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Dramatic improvements in survival have been achieved for children and adolescents with cancer.[
Characteristics of Myeloid Leukemias and Other Myeloid Malignancies in Children
Approximately 20% of childhood leukemias are of myeloid origin and they represent a spectrum of hematopoietic malignancies.[
The general characteristics of myeloid leukemias and other myeloid malignancies are described below:
TAM blasts most commonly have megakaryoblastic differentiation characteristics and distinctive mutations involving the GATA1 gene in the presence of trisomy 21.[
Early death from TAM-related complications occurs in 10% to 20% of affected infants.[
The presence of a karyotype abnormality in a hypocellular marrow is consistent with MDS and transformation to AML should be expected. Given the high association of MDS evolving into AML, patients with MDS are typically referred for stem cell transplantation before transformation to AML. For more information, see the Myelodysplastic Syndromes (MDS) section.
JMML characteristically presents with hepatosplenomegaly, lymphadenopathy, fever, and skin rash along with an elevated white blood cell (WBC) count and increased circulating monocytes.[
CML is a clonal panmyelopathy that involves all hematopoietic cell lineages. While the WBC count can be extremely elevated, the bone marrow does not show increased numbers of leukemic blasts during the chronic phase of this disease. CML is caused by the presence of the Philadelphia chromosome, a translocation between chromosomes 9 and 22 (i.e., t(9;22)) resulting in fusion of the BCR and ABL1 genes. For more information, see the Chronic Myelogenous Leukemia (CML) section.
Other chronic myeloproliferative syndromes, such as polycythemia vera and essential thrombocytosis, are extremely rare in children.
Conditions Associated With Myeloid Malignancies
Genetic abnormalities (cancer predisposition syndromes) are associated with the development of AML. There is a high concordance rate of AML in identical twins; however, this is not believed to be related to genetic risk, but rather to shared circulation and the inability of one twin to reject leukemic cells from the other twin during fetal development.[
The development of AML has also been associated with a variety of inherited/familial syndromes, which are recognized as a unique category within the 2016 World Health Organization (WHO) Classification of Myeloid Neoplasms and Acute Leukemia. There are also several acquired conditions that increase the risk of developing AML. These inherited and acquired conditions can induce leukemogenesis through mechanisms that include chromosomal imbalances or instabilities, defects in DNA repair, altered cytokine receptor or signal transduction pathway activation, and altered protein synthesis.[
Inherited syndromes
Acquired syndromes
The 2016 WHO classification system has categorized the myeloid neoplasms with germline predisposition as follows:
Nonsyndromic genetic susceptibility to AML is also being studied. For example, homozygosity for a specific IKZF1 polymorphism has been associated with an increased risk of infant AML.[
References:
French-American-British (FAB) Classification System for Childhood AML
The first comprehensive morphological-histochemical classification system for acute myeloid leukemia (AML) was developed by the FAB Cooperative Group.[
The major subtypes of AML include the following:
Other extremely rare subtypes of AML include acute eosinophilic leukemia and acute basophilic leukemia.
The FAB classification was superseded by the WHO classification described below but remains relevant as it forms the basis of the WHO's subcategory of AML, not otherwise specified (AML, NOS).
World Health Organization (WHO) Classification System for Childhood AML
In 2001, the WHO proposed a new classification system that incorporated diagnostic cytogenetic information and that more reliably correlated with outcome. In this classification, patients with t(8;21), inv(16), t(15;17), or KMT2A (MLL) translocations, which collectively constituted nearly half of the cases of childhood AML, were classified as AML with recurrent cytogenetic abnormalities. This classification system also decreased the bone marrow percentage of leukemic blast requirement for the diagnosis of AML from 30% to 20%; an additional clarification was made so that patients with recurrent cytogenetic abnormalities did not need to meet the minimum blast requirement to be considered an AML patient.[
In 2008, the WHO expanded the number of cytogenetic abnormalities linked to AML classification and, for the first time, included specific gene mutations (CEBPA and NPM) in its classification system.[
2016 WHO classification of AML and related neoplasms
2016 WHO classification of acute leukemias of ambiguous lineage
For the group of acute leukemias that have characteristics of both AML and acute lymphoblastic leukemia (ALL), the acute leukemias of ambiguous lineage, the WHO classification system is summarized in Table 1.[
Condition | Definition |
---|---|
NOS = not otherwise specified. | |
a Béné MC: Biphenotypic, bilineal, ambiguous or mixed lineage: strange leukemias! Haematologica 94 (7): 891-3, 2009.[ |
|
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::ABL1gene fusion | 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 | 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 | Acute leukemia meeting the diagnostic criteria for assignment to both B and myeloid lineage, in which the blasts lack genetic abnormalities involvingBCR::ABL1gene fusion orKMT2A |
Mixed phenotype acute leukemia, T/myeloid, NOS | Acute leukemia meeting the diagnostic criteria for assignment to both T and myeloid lineage, in which the blasts lack genetic abnormalities involvingBCR::ABL1gene fusion orKMT2A |
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 |
Lineage | Criteria |
---|---|
a Adapted from Arber et al.[ |
|
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:
Biphenotypic cases represent the majority of mixed phenotype leukemias.[
WHO Classification of Bone Marrow and Peripheral Blood Findings for Myelodysplastic Syndromes
The FAB classification of myelodysplastic syndromes (MDS) was not completely applicable to children.[
A modified classification schema for MDS and myeloproliferative disorders (MPDs) was published by the WHO in 2008 and included subsections that focused on pediatric MDS and MPD.[
Distinguishing MDS from similar-appearing, reactive causes of dysplasia and/or cytopenias is noted to be difficult. In general, the finding of more than 10% dysplasia in a cell lineage is a diagnostic criteria for MDS; however, the 2016 WHO guidelines caution that reactive etiologies, rather than clonal, may have more than 10% dysplasia and should be excluded especially when dysplasia is subtle and/or restricted to a single lineage.[
The International Prognostic Scoring System is used to determine the risk of progression to AML and the outcome in adult patients with MDS. When this system was applied to children with MDS or juvenile myelomonocytic leukemia (JMML), only a blast count of less than 5% and a platelet count of more than 100 × 109 /L were associated with a better survival in MDS, and a platelet count of more than 40 × 109 /L predicted a better outcome in JMML.[
Pediatric MDS can be grouped into several general categories, each with distinctive clinical and biological characteristics, as follows:[
Genomic characterization of pediatric primary MDS has identified specific subsets defined by alterations in selected genes. For example, germline mutations in GATA2,[
Type of MDS | Bone Marrow | Peripheral Blood | |
---|---|---|---|
a Adapted from Arber et al.[ |
|||
b Note that cases with pancytopenia would be classified as MDS-U. | |||
c When the marrow has <5% myeloblasts, but the peripheral blood has 2%–4% myeloblasts, the diagnosis is MDS-EB-1. | |||
d The diagnosis of MDS-EB-2 should be made if any one of the following criteria are met: marrow with 10%–19% blasts, peripheral blood with 5%–19% blasts, or presence of Auer rods. | |||
e Recurring chromosomal abnormalities in MDS: Unbalanced: +8, -7 or del(7q), -5 or del(5q), del(20q), -Y, i(17q) or t(17p), -13 or del(13q), del(11q), del(12p) or t(12p), del(9q), idic(X)(q13); Balanced: t(11;16)(q23;p13.3), t(3;21)(q26.2;q22.1), t(1;3)(p36.3;q21.2), t(2;11)(p21;q23), inv(3)(q21q26.2), t(6;9)(p23;q34). The WHO classification notes that the presence of these chromosomal abnormalities in presence of persistent cytopenias of undetermined origin should be considered to support a presumptive diagnosis of MDS when morphological characteristics are not observed. | |||
f The diagnostic criteria for childhood MDS (refractory cytopenia of childhood-provisional entry) include: 1) persistent cytopenia of 1–3 cell lines with <5% bone marrow blasts, <2% peripheral blood blasts, and no ringed sideroblasts and 2) dysplastic changes in 1–3 lineages should be present. | |||
MDS with single lineage dysplasia | Unilineage dysplasia: ≥10% in one myeloid lineage | 1–2 cytopeniasb | |
<5% blasts | Blasts <1%c | ||
<15% ring sideroblasts | |||
MDS with ring sideroblasts (MDS-RS) | Erythroid dysplasia only | ||
<5% blasts | No blasts | ||
≥15% ring sideroblasts | |||
MDS with multilineage dysplasia | Dysplasia in ≥10% of cells in ≥2 myeloid lineages | 1–3 cytopenias | |
<5% blasts | Blasts (none or <1%)c | ||
±15% ring sideroblasts | |||
No Auer rods | No Auer rods | ||
<1×109 monocytes/L | |||
MDS with excess blasts-1 (MDS-EB-1) | Single lineage or multilineage dysplasia | Cytopenia(s) | |
5%–9% blastsc | <5% blastsc | ||
No Auer rods | No Auer rods | ||
<1×109 monocytes/L | |||
MDS with excess blasts-2 (MDS-EB-2) | Single lineage or multilineage dysplasia | Cytopenia(s) | |
10%–19% blastsd | 5%–19% blastsd | ||
Auer rods ±d | Auer rods ±d | ||
<1×109 monocytes/L | |||
MDS with isolated del(5q) | Normal to increased megakaryocytes (hypolobulated nuclei) | Anemia | |
<5% blasts | Blasts (none or <1%) | ||
No Auer rods | Normal to increased platelet count | ||
Isolated del(5q) | |||
MDS-unclassifiable (MDS-U) | Dysplasia in <10% of cells in ≥1 myeloid cell lineage | Cytopenias | |
Cytogenetic abnormality associated with diagnosis of MDSe | ≤1% blastsc | ||
<5% blasts | |||
Provisional entity: Refractory cytopenia of childhoodf | For more information, see Table 4. |
| Erythroid Lineage | Myeloid Lineage | Megakaryocyte Lineage |
---|---|---|---|
a Adapted from Baumann et al.[ |
|||
b Bone marrow trephine/biopsy may be required as bone marrow in childhood refractory cytopenia of childhood is often hypocellular. | |||
c Characteristics include abnormal nuclear lobulation, multinuclear cells, presence of nuclear bridges. | |||
d Presence of pseudo–Pelger-Huet cells, hypo- or agranular cytoplasm, giantband forms. | |||
e Megakaryocytes have variable size and often round or separated nuclei; the absence of megakaryocytes does not exclude the diagnosis of refractory cytopenia of childhood. | |||
Bone Marrow Aspirateb | Dysplasia and/or megablastoid changes in ≥10% of erythroid precursorsc | Dysplasia in ≥10% of granulocytic precursors and neutrophils | Micromegakaryocytes plus other dysplastic featurese |
<5% blastsd | |||
Bone Marrow Biopsy | Presence of erythroid precursors | No additional criteria | Micromegakaryocytes plus other dysplastic featurese |
Increased proerythroblasts | Immunohistochemistry positive for CD61 and CD41 | ||
Increased number of mitoses | |||
Peripheral Blood | Dysplasia in ≥10% of neutrophils | ||
<2% blasts |
Histochemical, Immunophenotypic, and Molecular Evaluation for Childhood AML
Histochemical Evaluation
The treatment for children with acute myeloid leukemia (AML) differs significantly from that for acute lymphoblastic leukemia (ALL). As a consequence, it is critical to distinguish AML from ALL. Special histochemical stains performed on bone marrow specimens of children with acute leukemia can be helpful to confirm their diagnosis. The stains most commonly used include myeloperoxidase, periodic acid-Schiff, Sudan Black B, and esterase. In most cases, the staining pattern with these histochemical stains will distinguish AML from acute myelomonocytic leukemia (AMML) and ALL (see Table 5). Histochemical stains have been mostly replaced by flow cytometric immunophenotyping.
