%), and the worst outcome was observed in patients randomly assigned to receive high-dose methotrexate and no nelarabine (5-year DFS rate, 78.1%).
      • Patients with initial induction failure (M3 marrow at day 29, n = 43) were nonrandomly assigned to receive high-dose methotrexate and nelarabine; 20 of these patients were removed from the protocol therapy to undergo allogeneic HSCT in CR1. The overall 5-year EFS rate for induction-failure patients was 53%, with no difference in outcomes between HSCT and chemotherapy.

The use of prophylactic cranial radiation therapy in the treatment of patients with T-ALL is declining. Some groups, such as St. Jude Children's Research Hospital (SJCRH) and the Dutch Childhood Oncology Group (DCOG), do not use cranial radiation therapy in first-line treatment of ALL, and other groups, such as DFCI, COG, and BFM, are now limiting radiation therapy to patients with very high-risk features or CNS3 disease.

Treatment options under clinical evaluation for T-ALL

Information about NCI-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Infants With ALL

Infant ALL is uncommon, representing approximately 2% to 4% of cases of childhood ALL.[18] Because of their distinctive biological characteristics and their high risk of leukemia recurrence, infants with ALL are treated on protocols specifically designed for this patient population. Common therapeutic themes of the intensive chemotherapy regimens used to treat infants with ALL are the inclusion of postinduction intensification courses with high doses of cytarabine and methotrexate.[19,20,21,22]

Infants diagnosed within the first few months of life have a particularly poor outcome. In one study, patients diagnosed within 1 month of birth had a 2-year OS rate of 20%.[23][Level of evidence: 2A] In another study, the 5-year EFS rate for infants diagnosed at younger than 90 days was 16%.[21][Level of evidence: 2A]

For infants with KMT2A (MLL) gene rearrangements, the EFS rates at 4 to 5 years continue to be in the 35% range.[19,20,21,24][Level of evidence: 2A] Factors predicting poor outcome for infants with KMT2A rearrangements include the following:[20,21]; [25][Level of evidence: 3iDii]; [26][Level of evidence: 2A]

  • Younger age at diagnosis (≤90–180 days).
  • Extremely high presenting leukocyte count (≥200,000–300,000/μL).
  • Poor early response, as reflected by a poor response to a prednisone prophase or high levels of minimal residual disease (MRD) at the end of induction and consolidation phases of treatment.

Infants have significantly higher relapse rates than older children with ALL and are at higher risk of developing treatment-related toxicity, especially infection. With current treatment approaches for this population, treatment-related mortality has been reported to occur in about 10% of infants, a rate that is much higher than the rate in older children with ALL.[20,21] On the COG AALL0631 (NCT00557193) trial, an intensified induction regimen resulted in an induction death rate of 15.4% (4 of 26 patients); the trial was subsequently amended to include a less-intensive induction and enhanced supportive care guidelines, resulting in a significantly lower induction death rate (1.6%; 2 of 123 patients) and significantly higher complete remission (CR) rate (94% vs. 68% with the previous, more intensified induction regimen).[27]

Treatment options for infants withKMT2Arearrangements

Infants with KMT2A gene rearrangements are generally treated on intensified chemotherapy regimens using agents not typically incorporated into frontline therapy for older children with ALL. However, despite these intensified approaches, EFS rates remain poor for these patients.

Evidence (intensified chemotherapy regimens for infants with KMT2A rearrangements):

  1. The international Interfant-99 trial utilized a cytarabine-intensive chemotherapy regimen, with increased exposure to both low- and high-dose cytarabine during the first few months of therapy.[20]
    • The 5-year EFS rate was 37% for infants with KMT2A rearrangements.
  2. The COG tested intensification of therapy with a regimen that included multiple doses of high-dose methotrexate, cyclophosphamide, and etoposide.[19]
    • The 5-year EFS rate was 34% for infants with KMT2A rearrangements.
  3. On the COG P9407 (NCT00002756) trial, infants were treated with a shortened (46-week) intensive chemotherapy regimen.[21][Level of evidence: 2A]
    • The 5-year EFS rate was 36% for infants with KMT2A rearrangements.
  4. The international Interfant-06 study tested whether acute myeloid leukemia (AML)-style consolidation chemotherapy was superior to ALL-style chemotherapy.[26][Level of evidence: 2A]
    • The 6-year EFS rate was 46.1%, and the OS rate was 58.2%; these rates were not statistically different from the rates observed in the predecessor Interfant-99 protocol.
    • For infants with KMT2A rearrangements, the 6-year EFS rate was 36.4%, with no significant difference between the AML and ALL approach.
    • In a subsequent analysis of the subset of KMT2A-rearranged patients in whom MRD was evaluated, both end-of-induction (EOI) and end-of-consolidation (EOC) MRD were strongly predictive of outcome. Patients who were EOI MRD positive, but became EOC MRD negative, had similar outcomes to those who were EOI MRD negative (6-year DFS rates, 65.7% and 72.0%, respectively), while those with high EOC MRD had dismal outcomes (6-year DFS rate, 13.1%). Patients with negative EOI MRD had a higher 6-year DFS rate when treated with the ALL approach (78.2%) than did patients who were treated with the AML approach (45%). However, patients with high EOI MRD (≥5 × 10-4) who were treated with an AML approach had a superior 6-year DFS rate (45.9%) when compared with patients who were treated with the ALL approach (23.2%).[28][Level of evidence: 1iiDii]
  5. On the MLL-10 trial conducted by the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG), infants with KMT2A rearrangements were treated with an intensified chemotherapy backbone that included multiple phases using high-dose methotrexate, cyclophosphamide, etoposide, and high-dose cytarabine. Patients classified as high-risk on the basis of age and CNS status (75% of KMT2A-rearranged patients) were allocated to hematopoietic stem cell transplantation (HSCT) in first CR.[22]
    • The 5-year EFS rate was 66%, and the 5-year OS rate was 82%.