| M0 | AML, APL (M1-M3) | AMML (M4) | AMoL (M5) | AEL (M6) | AMKL (M7) | ALL | |
---|---|---|---|---|---|---|---|---|
AEL = acute erythroid leukemia; ALL = acute lymphoblastic leukemia; AML = acute myeloid leukemia; AMKL = acute megakaryocytic leukemia; AMML = acute myelomonocytic leukemia; AMoL = acute monocytic leukemia; APL = acute promyelocytic leukemia; PAS = periodic acid-Schiff. | ||||||||
a For more information about the morphological-histochemical classification system for AML, see the French-American-British (FAB) Classification for Childhood AMLsection. | ||||||||
b These reactions are inhibited by fluoride. | ||||||||
Myeloperoxidase | - | + | + | - | - | - | - | |
Nonspecific esterases | ||||||||
Chloracetate | - | + | + | ± | - | - | - | |
Alpha-naphthol acetate | - | - | +b | +b | - | ±b | - | |
Sudan Black B | - | + | + | - | - | - | - | |
PAS | - | - | ± | ± | + | - | + |
Immunophenotypic Evaluation
The use of monoclonal antibodies to determine cell-surface antigens of AML cells is helpful to reinforce the histologic diagnosis. Various lineage-specific monoclonal antibodies that detect antigens on AML cells should be used at the time of initial diagnostic workup, along with a battery of lineage-specific T-lymphocyte and B-lymphocyte markers to help distinguish AML from ALL and acute leukemias of ambiguous lineage. The expression of various cluster determinant (CD) proteins that are relatively lineage-specific for AML include CD33, CD13, CD14, CDw41 (or platelet antiglycoprotein IIb/IIIa), CD15, CD11B, CD36, and antiglycophorin A. Lineage-associated B-lymphocytic antigens CD10, CD19, CD20, CD22, and CD24 may be present in 10% to 20% of AML cases, but monoclonal surface immunoglobulin and cytoplasmic immunoglobulin heavy chains are usually absent; similarly, CD2, CD3, CD5, and CD7 lineage-associated T-lymphocytic antigens are present in 20% to 40% of AML cases.[
Immunophenotyping can also be helpful in distinguishing the following French-American-British (FAB) classification subtypes of AML:
Less than 5% of cases of acute leukemia in children are of ambiguous lineage, expressing features of both myeloid and lymphoid lineage.[
Molecular Evaluation
Molecular features of acute myeloid leukemia
Comprehensive molecular profiling of pediatric and adult AML has shown that AML is a disease demonstrating both commonalities and differences across the age spectrum.[
Genetic analysis of leukemia blast cells (using both conventional cytogenetic methods and molecular methods) is performed on children with AML because both chromosomal and molecular abnormalities are important diagnostic and prognostic markers.[
Detection of molecular abnormalities can also aid in risk stratification and treatment allocation. For example, mutations of NPM and CEBPA are associated with favorable outcomes while certain mutations of FLT3 portend a high risk of relapse, and identifying the latter mutations may allow for targeted therapy.[
The 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia emphasizes that recurrent chromosomal translocations in pediatric AML may be unique or have a different prevalence than in adult AML.[
Gene Fusion Product | Chromosomal Translocation | Prevalence in Pediatric AML (%) |
---|---|---|
a Cryptic chromosomal translocation. | ||
KMT2A(MLL) translocated | 11q23.3 | 25.0 |
NUP98::NSD1a | t(5;11)(q35.3;p15.5) | 7.0 |
CBFA2T3::GLIS2a | inv(16)(p13.3;q24.3) | 3.0 |
NUP98::KDM5Aa | t(11;12)(p15.5;p13.5) | 3.0 |
DEK::NUP214 | t(6;9)(p22.3;q34.1) | 1.7 |
RBM15(OTT)::MKL1(MAL) | t(1;22)(p13.3;q13.1) | 0.8 |
MNX1::ETV6 | t(7;12)(q36.3;p13.2) | 0.8 |
KAT6A::CREBBP | t(8;16)(p11.2;p13.3) | 0.5 |
RUNX1::RUNX1T1 | t(8;21)(q22;q22) | 13–14 |
CBFB::MYH11 | inv(16)(p13.1;q22) or t(16;16)(p13.1;q22) | 4–9 |
PML::RARA | t(15;17)(q24;q21) | 6–11 |
The genomic landscape of pediatric AML cases can change from diagnosis to relapse, with mutations detectable at diagnosis dropping out at relapse and, conversely, with new mutations appearing at relapse. In a study of 20 cases for which sequencing data were available at diagnosis and relapse, a key finding was that the variant allele frequency at diagnosis strongly correlated with persistence of mutations at relapse.[
Specific recurring cytogenetic and molecular abnormalities are briefly described below. The abnormalities are listed by those in clinical use that identify patients with favorable or unfavorable prognosis, followed by other abnormalities. The nomenclature of the 2016 revision to the WHO classification of myeloid neoplasms and acute leukemia is incorporated for disease entities where relevant.
Genetic abnormalities associated with a favorable prognosis
Genetic abnormalities associated with a favorable prognosis include the following:
Both RUNX1::RUNX1T1 and CBFB::MYH11 gene fusion subtypes commonly show mutations in genes that activate receptor tyrosine kinase signaling (e.g., NRAS, FLT3, and KIT); NRAS and KIT are the most commonly mutated genes for both subtypes. The prognostic significance of activating KIT mutations in adults with CBF AML has been studied with conflicting results. A meta-analysis found that KIT mutations appear to increase the risk of relapse without an impact on OS for adults with AML and RUNX1::RUNX1T1 fusions.[
Although both RUNX1::RUNX1T1 and CBFB::MYH11 fusion genes disrupt the activity of CBF, cases with these genomic alterations have distinctive secondary mutations.[
A study of 204 adults with AML and RUNX1::RUNX1T1 fusions found that ASXL2 mutations (present in 17% of cases) and ASXL1 or ASXL2 mutations (present in 25% of cases) lacked prognostic significance.[
Utilization of quantitative reverse transcriptase–polymerase chain reaction (RT-PCR) for PML::RARA transcripts has become standard practice.[
Studies of children with AML suggest a lower rate of occurrence of NPM1 mutations in children compared with adults with normal cytogenetics. NPM1 mutations occur in approximately 8% of pediatric patients with AML and are uncommon in children younger than 2 years.[
CEBPA mutations occur in approximately 5% of children with AML and have been preferentially found in the cytogenetically normal subtype of AML with FAB M1 or M2.
GATA1 mutations confer increased sensitivity to cytarabine by down-regulating cytidine deaminase expression, possibly providing an explanation for the superior outcome of children with Down syndrome and M7 AML when treated with cytarabine-containing regimens.[
Genetic abnormalities associated with an unfavorable prognosis
Genetic abnormalities associated with an unfavorable prognosis include the following:
In the past, patients with del(7q) were also considered to be at high risk of treatment failure, and data from adults with AML support a poor prognosis for both del(7q) and monosomy 7.[
Chromosome 5 and 7 abnormalities appear to lack prognostic significance in AML patients with Down syndrome who are aged 4 years and younger.[
Abnormalities involving MECOM can be detected in some AML cases with other 3q abnormalities and are also associated with poor prognosis.
The prognostic significance of FLT3 ITD is modified by the presence of other recurring genomic alterations. The prevalence of FLT3 ITD is increased in certain genomic subtypes of pediatric AML, including those with the NUP98::NSD1 fusion gene, of which 80% to 90% have FLT3 ITD.[
For APL, FLT3 ITD and point mutations occur in 30% to 40% of children and adults.[
Activating point mutations of FLT3 have also been identified in both adults and children with AML, although the clinical significance of these mutations is not clearly defined. Some of these point mutations appear to be specific to pediatric patients.[
Other genetic abnormalities observed in pediatric AML
Other genetic abnormalities observed in pediatric AML include the following:
The most common translocation, representing approximately 50% of KMT2A-rearranged cases in the pediatric AML population, is t(9;11)(p22;q23), in which the KMT2A gene is fused with the MLLT3 gene.[
The median age for 11q23/KMT2A-rearranged cases in children is approximately 2 years, and most translocation subgroups have a median age at presentation of younger than 5 years.[
Outcome for patients with de novo AML and KMT2A gene rearrangements is generally reported as being similar to or slightly worse than the outcome observed in other patients with AML.[
For patients with the most prevalent KMT2A-rearranged subtype of AML, t(9;11)(p21.3;q23.3)/MLLT3::KMT2A fusions, single clinical trial groups have variably described a more favorable prognosis; however, neither the international retrospective study nor the COG study confirmed the favorable prognosis for this subgroup.[
KMT2A-rearranged AML subgroups that are associated with poor outcome include the following:
t(6;9) AML appears to be associated with a high risk of treatment failure in children, particularly for those not proceeding to allogeneic stem cell transplantation.[
In a study of approximately 2,000 children with AML, the CBFA2T3::GLIS2 fusion was identified in 39 cases (1.9%), with a median age at presentation of 1.5 years, and with all cases observed in children younger than 3 years.[
An international collaborative retrospective study of 51 t(1;22) cases reported that patients with this abnormality had a 5-year EFS rate of 54.5% and an OS rate of 58.2%, similar to the rates for other children with AMKL.[
A substantial proportion of infants diagnosed with t(8;16) AML in the first month of life show spontaneous remission, although AML recurrence may occur months to years later.[
The NUP98::NSD1 gene fusion, which is often cytogenetically cryptic, results from the fusion of NUP98 (chromosome 11p15) with NSD1 (chromosome 5q35).[
The NUP98::KDM5A gene fusion results from the fusion of the NUP98 gene with the KDM5A gene, which results from a cytogenetically cryptic translocation, t(11;12)(p15;p13).[
The prognostic significance of activating KIT mutations in adults with CBF AML has been studied with conflicting results. A meta-analysis found that KIT mutations appear to increase the risk of relapse without an impact on OS for adults with AML and RUNX1::RUNX1T1 fusions.[
In children with AML, WT1 mutations are observed in approximately 10% of cases.[
In a study of children with refractory AML, WT1 was overrepresented compared with a cohort who did achieve remission (54% [15 of 28 patients] vs. 15%).[
Mutations in IDH1 and IDH2 are rare in pediatric AML, occurring in 0% to 4% of cases.[
Activating mutations in CSF3R are also observed in patients with severe congenital neutropenia. These mutations are not the cause of severe congenital neutropenia, but rather arise as somatic mutations and can represent an early step in the pathway to AML.[
References:
Leukemia is considered to be disseminated in the hematopoietic system at diagnosis, even in children with acute myeloid leukemia (AML) who present with isolated chloromas (also called granulocytic or myeloid sarcomas). If these children do not receive systemic chemotherapy, they invariably develop AML in months or years. AML may invade nonhematopoietic (extramedullary) tissue such as meninges, brain parenchyma, testes or ovaries, or skin (leukemia cutis). Extramedullary leukemia is more common in infants than in older children with AML.[
Childhood AML is diagnosed when bone marrow has 20% or greater blasts. The blasts have the morphological and histochemical characteristics of one of the French-American-British (FAB) subtypes of AML. It can also be diagnosed by biopsy of a chloroma. For treatment purposes, patients with clonal cytogenetic abnormalities typically associated with AML, such as t(8;21)(RUNX1::RUNX1T1 gene fusions), inv(16)(CBFB::MYH11 gene fusions), t(9;11)(MLLT3::KMT2A gene fusions) or t(15;17)(PML::RARA gene fusions) and who have less than 20% bone marrow blasts, are considered to have AML rather than a myelodysplastic syndrome.[
Complete remission (CR) has traditionally been defined in the United States using morphological criteria such as the following:
Alternative definitions of remission using morphology are used in AML because of the prolonged myelosuppression caused by intensive chemotherapy and include CR with incomplete platelet recovery (CRp) and CR with incomplete marrow recovery (typically absolute neutrophil count) (CRi). Whereas the use of CRp provides a clinically meaningful response, the traditional CR definition remains the gold standard because patients in CR were found to be more likely to survive longer than those in CRp.[
Achieving a hypoplastic bone marrow (using morphology) is usually the first step in obtaining remission in AML with the exception of the M3 subtype (acute promyelocytic leukemia [APL]); a hypoplastic marrow phase is often not necessary before the achievement of remission in APL. Additionally, early recovery marrows in any of the subtypes of AML may be difficult to distinguish from persistent leukemia, although the application of flow cytometric immunophenotyping and cytogenetic/molecular testing have made this less problematic. Correlation with blood cell counts and clinical status is imperative in passing final judgment on the results of early bone marrow findings in AML.[
In addition to morphology, more precise methodology (e.g., multiparameter flow cytometry or quantitative reverse transcriptase–polymerase chain reaction [RT-PCR]) is used to assess response and has been shown to be of greater prognostic significance than morphology. For more information about these methodologies, see the Prognostic Factors in Childhood AML section.
Treatment Approach
The mainstay of the therapeutic approach is systemically administered combination chemotherapy. Approaches involving risk-group stratification and biologically targeted therapies are being tested to improve antileukemic treatment while sparing normal tissue. Optimal treatment of AML requires control of bone marrow and systemic disease. Treatment of the CNS, usually with intrathecal medication, is a component of most pediatric AML protocols but has not yet been shown to contribute directly to an improvement in survival. CNS irradiation is not necessary in patients, either as prophylaxis or for those presenting with cerebrospinal fluid leukemia that clears with intrathecal and systemic chemotherapy.
Treatment is ordinarily divided into the following two phases:
Postremission therapy may consist of varying numbers of courses of intensive chemotherapy and/or allogeneic hematopoietic stem cell transplantation (HSCT). For example, ongoing trials of the Children's Oncology Group (COG) and the United Kingdom Medical Research Council (MRC) use similar chemotherapy regimens consisting of two courses of induction chemotherapy followed by two to three additional courses of intensification chemotherapy.[
Maintenance therapy is not part of most pediatric AML protocols because two randomized clinical trials failed to show a benefit for maintenance therapy when given after modern intensive chemotherapy.[
Attention to both acute and long-term complications is critical in children with AML. Modern AML treatment approaches are usually associated with severe, protracted myelosuppression with related complications. Children with AML should receive care under the direction of pediatric oncologists in cancer centers or hospitals with appropriate supportive care facilities (e.g., specialized blood products; pediatric intensive care; provision of emotional and developmental support). With improved supportive care, toxic death constitutes a smaller proportion of initial therapy failures than in the past.[
Children treated for AML are living longer and require close monitoring for cancer therapy side effects that may persist or develop months or years after treatment. The high cumulative doses of anthracyclines require long-term monitoring of cardiac function. The use of some modalities have declined, including total-body irradiation with HSCT because of its increased risk of growth failure, gonadal and thyroid dysfunction, cataract formation, and second malignancies.[
Prognostic Factors in Childhood AML
Prognostic factors in childhood AML can be categorized as follows:
Host risk factors
While outcome for infants with ALL remains inferior to that of older children, outcome for infants with AML is similar to that of older children when they are treated with standard AML regimens.[
Leukemia risk factors
In patients with APL, WBC at initial diagnosis alone is used to distinguish standard-risk and high-risk APL. A WBC count of 10,000 cells/μL or more denotes high risk, and these patients have an increased risk of both early death and relapse.[
In a retrospective study of non–Down syndrome M7 patients with samples available for molecular analysis, the presence of specific genetic abnormalities (CBFA2T3::GLIS2 gene fusions [cryptic inv(16)(p13q24)], NUP98::KDM5A gene fusions, t(11;12)(p15;p13), KMT2A [MLL] rearrangements, monosomy 7) was associated with a significantly worse outcome than for other M7 patients.[
COG trials (including AAML03P1 [NCT00070174], AAML0531 [NCT00372593], and AAML1031 [NCT01371981]) used a modified version of the CNS disease definitions, in which patients were dichotomously classified for treatment purposes as CNS positive or negative. The CNS-positive group included all patients with blasts on cytospin (regardless of CSF WBC) unless there were more than 100 RBC/μL in the CSF. Patients with 100 RBC/μL in the CSF were CNS positive only if the WBC/RBC ratio in the CSF was greater than or equal to twice the ratio in the peripheral blood. CNS outcomes on COG studies were analyzed utilizing the more traditional CNS1/2/3 definitions.[
CNS2 disease has been observed in approximately 13% to 16% of children with AML, and CNS3 disease has been observed in approximately 11% to 17% of children with AML.[
While CNS involvement (CNS2 or CNS3) at diagnosis has not been shown to be correlated with OS in most studies, a COG analysis of children with AML enrolled from 2003 to 2010 on two consecutive and identical backbone trials found that CNS involvement, especially CNS3 status, was associated with inferior outcomes, including complete remission rate, EFS, disease-free survival, and an increased risk of relapse involving the CNS.[
Therapeutic response risk factors
Molecular approaches to assessing MRD in AML (e.g., using quantitative RT-PCR) have been challenging to apply because of the genomic heterogeneity of pediatric AML and the instability of some genomic alterations. Quantitative RT-PCR detection of RUNX1::RUNX1T1 fusion transcripts can effectively predict higher risk of relapse for patients in clinical remission.[
For APL, MRD detection at the end of induction therapy lacks prognostic significance, likely related to the delayed clearance of differentiating leukemic cells destined to eventually die.[
Flow cytometric methods have been used for MRD detection and can detect leukemic blasts based on the expression of aberrant surface antigens that differ from the pattern observed in normal progenitors. In a COG analysis (AAML0531 [NCT00372593]) of 784 patients, 69% of patients (n = 544) were MRD negative (defined as <0.02%) in their bone marrow at the end of induction 1 (EOI1). Those patients had better disease-free survival rates (57%; 95% CI, 53%–61%; P < .001) and overall survival rates (73%; 95% CI, 69%–76%; P < .001) than patients who were MRD positive (DFS: 30%; 95% CI, 25%–36% and OS: 48%; 95% CI, 42%–54%).[
Risk Classification Systems
Risk classification for treatment assignment has been used by several cooperative groups performing clinical trials in children with AML. In the COG, stratifying therapeutic choices on the basis of risk factors is a relatively recent approach for the non-APL, non–Down syndrome patient. Classification is most directly derived from the observations of the MRC AML 10 trial for EFS and OS [
The following COG trials have used a risk classification system to stratify treatment choices:
Where risk factors contradicted each other, the following evidence-based table was used (see Table 7).