The role of allogeneic HSCT during first remission in infants with KMT2A gene rearrangements remains controversial.

Evidence (allogeneic HSCT in first remission for infants with KMT2A rearrangements):

  1. On a trial conducted by the JPLSG between 1998 and 2002, all infants with KMT2A rearrangements were intended to proceed to allogeneic HSCT from the best available donor (related, unrelated, or umbilical cord) 3 to 5 months after diagnosis.[29]
    • The 3-year EFS rate for all enrolled infants was 44%. This outcome resulted, in part, from the high frequency of early relapses, even with intensive chemotherapy; of the 41 infants with KMT2A rearrangements on that study who achieved CR, 11 infants (27%) relapsed before proceeding to transplant.
  2. In a follow-up trial conducted by the JPLSG between 2011 and 2015, allocation to HSCT in first CR was restricted to the patients with KMT2A rearrangements and classified as high risk (age <6 months and/or CNS3 status at diagnosis).[22]
    • Of the 56 patients that were classified as high risk (75% of all KMT2A-rearranged patients enrolled on the trial), 49 achieved CR, and 38 underwent HSCT.
    • In an intent-to-treat analysis of all high-risk patients enrolled on the trial, the 5-year EFS rate was 56.6%.
    • For the subset of patients who also met Interfant-06 criteria for high risk (age <6 months and WBC >300,000/µL or a prednisolone poor responder), the 5-year EFS rate was 45.2%.
  3. In a COG report that included 189 infants treated on CCG or POG infant ALL protocols between 1996 and 2000, there was no difference in EFS between patients who underwent HSCT in first CR and those who received chemotherapy alone.[30]
  4. The Interfant clinical trials group, after adjusting for waiting time to transplantation, also did not observe any difference in DFS in high-risk infants (defined by prednisone response) with KMT2A rearrangements treated on the Interfant-99 trial with either allogeneic HSCT in first CR or chemotherapy alone.[20]
    • In a subset analysis from the same trial, allogeneic HSCT in first remission was associated with a significantly better DFS for infants with KMT2A rearrangements who were younger than 6 months at diagnosis and had either a poor prednisone response at day 8 or leukocyte counts of at least 300,000/µL.[31] In this subset, HSCT in first remission was associated with a 64% reduction in the risk of failure resulting from relapse or death compared with chemotherapy alone.
  5. On the Interfant-06 study, infants considered to be high risk (all of the following: KMT2A rearrangements, age <6 months, and WBC ≥300,000/μL) were considered eligible for allogeneic HSCT in first CR.[26][Level of evidence: 2A]
    • About one-half of the high-risk patients did not proceed to transplant in the first CR primarily because of early relapse.
    • The 6-year EFS rate of the entire high-risk group was 21%.
    • For the highly-selected population who were transplanted, the 4-year DFS rate was 44%.

For infants with ALL who undergo transplantation in first CR, outcomes appear to be similar with non–total-body irradiation (TBI) regimens and TBI-based regimens.[30,32]

Treatment options for infants withoutKMT2Arearrangements

The optimal treatment for infants without KMT2A rearrangements also remains unclear, in part because of the paucity of data on the use of standard ALL regimens used in older children.

  1. On the Interfant-99 trial, patients without KMT2A rearrangements achieved a relatively favorable outcome with the cytarabine-intensive treatment regimen (4-year EFS rate was 74%).[20]
  2. The COG P9407 (NCT00002756) trial of intensified chemotherapy reported a 70% 5-year EFS rate in infants without the KMT2A rearrangement.[21][Level of evidence: 2A]
  3. A favorable outcome for this subset of patients was obtained in a Japanese study using therapy comparable to that used to treat older children with ALL;[24] however, that study was limited by small numbers (n = 22) and a highly unusual sex distribution (91% males).
  4. On the Interfant-06 study, the 6-year EFS rate for infants without KMT2A rearrangements was 73.9%, and the OS rate was 87.2%.[26][Level of evidence: 2A]

Treatment options under clinical evaluation for infants with ALL

Information about NCI-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following is an example of a national and/or institutional clinical trial that is currently being conducted:

  1. AALL15P1 (NCT02828358) (Azacitidine and Combination Chemotherapy in Treating Infants with ALL and KMT2A Gene Rearrangement): This COG protocol is a nonrandomized pilot study that is testing the feasibility of adding azacitidine (a DNA demethylating agent) to the Interfant chemotherapy backbone. Patients younger than 12 months with newly diagnosed B-cell ALL or acute leukemia of ambiguous lineage are eligible for enrollment. Patients begin treatment with a 4-week multiagent induction phase. Following induction, infants without KMT2A rearrangements discontinue therapy at the end of the induction phase, while infants with KMT2A rearrangements continue on the study, receiving four 5-day courses of azacitidine therapy, as epigenetic priming, just before each major block of postinduction chemotherapy on the Interfant chemotherapy backbone. The primary objective of this trial is to determine whether azacitidine can be safely incorporated into the Interfant chemotherapy backbone.