Risk Assignment: | Low Risk | High Risk | |||
---|---|---|---|---|---|
| Low-Risk Group 1 | Low-Risk Group 2 | High-Risk Group 1 | High-Risk Group 2 | High-Risk Group 3 |
ITD = internal tandem duplications. | |||||
a Groups are based on combinations of risk factors, which may be found in any individual patient. | |||||
bBold indicates the overriding risk factor in risk-group assignment. | |||||
c NPM1,CEBPA, t(8;21), inv(16). | |||||
d Monosomy 7, monosomy 5, del(5q). | |||||
FLT3ITD allelic ratio | Low/negative | Low/negative | High | Low/negative | Low/negative |
Good-risk molecular markersc | Present | Absent | Any | Absent | Absent |
Poor-risk cytogenetic markersd | Any | Absent | Any | Present | Absent |
Minimal residual disease | Any | Negative | Any | Any | Positive |
The high-risk group of patients was guided to transplantation in first remission with the most appropriate available donor. Patients in the low-risk group were instructed to pursue transplantation if they relapsed.[
Risk factors used for stratification vary by pediatric and adult cooperative clinical trial groups and the prognostic impact of a given risk factor may vary in their significance depending on the backbone of therapy used. Other pediatric cooperative groups use some or all of these same factors, generally choosing risk factors that have been reproducible across numerous trials and sometimes including additional risk factors previously used in their risk group stratification approach.
References:
Cancer in children and adolescents is rare, although the overall incidence has been slowly increasing since 1975.[
For specific information about supportive care for children and adolescents with cancer, see the summaries on Supportive and Palliative Care.
The American Academy of Pediatrics has outlined guidelines for pediatric cancer centers and their role in the treatment of children with cancer.[
References:
The general principles of therapy for children and adolescents with acute myeloid leukemia (AML) are discussed below, followed by a more specific discussion of the treatment of children with Down syndrome and acute promyelocytic leukemia (APL).
Overall survival (OS) rates have improved over the past three decades for children with AML, with 5-year survival rates now in the 55% to 65% range.[
Induction Therapy
Contemporary pediatric AML protocols result in 85% to 90% complete remission (CR) rates.[
Treatment options for children with AML during the induction phase may include the following:
Chemotherapy
The two most effective and essential drugs used to induce remission in children with AML are cytarabine and an anthracycline. Commonly used pediatric induction therapy regimens use cytarabine and an anthracycline in combination with other agents such as etoposide and/or thioguanine.[
Evidence (induction chemotherapy regimen):
The anthracycline that has been most used in induction regimens for children with AML is daunorubicin,[
Evidence (anthracycline):
Evidence (reduced-anthracycline induction regimen):
The intensity of induction therapy influences the overall outcome of therapy. The CCG-2891 study demonstrated that intensively timed induction therapy (4-day treatment courses separated by only 6 days) produced better EFS than standard-timing induction therapy (4-day treatment courses separated by 2 weeks or longer).[
In adults, another method of intensifying induction therapy is to use high-dose cytarabine. While studies in nonelderly adults suggest an advantage for intensifying induction therapy with high-dose cytarabine (2–3 g/m2 /dose) compared with standard-dose cytarabine,[
Immunotherapeutic approaches
Because further intensification of induction regimens has increased toxicity with little improvement in EFS or OS, alternative approaches, such as the use of gemtuzumab ozogamicin, have been examined.
Antibody-drug conjugate therapy (gemtuzumab ozogamicin)
Gemtuzumab ozogamicin is a CD33-directed monoclonal antibody linked to a calicheamicin, a cytotoxic agent.
Evidence (gemtuzumab ozogamicin during induction):
Targeted therapy
Similar to immunotherapeutic approaches, the use of targeted therapy attempts to circumvent the severe toxicity of traditional chemotherapy by employing agents that target leukemia-specific mutations and/or their abnormal present or missing byproducts. As opposed to adult AML (except in APL as described in a later section), randomized clinical trials have not yet demonstrated that targeted therapies improve outcomes in children with newly diagnosed AML; therefore, targeted therapies have not been incorporated into the standard therapeutic induction regimens outside of clinical trials. Because most data on the use of targeted agents are from adult clinical trials, the adult experience is initially described, followed by a description of the more limited experience in children.
FLT3 inhibitors in de novo AML
Because of the high prevalence of FLT3 mutations in adult AML and adverse impact in AML patients of all ages, the FLT3 target has received the greatest attention for target-specific drug development in AML. Among the various FLT3 inhibitors developed and clinically studied, midostaurin, a multikinase inhibitor, is the only one with U.S. Food and Drug Administration (FDA) approval for adult de novo AML; it was approved in 2017 for use with conventional backbone chemotherapy but not as a single agent.[
Midostaurin
Evidence (midostaurin for adults with de novo AML):
Midostaurin has been studied in children with relapsed/refractory AML,[
Sorafenib
Sorafenib, another multikinase inhibitor, has been approved for the treatment of other malignancies, but it has not been approved for use in AML. This agent has been evaluated for use in adult and pediatric patients with de novo FLT3-mutated AML.
Evidence (sorafenib):
Supportive care
In children with AML receiving modern intensive therapy, the estimated incidence of severe bacterial infections is 50% to 60%, and the estimated incidence of invasive fungal infections is 7.0% to 12.5%.[
Hematopoietic growth factors
Hematopoietic growth factors such as granulocyte-macrophage colony-stimulating factor (GM-CSF) or granulocyte colony-stimulating factor (G-CSF) during AML induction therapy have been evaluated in multiple placebo-controlled studies in adults with AML in attempts to reduce the toxicity associated with prolonged myelosuppression.[
Routine prophylactic use of hematopoietic growth factors is not recommended for children with AML.
Evidence (against the use of hematopoietic growth factors):
Antimicrobial prophylaxis
The use of antibacterial prophylaxis in children undergoing treatment for AML has been supported by several studies. Studies, including one prospective randomized trial, suggest a benefit to the use of antibiotic prophylaxis.
Evidence (antimicrobial prophylaxis):
Antifungal prophylaxis
Antifungal prophylaxis is important in the management of patients with AML.
Evidence (antifungal prophylaxis):
Cardiac monitoring
Bacteremia or sepsis and anthracycline use have been identified as significant risk factors in the development of cardiotoxicity, manifested as reduced left ventricular function.[
Evidence (cardiac monitoring/dexrazoxane impact):
Hospitalization
Hospitalization until adequate granulocyte (absolute neutrophil or phagocyte count) recovery has been used to reduce treatment-related mortality. The COG-2961 (NCT00002798) trial was the first to note a significant reduction in treatment-related mortality (19% before mandatory hospitalization was instituted in the trial along with other supportive care changes vs. 12% afterward); OS was also improved in this trial (P <.001).[
Induction failure (refractory AML)
Induction failure (the morphological presence of 5% or greater marrow blasts at the end of all induction courses) is seen in 10% to 15% of children with AML. Subsequent outcomes for patients with induction failure are similar to those for patients with AML who relapse early (<12 months after remission).[
Granulocytic sarcoma/chloroma
Granulocytic sarcoma (chloroma) describes extramedullary collections of leukemia cells. These collections can occur, albeit rarely, as the sole evidence of leukemia. In a review of three AML studies conducted by the former Children's Cancer Group, fewer than 1% of patients had isolated granulocytic sarcoma, and 11% had granulocytic sarcoma along with marrow disease at the time of diagnosis.[
Importantly, the patient who presents with an isolated tumor, without evidence of marrow involvement, must be treated as if there is systemic disease. Patients with isolated granulocytic sarcoma have a good prognosis if treated with current AML therapy.[
In a study of 1,459 children with newly diagnosed AML, patients with orbital granulocytic sarcoma and central nervous system (CNS) granulocytic sarcoma had better survival than did patients with marrow disease and granulocytic sarcoma at other sites and AML patients without any extramedullary disease.[
Central Nervous System (CNS) Prophylaxis for AML
CNS involvement in patients with AML and its impact on prognosis has been discussed above in the Prognostic Factors in Childhood AML section. Therapy with either radiation or intrathecal chemotherapy has been used to treat CNS leukemia present at diagnosis and to prevent later development of CNS leukemia. The use of radiation has essentially been abandoned as a means of prophylaxis because of the lack of documented benefit and long-term sequelae.[
Evidence (CNS prophylaxis):
Postremission Therapy for AML
A major challenge in the treatment of children with AML is to prolong the duration of the initial remission with additional chemotherapy or HSCT.
Treatment options for children with AML in postremission may include the following:
Chemotherapy
Postremission chemotherapy includes some of the drugs used in induction while also introducing non–cross-resistant drugs and, commonly, high-dose cytarabine. Studies in adults with AML have demonstrated that consolidation with a high-dose cytarabine regimen improves outcome compared with consolidation with a standard-dose cytarabine regimen, particularly in patients with inv(16) and t(8;21) AML subtypes.[
The optimal number of postremission courses of therapy remains unclear, but appears to require at least two to three courses of intensive therapy after induction.[
Evidence (number of postremission courses of chemotherapy):
Additional study of the number of intensification courses and specific agents used will better address this issue, but these data suggest that four chemotherapy courses should only be administered to the favorable group described above, and that all other patients who do not undergo HSCT should receive five chemotherapy courses.