Adolescents and Young Adults With ALL

Adolescents and young adults with ALL have been recognized as high risk for decades. Outcomes in almost all studies of treatment are inferior in this age group compared with children younger than 10 years.[33,34,35] The reasons for this difference include more frequent presentation of adverse prognostic factors at diagnosis, including the following:

  • T-cell immunophenotype.
  • Philadelphia chromosome–positivity (Ph+) and Ph-like (BCR-ABL1-like) disease.
  • Lower incidence of favorable cytogenetic abnormalities.

In addition to more frequent adverse prognostic factors, patients in this age group have higher rates of treatment-related mortality [34,35,36,37] and nonadherence to therapy.[36,38]

Treatment options for adolescents and young adults with ALL

Studies from the United States and France were among the first to identify the difference in outcome based on treatment regimens.[39] Other studies have confirmed that older adolescent and young adult patients fare better on pediatric rather than adult regimens.[39,40,41,42,43,44,45,46,47]; [48][Level of evidence: 2A] These study results are summarized in Table 12.

Given the relatively favorable outcome that can be obtained in these patients with chemotherapy regimens used for high-risk pediatric ALL, there is no role for the routine use of allogeneic HSCT for adolescents and young adults with ALL in first remission.[35]

Evidence (use of a pediatric treatment regimen for adolescents and young adults with ALL):

  1. The CALGB-10403 (NCT00558519) trial prospectively studied the feasibility and efficacy of using a pediatric treatment regimen (administered by medical oncologists) for adolescent and young adult patients with newly diagnosed ALL. Of the 318 patients enrolled, 295 were eligible and evaluable for response. The median age was 24 years (range, 17–39 years).[47,49]
    • Use of the pediatric regimen (from the COG AALL0232 study, which included escalating doses of methotrexate without leucovorin followed by asparaginase) was deemed safe, and the overall treatment-related mortality was 3%.
    • The median EFS was 78.1 months, which is more than double the historical control of 30 months. The 3-year EFS rate was 59%, and the median OS was not reached. The estimated 3-year OS rate was 73%.
    • Pretreatment risk factors associated with a worse outcome were obesity and the presence of the Ph-like expression signature. Of the evaluable patients, 31% had a Ph-like fusion; these patients had a significantly worse outcome, with a 3-year EFS rate of 42%, compared with an EFS rate of 69% for patients without the fusion (hazard ratio, 2.06; log-rank P = .008).
  2. Investigators reported on 197 patients aged 16 to 21 years treated on the CCG study (a pediatric ALL regimen) compared with 124 adolescents and young adults treated on the Cancer and Leukemia Group B (CALGB) study (an adult ALL regimen).[39]
    • For the patients treated with a pediatric ALL regimen, the 7-year EFS rate was 63%.
    • For the patients treated with an adult ALL regimen, the 7-year EFS rate was 34%.
  3. In a Canadian population-based cohort study, the effect of adapting pediatric protocols for adolescent and young adult patients with ALL was determined over a 20-year period.[50]
    • The 5-year EFS rate of adolescent and young adult patients treated at pediatric centers was 72%, compared with an EFS rate of 56% for adolescent and young adult patients treated at adult centers (P = .03).
    • In the most recent period (2006–2011), the outcome of adolescent and young adult patients treated at adult centers with pediatric protocols was superior to those treated with adult protocols (EFS rate, 72% vs. 60%), but inferior to adolescent and young adult patients treated at pediatric centers (EFS rate, 81%; P = .02).
    • The authors conclude that besides protocol therapy, there may be other differences between adult and pediatric centers that may explain the disparate outcomes.

The reason that adolescents and young adults achieve superior outcomes with pediatric regimens is not known, although possible explanations include the following:[40]

  • Treatment setting (i.e., site experience in treating ALL).
  • Adherence to protocol therapy.[38]
  • The components of protocol therapy.
Table 12. Outcome According to Treatment Protocol for Adolescents and Young Adults with ALL
Site and Study Group Adolescent and Young Adult Patients (No.) Median age (y) Survival (%)
ALL = acute lymphoblastic leukemia; EFS = event-free survival; OS = overall survival.
AIEOP = Associazione Italiana di Ematologia e Oncologia Pediatrica; CALGB = Cancer and Leukemia Group B; CCG = Children's Cancer Group; DCOG = Dutch Childhood Oncology Group; FRALLE = French Acute Lymphoblastic Leukaemia Study Group; GIMEMA = Gruppo Italiano Malattie EMatologiche dell'Adulto; HOVON = Dutch-Belgian Hemato-Oncology Cooperative Group; LALA = France-Belgium Group for Lymphoblastic Acute Leukemia in Adults; MRC = Medical Research Council (United Kingdom); NOPHO = Nordic Society for Pediatric Hematology and Oncology; UKALL = United Kingdom Acute Lymphoblastic Leukaemia.
United States[39]
CCG (Pediatric) 197 16 67, OS 7 y
CALGB (Adult) 124 19 46
France[44]
FRALLE 93 (Pediatric) 77 16 67 EFS
LALA 94 100 18 41
Italy[51]
AIEOP (Pediatric) 150 15 80, OS 2 y
GIMEMA (Adult) 95 16 71
Netherlands[52]
DCOG (Pediatric) 47 12 71 EFS
HOVON 44 20 38
Sweden[53]
NOPHO 92 (Pediatric) 36 16 74, OS 5 y
Adult ALL 99 18 39
United Kingdom[42]
MRC ALL (Pediatric) 61 15–17 71, OS 5 y
UKALL XII (Adult) 67 15–17 56
UKALL 2003[54] 229 16–24 72 EFS

Osteonecrosis

Adolescents with ALL appear to be at higher risk than younger children for developing therapy-related complications, including osteonecrosis, deep venous thromboses, and pancreatitis.[41,55,56] Before the use of postinduction intensification for treatment of ALL, osteonecrosis was infrequent. The improvement in outcome for children and adolescents aged 10 years and older was accompanied by an increased incidence of osteonecrosis.

The weight-bearing joints are affected in 95% of patients who develop osteonecrosis and operative interventions were needed for management of symptoms and impaired mobility in more than 40% of cases. Most cases are diagnosed within the first 2 years of therapy and the symptoms are often recognized during maintenance.

Evidence (osteonecrosis):

  1. In the CCG-1961 high-risk ALL study, alternate-week dosing of dexamethasone was compared with standard continuous dexamethasone during delayed intensification to determine whether the osteonecrosis risk could be reduced.[55]
    • The median age at symptom onset was 16 years.
    • The cumulative incidence was higher in adolescents and young adults aged 16 to 21 years (20% at 5 years) than in those aged 10 to 15 years (9.9%) or in patients aged 1 to 9 years (1%).
    • Operative interventions were needed for management of symptoms and impaired mobility in more than 40% of cases.
    • The use of alternate-week dosing of dexamethasone as compared with standard continuous dexamethasone during delayed intensification in CCG-1961 reduced the risk of osteonecrosis. The greatest impact was seen in females aged 16 to 21 years, who showed the highest incidence of osteonecrosis with standard therapy containing continuous dexamethasone; osteonecrosis was reduced with alternate-week dexamethasone postinduction (57.6% to 5.6%).
  2. In the COG AALL0232 (NCT00075725) high-risk ALL trial, patients were randomly assigned during induction to receive either 14 days of dexamethasone or 28 days of prednisone.[57]
    • The incidence of osteonecrosis in patients older than 10 years who received dexamethasone was 24.3%, compared with an incidence of 15.9% in those who received prednisone (P = .001)
    • Efficacy and other toxicities were comparable in the two arms.

Treatment options under clinical evaluation for adolescent and young adult patients with ALL

Information about NCI-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following are examples of national and/or institutional clinical trials that are currently being conducted:

  1. A041501 (NCT03150693) (Inotuzumab Ozogamicin and Frontline Chemotherapy in Treating Young Adults With Newly Diagnosed B-cell ALL): This is a National Clinical Trials Network trial to further expand on the experience of using a pediatric-inspired chemotherapy backbone in young adults with ALL. Eligibility includes patients aged 18 to 39 years with newly diagnosed CD22-positive ALL. Patients who are in remission after induction will be randomly assigned to receive the pediatric backbone either with or without two courses of inotuzumab ozogamicin (a toxin-conjugated anti-CD22 monoclonal antibody) before starting consolidation therapy.
  2. COG-AALL1521 (NCT02723994) (A Phase II Study of Ruxolitinib With Chemotherapy in Children With ALL): This is a nonrandomized study of ruxolitinib in combination with a standard multiagent chemotherapy regimen for the treatment of B-ALL. Part 1 of the study will optimize the dose of study drug (ruxolitinib) in combination with the chemotherapy regimen. Part 2 will evaluate the efficacy of combination chemotherapy and ruxolitinib at the recommended dose determined in part 1.
  3. COG-AALL1721 (NCT03876769) (Study of Efficacy and Safety of Tisagenlecleucel in High-Risk B-ALL End-of-Consolidation MRD-Positive Patients): The objective of the study is to evaluate the efficacy of CD19 chimeric antigen receptor (CAR) T-cell therapy (tisagenlecleucel) in patients who are MRD positive at the end of consolidation by measuring 5-year EFS. Other objectives include assessing proportion of subjects who are disease free without allogeneic transplant at 1 year, OS, and proportion of subjects who achieve MRD-negative CR or CRI at 3 months after tisagenlecleucel.
  4. COG-AALL1731 (NCT03914625) (A Study to Determine the Outcomes of Patients With Localized B-Cell Lymphoblastic Lymphoma When Treated With Standard-Risk B-ALL Therapy): This study will test whether the addition of blinatumomab to standard chemotherapy will improve DFS. All Down syndrome patients (including adolescent and young adult patients aged <31 years) are eligible for enrollment. Patients with Down syndrome and high-risk features will be nonrandomly assigned to receive blinatumomab added to a chemotherapy backbone that omits intensive elements of therapy. Patients with Down syndrome without high-risk features will be eligible for randomization to chemotherapy with or without blinatumomab. Patients with Murphy stage I and stage II B-cell lymphoblastic lymphoma will receive standard B-ALL therapy without blinatumomab.
  5. COG-AALL1732 (NCT03959085) (A Phase III Randomized Trial of Inotuzumab Ozogamicin for Newly Diagnosed High-Risk B-ALL; Risk-Adapted Postinduction Therapy for High-Risk B-ALL, Mixed Phenotype Acute Leukemia [MPAL], and Disseminated B-Lymphoblastic Lymphoma): This protocol is open for patients younger than 25 years at diagnosis who meet any of the following diagnoses: NCI high-risk non-Down syndrome B-ALL, MPAL, and disseminated B-lymphoblastic lymphoma. For patients with B-ALL, the protocol is testing whether the addition of two blocks of inotuzumab ozogamicin to a modified-BFM backbone will improve DFS. For patients with MPAL and disseminated B-lymphoblastic lymphoma, the study aims to determine the EFS associated with treatment using a standard high-risk B-ALL modified-BFM backbone.