HSCT
The use of HSCT in first remission has been under evaluation since the late 1970s, and evidence-based appraisals concerning indications for autologous and allogeneic HSCT have been published. Prospective trials of transplantation in children with AML suggest that overall, 60% to 70% of children with HLA-matched donors available who undergo allogeneic HSCT during their first remission experience long-term remissions,[
In prospective trials that compared allogeneic HSCT with chemotherapy and/or autologous HSCT, superior DFS rates were observed for patients who were assigned to allogeneic HSCT on the basis of family 6/6 or 5/6 HLA-matched donors in adults and children.[
Current application of allogeneic HSCT involves incorporation of risk classification to determine whether transplantation should be pursued in first remission. Because of the improved outcome in patients with favorable prognostic features (low-risk cytogenetic or molecular mutations) receiving contemporary chemotherapy regimens and the lack of demonstrable superiority for HSCT in this patient population, this group of patients typically receives matched-family donor (MFD) HSCT only after first relapse and the achievement of a second CR.[
An analysis from the Center for International Blood and Marrow Transplant Research (CIBMTR) examined pretransplant variables to create a model for predicting leukemia-free survival (LFS) posttransplant in pediatric patients (aged <18 years). All patients were first transplant recipients who had myeloablative conditioning, and all stem cells sources were included. For patients with AML, the predictors associated with lower LFS included age younger than 3 years, intermediate-risk or poor-risk cytogenetics, and second CR or higher with MRD positivity or not in CR. A scale was established to stratify patients on the basis of risk factors to predict survival. The 5-year LFS rate was 78% for the low-risk group, 53% for the intermediate-risk group, 40% for the high-risk group, and 25% for the very high-risk group.[
There is conflicting evidence regarding the role of allogeneic HSCT in first remission for patients with intermediate-risk characteristics (neither low-risk or high-risk cytogenetics or molecular mutations):
Evidence (allogeneic HSCT in first remission for patients with intermediate-risk AML):
Given the improved outcome for patients with intermediate-risk AML in recent clinical trials and the burden of acute and chronic toxicities associated with allogeneic transplantation, many childhood AML treatment groups (including the COG) employ chemotherapy for intermediate-risk patients in first remission and reserve allogeneic HSCT for use after potential relapse.[
There are conflicting data regarding the role of allogeneic HSCT in first remission for patients with high-risk disease, complicated by the differing definitions of high risk used by different study groups.
Evidence (allogeneic HSCT in first remission for patients with high-risk AML):
Many, but not all, pediatric clinical trial groups prescribe allogeneic HSCT for high-risk patients in first remission.[
Because definitions of high-, intermediate-, and low-risk AML are evolving because of the ongoing association of molecular characteristics of the tumor with outcome (e.g., FLT3 ITD, WT1 mutations, and NPM1 mutations) and response to therapy (e.g., MRD assessments postinduction therapy), further analysis of subpopulations of patients treated with allogeneic HSCT will be an ongoing need in current and future clinical trials.
If transplant is chosen in first CR, the optimal preparative regimen and source of donor cells has not been determined, although alternative donor sources, including haploidentical donors, are being studied.[
Evidence (myeloablative regimen):
Other than the APL subtype, there are no data that demonstrate that maintenance therapy given after intensive postremission therapy significantly prolongs remission duration. Maintenance chemotherapy failed to show benefit in two randomized studies that used modern intensive consolidation therapy,[
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.
Recurrent or Refractory Childhood AML and Other Myeloid Malignancies
The diagnosis of recurrent or relapsed AML according to COG criteria is essentially the same as the criteria for making the diagnosis of AML. Usually this is defined as patients having more than 5% bone marrow blasts who were in previous remission after therapy for a diagnosis of AML according to WHO classification criteria.[
Despite second remission induction in over one-half of children with AML treated with drugs similar to drugs used in initial induction therapy, the prognosis for a child with recurrent or progressive AML is generally poor.[
Recurrent childhood AML
Approximately 50% to 60% of relapses occur within the first year after diagnosis, with most relapses occurring by 4 years from diagnosis.[
Prognosis and prognostic factors
Factors affecting the ability to attain a second remission include the following:
Additional prognostic factors were identified in the following studies:
Treatment of recurrent AML
Treatment options for children with recurrent AML may include the following:
Chemotherapy
Regimens that have been successfully used to induce remission in children with recurrent AML have commonly included high-dose cytarabine given in combination with the following agents:
Regimens built upon clofarabine and [
The standard-dose cytarabine regimens used in the United Kingdom MRC AML10 study for newly diagnosed children with AML (cytarabine and daunorubicin plus either etoposide or thioguanine) have, when used in the setting of relapse, produced remission rates similar to those achieved with high-dose cytarabine regimens.[
Immunotherapeutic approaches
Before its FDA approval for use in children with de novo AML in 2020, gemtuzumab ozogamicin was approved for children with relapsed or refractory AML in patients aged 2 years and older.
Targeted therapy (FLT3 inhibitors)
Midostaurin. There is limited experience with midostaurin in pediatric patients with AML.
Gilteritinib. As in de novo AML, most of the focus and published experience with FLT3 inhibitors is in adults with AML and this applies to the relapsed and refractory setting as well. In relapsed or refractory AML, gilteritinib, a type 1 selective FLT3 inhibitor with activity against both FLT3 mutations (ITD and D835/I836 tyrosine kinase domain [TKD]), is the first and only FLT3 inhibitor that has received FDA approval for single-agent use in adults based on the ADMIRAL (NCT02421939) trial.[
Gilteritinib is now being studied in children with FLT3-positive de novo AML in the COG AAML1831 (NCT04293562) trial.
Sorafenib. Sorafenib has been evaluated in pediatric patients with relapsed and refractory AML.
HSCT
The selection of additional treatment after the achievement of a second complete remission depends on previous treatment and individual considerations. Consolidation chemotherapy followed by HSCT is conventionally recommended, although there are no controlled prospective data regarding the contribution of additional courses of therapy once a second complete remission is obtained.[
Evidence (HSCT after second complete remission):
Second transplant after relapse following a first transplant
There is evidence that long-term survival can be achieved in a portion of pediatric patients who undergo a second transplant subsequent to relapse after a first myeloablative transplant. Survival was associated with late relapse (>6–12 months from first transplant), achievement of complete response before the second procedure, and use of a second myeloablative regimen if possible.[
CNS relapse
Isolated CNS relapse occurs in 3% to 6% of pediatric AML patients.[
The risk of CNS relapse increases with more CNS leukemic involvement at initial AML diagnosis (CNS1: 0.6%, CNS2: 2.6%, CNS3: 5.8% incidence of isolated CNS relapse, P < .001; multivariate HR for CNS3: 7.82, P = .0003).[
Refractory childhood AML (induction failure)
Treatment options for children with refractory AML may include the following:
Like patients with relapsed AML, induction failure patients are typically directed towards HSCT once they attain a remission, because studies suggest a better EFS than in patients treated with chemotherapy only (31.2% vs. 5%, P < .0001). Attainment of morphological CR for these patients is a significant prognostic factor for DFS after HSCT (46% vs. 0%; P = .02), with failure primarily resulting from relapse (relapse risk, 53.9% vs. 88.9%; P = .02).[
Evidence (treatment of refractory childhood AML with gemtuzumab ozogamicin):
Treatment options under clinical evaluation
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
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.
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.
References:
Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML) because of several factors, including the following:
These unique features of APL mandate a high index of suspicion at diagnosis so as to initiate proper supportive care measures to avoid coagulopathic complications during the first days of therapy. It is also critical to institute a different induction regimen of therapy to minimize the risk of coagulopathic complications and to provide a much improved long-term relapse-free survival and overall survival (OS) than with past approaches to treating APL and compared with outcomes for patients with the other forms of AML.[
Molecular Abnormality
The characteristic chromosomal abnormality associated with APL is t(15;17). This translocation involves a breakpoint that includes the retinoic acid receptor and leads to production of the promyelocytic leukemia (PML)::retinoic acid receptor alpha (RARA) fusion protein.[
Patients with a suspected diagnosis of APL can have their diagnosis confirmed by detection of the PML::RARA fusion protein (e.g., through fluorescence in situ hybridization [FISH], reverse transcriptase–polymerase chain reaction [RT-PCR], or conventional cytogenetics). An immunofluorescence method using an anti-PML monoclonal antibody can rapidly establish the presence of the PML::RARA fusion protein based on the characteristic distribution pattern of PML that occurs in the presence of the fusion protein.[
Clinical Presentation
Clinically, APL is characterized by severe coagulopathy that is often present at the time of diagnosis.[
Tretinoin therapy is initiated as soon as APL is suspected on the basis of morphological and clinical presentation,[
APL in children is generally similar to APL in adults, although children have a higher incidence of hyperleukocytosis (defined as WBC count higher than 10 × 109 /L) and a higher incidence of the microgranular morphological subtype.[
Risk Classification for Treatment Stratification
The prognostic significance of WBC count is used to define high-risk and low-risk patient populations and to assign postinduction treatment, with high-risk patients most commonly defined by WBC count of 10 × 109 /L or greater.[
In the COG AAML0631 (NCT00866918) trial, which included treatment with chemotherapy, tretinoin, and arsenic trioxide, risk classification primarily defined early death risk rather than relapse risk (standard risk, 0 of 66 patients vs. high risk, 4 of 35 patients).[
The Central Nervous System (CNS) and APL
CNS involvement at the time of diagnosis is not ascertained in most patients with APL because of the presence of disseminated intravascular coagulation. The COG AAML0631 (NCT00866918) trial identified 28 patients out of 101 enrolled children who had cerebrospinal fluid (CSF) exams at diagnosis, and in 7 of these children, blasts were identified in atraumatic taps.[
Overall, CNS relapse is uncommon for patients with APL, particularly for those with WBC counts of less than 10 × 109 /L.[
Treatment of APL
Modern treatment programs for APL are based on the sensitivity of leukemia cells from APL patients to the differentiation-inducing and apoptotic effects of tretinoin and arsenic trioxide. APL therapy first diverged from the therapy of other non-APL subtypes of AML with the addition of tretinoin to chemotherapy. With the incorporation of arsenic trioxide into modern treatment regimens, the use of traditional chemotherapy in adults and children is increasingly restricted to the induction phase for high-risk patients.[
Treatment options for children with APL may include the following:
Given the very high level of activity for the combination of arsenic trioxide and tretinoin for adults with APL,[
Before this approach was discovered, chemotherapy was used in all or most phases of therapy including induction, consolidation, and maintenance for pediatric trials like AAML0631 (NCT00866918). The regimens that use chemotherapy are now primarily of historical interest. They can also be used as a reference in refractory cases because of the findings from randomized clinical trials that compared regimens with the combination of tretinoin and arsenic trioxide with or without chemotherapy. Results from the completed cooperative group trial (COG AAML1331 [NCT02339740]) verified the benefit of treatment with tretinoin and arsenic trioxide for children with newly diagnosed APL,[
Almost all children with APL who were treated with tretinoin, arsenic trioxide, and modern supportive care (outlined below) achieved CR in the absence of coagulopathy-related mortality.[
Assessment of response to induction therapy in the first month of treatment using morphological and molecular criteria may provide misleading results because delayed persistence of differentiating leukemia cells can occur in patients who will ultimately achieve CR.[
For patients with APL, consolidation therapy may include repeated cycles of tretinoin and arsenic trioxide without additional chemotherapy, based on the adult and pediatric experience.[
Maintenance therapy is likely unnecessary for patients with APL who are treated with tretinoin and arsenic trioxide based on data from adult trials and the COG AAML1331 (NCT02339740) trial.[
Arsenic trioxide is the most active agent in the treatment of APL, and while initially used in relapsed APL, it is now incorporated into the treatment of newly diagnosed patients. Data supporting the use of arsenic trioxide initially came from trials that included adult patients only, but more recently, its efficacy has been seen in trials that included pediatric patients.
Evidence (arsenic trioxide therapy):
Standard-risk patients received tretinoin plus arsenic trioxide on days 1 to 28, with the possibility of continuing treatment up to day 70 to achieve a CR. High-risk patients received the same induction therapy schedule as standard-risk patients, with the addition of idarubicin on induction days 1, 3, 5, and 7. High-risk patients also received daily dexamethasone as a prophylactic treatment to prevent differentiation syndrome on days 1 to 14. All patients received the same consolidation therapy, which consisted of tretinoin on days 1 to 14 and days 29 to 42. Patients were also given arsenic trioxide 5 days each week for 4 consecutive weeks in every 8-week cycle (three rounds). The fourth consolidation therapy cycle concluded on day 28. There was no maintenance therapy phase.
In summary, survival rates for children with APL exceeding 90% are achievable using treatment programs that prescribe the rapid initiation of tretinoin with appropriate supportive care measures and that combine arsenic trioxide with tretinoin for induction and consolidation therapy.[
Treatment options under clinical evaluation
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.
Complications unique to APL therapy
In addition to the previously mentioned universal presence of coagulopathy in patients newly diagnosed with APL (further described below), several other unique complications occur in patients with APL for which the clinician should be aware. These include two tretinoin-related conditions, pseudotumor cerebri and differentiation syndrome (also called retinoic acid syndrome), and an arsenic trioxide–related complication, QT interval prolongation.
The incidence of pseudotumor cerebri has been reported to be as low as 1.7% with very strict definitions of the complication and as high as 6% to 16% in pediatric trials.[
When a diagnosis of pseudotumor cerebri is suspected, tretinoin is with held until symptoms abate and then is slowly escalated to full dose as tolerated.[
Since differentiation syndrome occurs more often in high-risk patients, dexamethasone is given with tretinoin and/or arsenic trioxide to prevent this complication.[
Minimal disease monitoring
The induction and consolidation therapies currently employed result in molecular remission, as measured by RT-PCR for PML::RARA fusion protein, in most APL patients, with 1% or fewer showing molecular evidence of disease at the end of consolidation therapy.[
Patients with persistent or relapsing disease on the basis of PML::RARA fusion protein RT-PCR measurement may benefit from intervention with relapse therapies [
Molecular Variants of APL Other ThanPML::RARAand Therapeutic Impact
Uncommon molecular variants of APL produce fusion proteins that join distinctive gene partners (e.g., ZBTB16, NPM1, STAT5B, and NUMA1) to RARA.[
Treatment of Recurrent APL
Historically, 10% to 20% of patients with APL relapsed; however, current studies that incorporated arsenic trioxide therapy showed a cumulative incidence of relapse of less than 5%.[
In patients who initially received chemotherapy-based treatments, the duration of their first remission was prognostic in APL, with patients who relapsed within 12 to 18 months of initial diagnosis having a worse outcome.[
Many children with APL who relapsed were exposed to anthracyclines in previous trials (exposures ranged from 400 mg/m2 to 750 mg/m2).[
Treatment options for children with recurrent APL may include the following:
Arsenic trioxide
For children with recurrent APL, the use of arsenic trioxide as a single agent or in regimens including tretinoin should be considered, depending on the therapy given during first remission. Arsenic trioxide is an active agent in patients with recurrent APL, with approximately 85% to 94% of patients achieving remission after treatment with this agent.[
For adults with relapsed APL, approximately 85% to 94% achieve morphological remission after treatment with arsenic trioxide.[
Because arsenic trioxide causes QT-interval prolongation that can lead to life-threatening arrhythmias,[
Gemtuzumab ozogamicin
The use of gemtuzumab ozogamicin, an anti-CD33/calicheamicin monoclonal antibody, as a single agent resulted in a 91% (9 of 11 patients) molecular remission after two doses and a 100% (13 of 13 patients) molecular remission after three doses, thus, demonstrating excellent activity of this agent in patients with relapsed APL.[
HSCT
Retrospective pediatric studies have reported 5-year EFS rates after either autologous or allogeneic transplantation approaches to be similar, at approximately 70%.[
Evidence (autologous HSCT):
Such data support the use of autologous transplantation in patients who are MRD negative in second CR and have MRD-negative stem cell collections.
Because of the rarity of APL in children and the favorable outcome for this disease, clinical trials in relapsed APL to compare treatment approaches are likely not feasible. However, an international expert panel provided recommendations for the treatment of relapsed APL on the basis of the reported pediatric and adult experience.[
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.
References:
Myeloid leukemias that arise in children with Down syndrome, particularly in patients younger than 4 years, are a distinct subset of AML characterized by the co-existence of trisomy 21 and GATA1 mutations within the leukemic blasts that are often, but not always, megakaryoblastic. This distinct leukemia is further subdivided into two versions: a transient newborn and young-infant version called transient abnormal myelopoiesis (TAM), which spontaneously remits over time; and an unremitting but chemosensitive version that appears later, between the ages of 90 days and 3 years.[
Transient Abnormal Myelopoiesis (TAM) Associated With Down Syndrome
Approximately 10% of neonates with Down syndrome develop a TAM (also termed transient myeloproliferative disorder [TMD]).[
Although TAM is usually a self-resolving condition, it can be associated with significant morbidity and may be fatal in 10% to 17% of affected infants.[
The following three risk groups have been identified on the basis of the diagnostic clinical findings of hepatomegaly with or without life-threatening symptoms:[
Therapeutic intervention is warranted in patients with apparent severe hydrops or organ failure. Because TAM eventually spontaneously remits, treatment is short in duration and primarily aimed at the reduction of leukemic burden and resolution of immediate symptoms. Several treatment approaches have been used, including the following:
Subsequent development of myeloid leukemia associated with Down syndrome is seen in 10% to 30% of children who have a spontaneous remission of TAM and has been reported at a mean age of 16 months (range, 1–30 months).[
Myeloid Leukemia Associated With Down Syndrome
Children with Down syndrome have a 10-fold to 45-fold increased risk of leukemia when compared with children without Down syndrome.[
Prognosis and Treatment of Children With Down Syndrome and AML
Outcome is generally favorable for children with Down syndrome who develop AML (called myeloid leukemia associated with Down syndrome in the World Health Organization classification).[
Prognostic factors for children with Down syndrome and AML include the following:
Approximately 29% to 47% of Down syndrome patients present with myelodysplastic syndromes (MDS) (<20% blasts) but their outcomes are similar to those with AML.[
Treatment options for newly diagnosed children with Down syndrome and AML include the following:
Appropriate therapy for younger children (aged ≤4 years) with Down syndrome and AML is less intensive than current standard childhood AML therapy. Hematopoietic stem cell transplant is not indicated in first remission.[
Evidence (chemotherapy):
The following two prognostic factors were identified:[
Children with mosaicism for trisomy 21 are treated similarly to those children with clinically evident Down syndrome.[
Treatment options under clinical evaluation
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.