Philadelphia Chromosome–positive (BCR-ABL1–positive) ALL

Philadelphia chromosome–positive (Ph+) ALL is seen in about 3% of pediatric ALL cases, increases in adolescence, and is seen in 15% to 25% of adults. In the past, this subtype of ALL has been recognized as extremely difficult to treat with a poor outcome. In 2000, an international pediatric leukemia group reported a 7-year EFS rate of 25%, with an OS rate of 36%.[58] In 2010, the same group reported a 7-year EFS rate of 31% and an OS rate of 44% in Ph+ ALL patients treated without tyrosine kinase inhibitors.[59] Treatment of this subgroup has evolved from emphasis on aggressive chemotherapy, to bone marrow transplantation, and currently to combination therapy using chemotherapy plus a tyrosine kinase inhibitor.

Treatment options for patients with Ph+ ALL

Standard therapy for patients with Ph+ ALL includes the use of a tyrosine kinase inhibitor (e.g., imatinib or dasatinib) in combination with cytotoxic chemotherapy, with or without allogeneic HSCT in first CR.

Imatinib mesylate is a selective inhibitor of the BCR-ABL protein kinase. Phase I and phase II studies of single-agent imatinib in children and adults with relapsed or refractory Ph+ ALL have demonstrated relatively high response rates, although these responses tended to be of short duration.[60,61]

Clinical trials in adults and children with Ph+ ALL have demonstrated the feasibility of administering imatinib mesylate in combination with multiagent chemotherapy.[62,63,64] Patients with Ph+ ALL demonstrated a better outcome after HSCT if imatinib was given before or after transplant.[65,66,67,68,69] Clinical trials have also demonstrated that many pediatric patients with Ph+ ALL will have a comparable EFS using chemotherapy and a tyrosine kinase inhibitor than with transplant.[69,70]

Dasatinib, a second-generation inhibitor of tyrosine kinases, has also been studied in the treatment of Ph+ ALL. Dasatinib has shown significant activity in the CNS, both in a mouse model and a series of patients with CNS-positive leukemia.[71] The results of a phase I trial of dasatinib in pediatric patients indicated that once-daily dosing was associated with an acceptable toxicity profile, with few nonhematologic grade 3 or grade 4 adverse events.[72]

Evidence (tyrosine kinase inhibitor):