Refractory Disease or Relapse in Children With Down Syndrome
A small number of publications address outcomes in children with Down syndrome who relapse after initial therapy or who have refractory AML. In three prospective trials of children with Down Syndrome and newly diagnosed AML, outcomes were poor for those who relapsed (4 of 11, 2 of 9, and 2 of 12 patients who relapsed survived).[
Treatment options for children with Down syndrome with refractory or relapsed AML include the following:
Evidence (treatment of children with Down syndrome with refractory or relapsed AML):
References:
Myelodysplastic syndromes (MDS) and myeloproliferative syndromes (MPS) represent between 5% and 10% of all myeloid malignancies in children. They are a heterogeneous group of disorders, with MDS usually presenting with cytopenias and MPS presenting with increased peripheral white blood cell, red blood cell, or platelet counts. MDS is characterized by ineffective hematopoiesis and increased cell death, while MPS is associated with increased progenitor proliferation and survival. Because they both represent disorders of very primitive, multipotential hematopoietic stem cells, curative therapeutic approaches nearly always require allogeneic hematopoietic stem cell transplantation (HSCT).
Risk Factors
Patients with the following germline mutations or inherited disorders have a significantly increased risk of developing MDS:
A retrospective analysis that used a capture assay to target mutations known to predispose to marrow failure and MDS was performed on genomic DNA from peripheral blood mononuclear cell samples from patients undergoing HSCT for MDS and aplastic anemia. Among the 46 children aged 18 years and younger with MDS, 10 patients (22%) harbored constitutional predisposition genetic mutations (5 GATA2, 1 each of MPL, RTEL1, SBDS, TINF2, and TP53), of which only 2 were suspected before transplant. This is considered a high incidence of genetic mutations compared with only 8% (4 of 64) in patients aged 18 to 40 years.[
Clinical Presentation
Patients usually present with signs of cytopenias, including pallor, infection, or bruising.
The bone marrow is usually characterized by hypercellularity and dysplastic changes in myeloid precursors. Clonal evolution can eventually lead to the development of AML. The percentage of abnormal blasts is less than 20% and lack common AML recurrent cytogenetic abnormalities (t(8;21), inv(16), t(15;17), or KMT2A translocations).
The less common hypocellular MDS can be distinguished from aplastic anemia in part by its marked dysplasia, clonal nature, and higher percentage of CD34-positive precursors.[
Molecular Abnormalities
Molecular features of myelodysplastic syndromes (MDS)
Pediatric MDS are associated with a distinctive constellation of genetic alterations compared with MDS arising in adults. In adults, MDS often evolves from clonal hematopoiesis and is characterized by mutations in TET2, DNMT3A, and TP53. In contrast, mutations in these genes are rare in pediatric MDS, while mutations in GATA2, SAMD9, SAMD9L, SETBP1, ASXL1, and RAS/MAPK pathway genes are observed in subsets of pediatric MDS cases.[
A report of the genomic landscape of pediatric MDS described the results of whole-exome sequencing for 32 pediatric patients with primary MDS and targeted sequencing for another 14 cases.[
A second report described the application of a targeted sequencing panel of 105 genes to 50 pediatric patients with MDS (refractory cytopenia of childhood = 31 and MDS-EB = 19) and was enriched for cases with monosomy 7 (48%).[
Patients with germline GATA2 mutations, in addition to MDS, show a wide range of hematopoietic and immune defects as well as nonhematopoietic manifestations.[
Germline GATA2 mutations were studied in 426 pediatric patients with primary MDS and 82 cases with secondary MDS who were enrolled in consecutive studies of the European Working Group of MDS in Childhood (EWOG-MDS).[
SAMD9 and SAMD9L germline mutations are both associated with pediatric MDS cases in which there is an additional loss of all or part of chromosome 7.[
In 2016, SAMD9 was identified as the cause of the MIRAGE syndrome (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy), which is associated with early-onset MDS with monosomy 7.[
The presence of an isolated monosomy 7 is the most common cytogenetic abnormality, although it does not appear to portend a poor prognosis compared with its presence in overt AML. However, the presence of monosomy 7 in combination with other cytogenetic abnormalities is associated with a poor prognosis.[
For more information about the World Health Organization (WHO) classification system of MDS, see the WHO Classification of Bone Marrow and Peripheral Blood Findings for Myelodysplastic Syndromes section.
Classification of MDS
The French-American-British (FAB) and WHO classification systems of MDS and MPS have been difficult to apply to pediatric patients. Alternative classification systems for children have been proposed, but none have been uniformly adopted, with the exception of the modified 2008 WHO classification system.[
The refractory cytopenia subtype represents approximately 50% of all childhood cases of MDS. The presence of an isolated monosomy 7 is the most common cytogenetic abnormality, although it does not appear to portend a poor prognosis compared with its presence in overt AML. However, the presence of monosomy 7 in combination with other cytogenetic abnormalities is associated with a poor prognosis.[
The R-IPSS prognostic groups and associated cytogenetic abnormalities include the following:[
The IPSS can help to distinguish low-risk from high-risk MDS, although its utility in children with MDS is more limited than in adults because many characteristics differ between children and adults.[
Treatment of Childhood MDS
Treatment options for children with MDS include the following:
HSCT
MDS and associated disorders usually involve a primitive hematopoietic stem cell. Thus, allogeneic HSCT is considered to be the optimal approach to treatment for pediatric patients with MDS. Although matched sibling transplantation is preferred, similar survival has been noted with well-matched, unrelated cord blood and haploidentical approaches.[
When making treatment decisions, some data should be considered. For example, survival as high as 80% has been reported for patients with early-stage MDS who proceeded to transplant within a few months of diagnosis. Additionally, early transplant and not receiving pretransplant chemotherapy have been associated with improved survival in children with MDS.[
The question of whether chemotherapy should be used in high-risk MDS has been examined.
Evidence (HSCT):
When analyzing these results, it is important to consider that the subtype refractory anemia with excess blasts in transformation is likely to represent patients with overt AML, while refractory anemia and refractory anemia with excess blasts represents MDS. The WHO classification has now omitted the category of refractory anemia with excess blasts in transformation, concluding that this entity was essentially AML.
Because survival after HSCT is improved in children with early forms of MDS (refractory anemia), transplantation before progression to late MDS or AML should be considered. HSCT should especially be considered when transfusions or other treatment are required, as is usually the case in patients with severe symptomatic cytopenias.[
Because MDS in children is often associated with inherited predisposition syndromes, reports of transplantation in small numbers of patients with these disorders have been documented. For example, in patients with Fanconi anemia and AML or advanced MDS, the 5-year overall survival (OS) rate has been reported to be 33% to 55%.[
While some patients with inherited predisposition syndromes require significant modification of their transplant approaches because of excess toxicity (e.g., Fanconi anemia), other syndromes have no detectable excessive toxicity associated with the transplant process. Inherited GATA2 is a good example of the latter. One study compared HSCT outcomes of 65 children with GATA2 germline mutations and MDS with the outcomes of 404 children with MDS and wild-type germline GATA2. Disease-free survival, relapse, and nonrelapse mortality were similar in the two populations.[
For patients with clinically significant cytopenias, supportive care that includes transfusions and prophylactic antibiotics are considered standard of care. The use of hematopoietic growth factors can improve the hematopoietic status, but concerns remain that such treatment could accelerate conversion to AML.[
Other therapies
Other supportive therapies that have been studied include the following:
Treatment Options Under Clinical Evaluation
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see 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.
References:
Pathogenesis
The development of acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) after treatment with ionizing radiation or chemotherapy, particularly alkylating agents and topoisomerase inhibitors, is termed therapy-related AML (t-AML) or therapy-related MDS (t-MDS). In addition to genotoxic exposures, genetic predisposition susceptibilities (such as polymorphisms in drug detoxification and DNA repair pathway components) may contribute to the occurrence of secondary AML/MDS.[
The risk of t-AML or t-MDS is regimen-dependent and often related to the cumulative doses of chemotherapy agents received and the dose and field of radiation administered.[
t-AML or t-MDS resulting from epipodophyllotoxins and other topoisomerase II inhibitors (e.g., anthracyclines) usually occur within 2 years of exposure and are commonly associated with chromosome 11q23 abnormalities,[
Treatment of t-AML or t-MDS
Treatment options for t-AML or t-MDS include the following:
The goal of treatment is to achieve an initial complete remission (CR) using AML-directed regimens and then, usually, to proceed directly to HSCT with the best available donor. However, treatment is challenging because of the following:[
Accordingly, CR rates and overall survival (OS) rates are usually lower for patients with t-AML compared with patients with de novo AML.[
Patients with t-MDS-refractory anemia usually have not needed induction chemotherapy before transplant; the role of induction therapy before transplant is controversial in patients with refractory anemia with excess blasts-1.
Only a few reports describe the outcome of children undergoing HSCT for t-AML.
Evidence (HSCT for t-AML or t-MDS):
Because t-AML is rare in children, it is not known whether the significant decrease in transplant-related mortality after unrelated donor HSCT noted over the past several years will translate to improved survival in this population. Patients should be carefully assessed for pre-HSCT morbidities caused by earlier therapies, and treatment approaches should be adapted to give adequate intensity while minimizing transplant-related mortality.