  1. A retrospective study of 30 pediatric patients with Ph+ ALL (19 patients treated between 1991–2004 without a tyrosine kinase inhibitor, and 11 patients treated between 2004–2012 with either imatinib or dasatinib) indicated that tyrosine kinase inhibitors, when started midinduction, were associated with lower end-induction MRD.[73]
  2. The COG-AALL0031 study evaluated whether imatinib mesylate could be incorporated into an intensive chemotherapy regimen for children with Ph+ ALL. Patients received imatinib mesylate in conjunction with chemotherapy during postinduction therapy. Some children proceeded to allogeneic HSCT after two cycles of consolidation chemotherapy with imatinib mesylate, while other patients received imatinib mesylate in combination with chemotherapy throughout all treatment phases.[64,69]
    • The 5-year DFS rate for the 25 patients who received intensive chemotherapy with continuous dosing of imatinib mesylate was 70% (± 12%). These patients fared better than historic controls who were treated with chemotherapy alone (without imatinib mesylate), and at least as well as the other patients on the trial who underwent allogeneic transplantation. The 5-year DFS rate was 66% for patients who underwent sibling-donor transplant (n = 21) and 59% for those who underwent unrelated donor transplant (n = 13).
    • Patients with additional cytogenetic abnormalities had worse outcomes (P = .05).
  3. The COG-AALL0622 (NCT00720109) study tested the use of dasatinib (instead of imatinib) combined with a chemotherapy backbone similar to that used in COG-AALL0031.[74][Level of evidence: 2A] On this trial, dasatinib was started on day 15 of induction, resulting in higher rates of CR and a higher proportion of patients with low end-induction MRD compared with AALL0031, on which imatinib was not started until after the induction phase was completed.
    • Outcomes in the two trials were similar: the 5-year OS rates were 81% and 86%, and the 5-year DFS rates were 68% and 60% for AALL0031 and AALL0622, respectively.
    • Excessive toxicity with dasatinib was not observed.
    • In a subset analysis that included patients who had diagnostic banked samples available, IKZF1 deletion was identified in 57% of patients and was associated with inferior EFS and OS.
  4. The EsPhALL2004 trial tested whether imatinib (administered discontinuously) given in the context of intensive chemotherapy improved outcome for pediatric Ph+ ALL patients, most of whom (80%) received an allogeneic HSCT in first CR. Patients were classified as either good risk or poor risk on the basis of early response measures and remission status at the end of induction. Good-risk patients (n = 90) were randomly assigned to receive imatinib or no imatinib; poor-risk patients (n = 70) were directly assigned to treatment with imatinib. Interpretation of this study is limited because of the high noncompliance rate with randomized assignment in good-risk patients and early closure before reaching goal accrual because of the publication of the results of the COG AALL0031 trial on which imatinib had been given continuously with chemotherapy.[70]
    • The overall DFS of patients treated on this trial appeared to be better than historic controls, and when analyzed as-treated (and not by intent-to-treat), good-risk patients who received imatinib had a superior DFS (4-year DFS rate was 75% for patients who received imatinib and 56% for patients who did not receive imatinib).[75]
  5. The subsequent EsPhALL2010 (NCT00287105) trial was a result of amendments to the 2004 trial, which included earlier initiation of imatinib therapy at day 15 of induction and continuous dosing of imatinib until the end of therapy or 1 year after transplant. A subsequent amendment in the trial also changed the indication for HSCT in first CR to only the poor-risk patients. This resulted in an increased rate of CR to 97% at the end of induction (from 78% in the previous trial) and fewer patients being allocated to HSCT (38% on amended trial vs. 81% on initial trial).[76]
    • The EFS and OS rates were similar between the amended trial and the initial trial, even though significantly fewer patients received HSCT in first CR on the amended trial.
    • The EsPhALL chemotherapy backbone combined with continuous dosing of imatinib was associated with a high rate of toxicity (primarily infections) and treatment-related mortality.
  6. The Chinese Children's Cancer Group ALL-2015 trial randomly assigned 189 patients to receive either dasatinib or imatinib combined with a multiagent regimen based on SJCRH ALL protocols. On this trial, dasatinib was administered at a higher dose (80 mg/m2 instead of 60 mg/m2) and imatinib was administered at a lower dose (300 mg/m2 instead of 340 mg/m2) than they were administered on previous pediatric Ph+ ALL trials conducted by other groups.[77][Level of evidence: 1iiA]
    • With a median follow-up of 26.4 months, the 4-year EFS and OS rates were 71% and 88.4%, respectively, for patients randomly assigned to receive dasatinib, compared with 48.9% and 69.2%, respectively, for patients randomly assigned to receive imatinib.
    • Toxicity was similar between the two treatment arms.
    • Caution is needed in interpreting these results because of the short median follow-up time and because the outcomes of patients who received imatinib on this trial were inferior to the outcomes of imatinib-treated patients reported in previous trials.

Treatment options under clinical evaluation for Ph+ ALL

Information about NCI-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following is an example of a national and/or institutional clinical trial that is currently being conducted:

  1. AALL1631 (NCT03007147) (Imatinib Mesylate and Combination Chemotherapy in Treating Patients with Newly Diagnosed Ph+ ALL): AALL1631 is an international collaborative protocol conducted by the COG and the European EsPhALL group. Ph+ ALL patients enter the trial at day 15 of induction IA and begin daily imatinib at that time. After the induction IB phase (weeks 10–12), MRD is assessed by immunoglobulin H/T-cell receptor (IgH-TCR) PCR, and patients are classified as standard risk (MRD <0.05%) or high risk (MRD >0.05%). Standard-risk patients are randomly assigned to receive one of the following two cytotoxic chemotherapy backbones:
    • The EsPhALL backbone used in previous EsPhALL protocols and COG AALL1122; or
    • A less-intensive regimen similar to those typically administered to non-Ph+ high-risk B-cell ALL patients on COG trials.

    Standard-risk patients on both arms will continue to receive imatinib until the completion of all planned chemotherapy (2 years of treatment). The objective of the standard-risk randomization is to determine whether the less-intensive chemotherapy backbone is associated with a similar DFS but lower rates of treatment-related toxicity compared with the standard therapy (EsPhALL chemotherapy backbone).

    High-risk patients (approximately 15%–20% of patients) will proceed to HSCT after completion of three consolidation blocks of chemotherapy. Imatinib will be restarted after HSCT and administered from day +56 until day +365 to test the feasibility of post-HSCT administration of this agent and describe the outcome of patients treated in this manner.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

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  49. Stock W, Luger SM, Advani AS, et al.: A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403. Blood 133 (14): 1548-1559, 2019.
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  55. Mattano LA, Devidas M, Nachman JB, et al.: Effect of alternate-week versus continuous dexamethasone scheduling on the risk of osteonecrosis in paediatric patients with acute lymphoblastic leukaemia: results from the CCG-1961 randomised cohort trial. Lancet Oncol 13 (9): 906-15, 2012.
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  57. Larsen EC, Devidas M, Chen S, et al.: Dexamethasone and High-Dose Methotrexate Improve Outcome for Children and Young Adults With High-Risk B-Acute Lymphoblastic Leukemia: A Report From Children's Oncology Group Study AALL0232. J Clin Oncol 34 (20): 2380-8, 2016.
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  61. Ottmann OG, Druker BJ, Sawyers CL, et al.: A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias. Blood 100 (6): 1965-71, 2002.
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Treatment of Relapsed Childhood ALL

Prognostic Factors After First Relapse of Childhood ALL

The prognosis for a child with acute lymphoblastic leukemia (ALL) whose disease recurs depends on multiple factors.[1,2,3,4,5,6,7,8,9,10,11,12,13,14]; [15][Level of evidence: 3iiDi]

The following two important risk factors after first relapse of childhood ALL are key to determining prognosis and treatment approach:

  • Site of relapse.
  • Time from diagnosis to relapse.

Other prognostic factors include the following:

  • Patient characteristics (e.g., age and peripheral blast count at time of relapse).
  • Risk group classification at initial diagnosis.
  • Response to reinduction therapy.
  • Cytogenetics/genomic alterations.
  • Immunophenotype.

Site of relapse

Patients who have isolated extramedullary relapse fare better than those who have relapse involving the marrow. In some studies, patients with combined marrow/extramedullary relapse had a better prognosis than did those with a marrow only relapse; however, other studies have not confirmed this finding.[5,13,16]

Time from diagnosis to relapse

For patients with relapsed B-ALL, early relapses fare worse than later relapses, and marrow relapses fare worse than isolated extramedullary relapses. For example, survival rates range from less than 20% for patients with marrow relapses occurring within 18 months from diagnosis to higher than 60% for those whose relapses occur more than 36 months from diagnosis.[5,13,17]

For patients with isolated central nervous system (CNS) relapses, the overall survival (OS) rates are 40% to 50% for early relapse (<18 months from diagnosis) and 75% to 80% for those with late relapses (>18 months from diagnosis).[13,18] No evidence exists that early detection of relapse by frequent surveillance (complete blood counts or bone marrow tests) in off-therapy patients improves outcome.[19]

Patient characteristics

Age 10 years and older at diagnosis and at relapse have been reported as independent predictors of poor outcome.[13,16] A Children's Oncology Group (COG) study further showed that although patients aged 10 to 15 years at initial diagnosis do worse than patients aged 1 to 9 years (35% vs. 48%, 3-year postrelapse survival), those older than age 15 years did much worse (3-year OS rate, 15%; P = .001).[20]

For patients with B-ALL who were diagnosed at age 18 years or younger and experienced a late relapse, age was not a significant predictor of subsequent outcome when analyzed by quartiles. However, the outcome for patients aged 18 years and older at time of relapse was significantly inferior to the outcome for patients relapsing at age younger than 18 years (39.5% vs. 68.7%; P = .0001).[21]

The Berlin-Frankfurt-Münster (BFM) group has also reported that high peripheral blast counts (>10,000/μL) at the time of relapse were associated with inferior outcomes in patients with late marrow relapses.[10]

Children with Down syndrome and ALL who relapse have generally had inferior outcomes resulting from increased induction deaths, treatment-related mortality, and relapse.

  • The BFM group showed that since 2000, improvements in supportive care have led to decreases in treatment-related mortality in children with Down syndrome, but the risk of relapse remains high.[22]
  • An analysis of data from the Center for International Blood and Marrow Transplant Research (CIBMTR) on 27 Down syndrome patients with ALL who underwent hematopoietic stem cell transplantation (HSCT) between 2000 and 2009 substantiated this finding. They noted that with current transplant practices, hematopoietic recovery, graft-versus-host disease (GVHD), and transplant-related mortality were within the expected range compared with non–Down syndrome ALL patients. However, relapse was higher than expected (>50%) and was the primary cause of treatment failure, leading to poor survival (24% disease-free survival [DFS] rate at 3 years).[23][Level of evidence: 3iiiA]

Risk group classification at initial diagnosis

The COG reported that risk group classification at the time of initial diagnosis was prognostically significant after relapse; patients who met National Cancer Institute (NCI) standard-risk criteria at initial diagnosis fared better after relapse than did NCI high-risk patients.[13]

Response to reinduction therapy

Patients with marrow relapses who have persistent morphologic disease at the end of the first month of reinduction therapy have an extremely poor prognosis, even if they subsequently achieve a second complete remission (CR).[24][Level of evidence: 2Di]; [25][Level of evidence: 3iiiA] Several studies have demonstrated that minimal residual disease (MRD) levels after the achievement of second CR are of prognostic significance in relapsed ALL.[21,24,26,27,28]; [29][Level of evidence: 3iiiDi] High levels of MRD at the end of reinduction and at later time points have been correlated with an extremely high risk of subsequent relapse.[21]

Cytogenetics/genomic alterations

Changes in mutation profiles from diagnosis to relapse have been identified by gene sequencing.[30,31] While oncogenic gene fusions (e.g., TCF3-PBX1, ETV6-RUNX1) are almost always observed between the time of initial diagnosis and relapse, single nucleotide variants and copy number variants may be present at diagnosis, but not at relapse, and vice versa.[30] For example, while RAS family mutations are common at both diagnosis and relapse, the specific RAS family mutations may change from diagnosis to relapse as specific leukemic subclones rise and fall during the course of treatment.[30] By contrast, relapse-specific mutations in NT5C2 (a gene involved in nucleotide metabolism) have been noted in as many as 45% of ALL cases with early relapse.[30,32,33]

TP53 alterations (mutations and/or copy number alterations) are observed in approximately 10% of patients with ALL at first relapse and have been associated with an increased likelihood of persistent leukemia after initial reinduction and poor event-free survival (EFS) rates.[21,34] In one study, approximately one-half of the TP53 alterations were present at initial diagnosis and half were newly observed at time of relapse.[34]

IKZF1 deletions have also been reported to be associated with a poor prognosis in patients with B-ALL in first bone marrow relapse.[35] However, in a BFM study of patients with B-ALL who experienced a late first marrow relapse, IKZF1 deletions were not prognostically significant.[21]

RAS pathway mutations (KRAS, NRAS, FLT3, and PTPN11) are common at relapse in B-ALL patients, and they were found in approximately 40% of patients at first relapse in one study of 206 children.[30,36] As observed at diagnosis, the frequency of RAS pathway mutations at relapse differs by cytogenetic subtype (e.g., high frequency in hyperdiploid cases and low frequency in ETV6-RUNX1 cases). The presence of RAS pathway mutations at relapse was associated with early relapse. However, presence of RAS pathway mutations at relapse was not an independent predictor of outcome.

Patients with ETV6-RUNX1-positive ALL appear to have a relatively favorable prognosis at first relapse, consistent with the high percentage of such patients who relapse more than 36 months after diagnosis.[35,37]

  • In the ALL-REZ BFM 2002 (NCT00114348) study, an EFS rate of 84% (± 7%) was observed for patients with ETV6-RUNX1 ALL with bone marrow relapse.[35] In this study, 94% of patients with ETV6-RUNX1 had a duration of first remission that extended at least 6 months beyond completion of their primary treatment, and on multivariate analysis, time to relapse (and not the presence of ETV6-RUNX1) was an independent predictor of outcome.
  • Similarly, the 5-year OS rate for ETV6-RUNX1 patients enrolled on the French Acute Lymphoblastic Leukaemia Study Group (FRALLE) 93 trial who relapsed at any site more than 36 months after diagnosis was 81%, and the presence of ETV6-RUNX1 was associated with a favorable survival outcome compared with other late relapsing patients.[37] However, the 3-year OS rate of ETV6-RUNX1 patients who experienced an early relapse (<36 months) was only 31%.

Immunophenotype

Immunophenotype is an important prognostic factor at relapse. Patients with T-ALL who experience a marrow relapse (isolated or combined) at any time during treatment or posttreatment are less likely to achieve a second remission and long-term EFS than are patients with B-ALL.[5,24]

Standard Treatment Options for First Bone Marrow Relapse of Childhood ALL

Standard treatment options for first bone marrow relapse include the following:

  1. Reinduction chemotherapy.
  2. Postreinduction therapy for patients achieving a second CR.

Reinduction chemotherapy

Initial treatment of relapse consists of reinduction therapy to achieve a second CR. Using either a four-drug reinduction regimen (similar to that administered to newly diagnosed high-risk patients) or an alternative regimen including high-dose methotrexate and high-dose cytarabine, approximately 85% of patients with a marrow relapse achieve a second CR at the end of the first month of treatment.[5]; [38][Level of evidence: 2A]; [24][Level of evidence: 2Di] Patients with early marrow relapses have a lower rate of achieving a morphologic second CR (approximately 70%) than do those with late marrow relapses (approximately 95%).[24,38]

Evidence (reinduction chemotherapy):

  1. A COG study used three blocks of intensive reinduction therapy with an initial four-drug combination that included doxorubicin followed by two intensive consolidation blocks before either HSCT or chemotherapy continuation.[24]
    • Second remission was achieved after block 1 in 68% of patients with early relapse (<36 months from initial diagnosis) and in 96% of those with later relapse.
    • Blocks 2 and 3 reduced MRD in 40 of 56 patients who were MRD positive after block 1.