References:
Incidence
Juvenile myelomonocytic leukemia (JMML) is a rare leukemia that occurs approximately ten times less frequently than acute myeloid leukemia (AML) in children, with an annual incidence of about 1 to 2 cases per 1 million people.[
Clinical Presentation and Diagnostic Criteria
Common clinical features at diagnosis include the following:[
In children presenting with clinical features suggestive of JMML, current criteria used for a definitive diagnosis are described in Table 8.[
Category 1 (All are Required) | Category 2 (One is Sufficient)a | Category 3 (Patients Without Genetic Features Must Have the Following in Addition to Category 1b) |
---|---|---|
Clinical and Hematologic Features | Genetic Studies | Other Features |
GM-CSF = granulocyte-macrophage colony-stimulating factor; NF1 = neurofibromatosis type 1. | ||
a Patients who are found to have a category 2 lesion need to meet the criteria in category 1 but do not need to meet the category 3 criteria. Patients who are not found to have a category 2 lesion must meet the category 1 and 3 criteria. | ||
b Note that only 7% of patients with JMML will NOT present with splenomegaly, but virtually all patients develop splenomegaly within several weeks to months of initial presentation. | ||
Absence of theBCR::ABL1gene fusion | Somatic mutation inKRAS,NRAS, orPTPN11(germline mutations need to be excluded) | Monosomy 7 or other chromosomal abnormality, or at least 2 of the criteria listed below: |
>1 × 109 /L circulating monocytes | Clinical diagnosis of NF1 orNF1gene mutation | — Circulating myeloid or erythroid precursors |
<20% blasts in the peripheral blood and bone marrow | GermlineCBLmutation and loss of heterozygosity ofCBL | — Increased hemoglobin F for age |
Splenomegaly | — Hyperphosphorylation of STAT5 | |
— GM-CSF hypersensitivity |
Pathogenesis and Related Syndromes
The pathogenesis of JMML has been closely linked to activation of the RAS oncogene pathway, along with related syndromes (see Figure 1).[
Figure 1. Schematic diagram showing ligand-stimulated Ras activation, the Ras-Erk pathway, and the gene mutations found to date contributing to the neuro-cardio-facio-cutaneous congenital disorders and JMML. NL/MGCL: Noonan-like/multiple giant cell lesion; CFC: cardia-facio-cutaneous; JMML: juvenile myelomonocytic leukemia. Reprinted from Leukemia Research, 33 (3), Rebecca J. Chan, Todd Cooper, Christian P. Kratz, Brian Weiss, Mignon L. Loh, Juvenile myelomonocytic leukemia: A report from the 2nd International JMML Symposium, Pages 355-62, Copyright 2009, with permission from Elsevier.
Children with neurofibromatosis type 1 (NF1) and Noonan syndrome are at increased risk of developing JMML:[
Importantly, some children with Noonan syndrome have a hematologic picture indistinguishable from JMML that self-resolves during infancy, similar to what happens in children with Down syndrome and transient myeloproliferative disorder.[
Within a large prospective cohort of 641 patients with Noonan syndrome and a germline PTPN11 mutation, 36 patients (approximately 6%) showed myeloproliferative features, with 20 patients (approximately 3%) meeting the consensus diagnostic criteria for JMML.[
Mutations in the CBL gene, an E3 ubiquitin-protein ligase that is involved in targeting proteins, particularly tyrosine kinases, for proteasomal degradation occur in 10% to 15% of JMML cases,[
Genomics of JMML
Molecular features of JMML
The genomic landscape of JMML is characterized by mutations in one of five genes of the RAS pathway: NF1, NRAS, KRAS, PTPN11, and CBL.[
The mutation rate in JMML leukemia cells is very low, but additional mutations beyond those of the five RAS pathway genes described above are observed.[
A report describing the genomic landscape of JMML found that 16 of 150 patients (11%) lacked canonical RAS pathway mutations. Among these 16 patients, 3 were observed to have in-frame fusions involving receptor tyrosine kinases (DCTN1::ALK, RANBP2::ALK, and TBL1XR1::ROS1 gene fusions). These patients all had monosomy 7 and were aged 56 months or older. One patient with an ALK fusion was treated with crizotinib plus conventional chemotherapy and achieved a complete molecular remission and proceeded to allogeneic bone marrow transplantation.[
Figure 2. Alteration profiles in individual JMML cases. Germline and somatically acquired alterations with recurring hits in the RAS pathway and PRC2 network are shown for 118 patients with JMML who underwent detailed genetic analysis. Blast excess was defined as a blast count ≥10% but <20% of nucleated cells in the bone marrow at diagnosis. Blast crisis was defined as a blast count ≥20% of nucleated cells in the bone marrow. NS, Noonan syndrome. Reprinted by permission from Macmillan Publishers Ltd: Nature Genetics (Caye A, Strullu M, Guidez F, et al.: Juvenile myelomonocytic leukemia displays mutations in components of the RAS pathway and the PRC2 network. Nat Genet 47 [11]: 1334-40, 2015), copyright (2015).
Prognosis (genomic and molecular factors)
Several genomic factors affect the prognosis of patients with JMML, including the following:
Prognosis (Clinical Factors)
Age, platelet count, and fetal hemoglobin level after any treatment. Historically, more than 90% of patients with JMML died despite the use of chemotherapy;[
Favorable prognostic factors for survival after any therapy include age younger than 2 years, platelet count greater than 33 × 109 /L, and low age-adjusted fetal hemoglobin levels.[
Treatment of JMML
Treatment options for JMML include the following:
The role of conventional antileukemia therapy in the treatment of JMML is not defined. Determining the role of specific agents in the treatment of JMML is complicated because of the absence of consensus response criteria.[
HSCT currently offers the best chance of cure for JMML.[
Evidence (HSCT):
Disease recurrence is the primary cause of treatment failure for children with JMML after HSCT and occurs in 30% to 40% of cases.[
Treatment Options Under Clinical Evaluation
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
References:
Incidence
Chronic myelogenous leukemia (CML) accounts for less than 5% of all childhood leukemia, and in the pediatric age range, occurs most commonly in older adolescents.[
Molecular Abnormality
The cytogenetic abnormality most characteristic of CML is the Philadelphia chromosome (Ph), which represents a translocation of chromosomes 9 and 22 (t(9;22)) resulting in a BCR::ABL1 protein fusion.[
Clinical Presentation
CML is characterized by a marked leukocytosis and is often associated with thrombocytosis, sometimes with abnormal platelet function. Bone marrow aspiration or biopsy reveals hypercellularity with relatively normal granulocytic maturation and no significant increase in leukemic blasts. Although reduced leukocyte alkaline phosphatase activity is seen in CML, this is not a specific finding.
CML has the following three clinical phases:
Treatment of CML: Historical Perspective
Before the tyrosine kinase inhibitor (TKI) era, allogeneic hematopoietic stem cell transplantation (HSCT) was the primary treatment for children with CML. Published reports from this period described survival rates of 70% to 80% when an HLA–matched-family donor (MFD) was used in the treatment of children in early chronic phase, with lower survival rates when HLA–matched-unrelated donors were used.[
Relapse rates were low (less than 20%) when transplant was performed in chronic phase.[
Compared with transplantation in chronic phase, transplantation in accelerated phase or blast crisis and in second-chronic phase resulted in significantly reduced survival.[
The introduction of the TKI imatinib as a therapeutic drug targeted at inhibiting the BCR::ABL1 fusion kinase revolutionized the treatment of patients with CML, for both children and adults.[
Treatment of Adult CML With TKIs
Imatinib is a potent inhibitor of the ABL1 tyrosine kinase, platelet-derived growth factor (PDGF) receptors (alpha and beta), and KIT. Imatinib treatment achieves clinical, cytogenetic, and molecular remissions (as defined by the absence of BCR::ABL1 fusion transcripts) in a high proportion of CML patients treated in chronic phase.[
Evidence (imatinib for adults):
Guidelines for imatinib treatment have been developed for adults with CML on the basis of patient response to treatment, including the timing of achieving complete hematologic response, complete cytogenetic response, and major molecular response (defined as attainment of a 3-log reduction in BCR::ABL1 gene fusion/control gene ratio).[
Poor adherence is a major reason for loss of complete cytogenetic response and imatinib failure for adult patients with CML on long-term therapy.[
Two TKIs, dasatinib and nilotinib, have been shown to be effective in patients who have an inadequate response to imatinib, although not in patients with the T315I mutation. Both dasatinib and nilotinib have also received regulatory approval for the treatment of newly diagnosed chronic-phase CML in adults, on the basis of the following studies:
Because of the superiority over imatinib in terms of complete cytogenetic response rate and major molecular response rate, both dasatinib and nilotinib are extensively used as first-line therapy in adults with CML. However, despite more rapid responses with dasatinib and nilotinib than with imatinib when used as frontline therapy, PFS and OS appear to be similar for all three agents.[
Bosutinib is another TKI that targets the BCR::ABL1 gene fusion and has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of all phases of CML in adults who show intolerance to or whose disease shows resistance to previous therapy with another TKI. Bosutinib has not been studied in the pediatric population.
Ponatinib is a BCR::ABL1 protein fusion inhibitor that is effective against the T315I mutation.[
For adult patients with CML who proceed to allogeneic HSCT, there is no evidence that pretransplant imatinib adversely impacts outcome.
Evidence (imatinib followed by HSCT in adults):
For adult patients treated with a TKI alone (without HSCT), the optimal duration of therapy remains unknown, and most patients continue TKI treatment indefinitely. Studies are ongoing to determine the safety of discontinuing TKI therapy and the criteria most prognostic of sustained remissions after ending TKI therapy.
Evidence (length of imatinib therapy in adults):
Additional research is required before cessation of imatinib or other BCR::ABL1 targeted therapy for selected patients with CML in molecular remission can be recommended as a standard clinical practice.
Treatment of Childhood CML
Treatment options for children with CML may include the following:
Imatinib has shown a high level of activity in children with CML that is comparable with the activity observed in adults.[
Evidence (imatinib in children):
As a result of this high level of activity, it is common to initiate imatinib treatment in children with CML rather than proceeding immediately to allogeneic stem cell transplantation.[
Doses of imatinib used in phase II trials for children with CML have ranged from 260 mg/m2 to 340 mg/m2, which provide comparable drug exposures as the adult flat-doses of 400 mg to 600 mg.[
Evidence (imatinib dose in children):
Thus, it appears that starting with the higher dose of 340 mg/m2 has superior efficacy and is typically tolerable, with dose adjustment as needed for toxicity.[
The monitoring guidelines described above for adults with CML are reasonable to use in children.
Imatinib is generally well tolerated in children, with adverse effects generally being mild to moderate and reversible with treatment discontinuation or dose reduction.[
There are fewer published data regarding the efficacy and toxicities of the two other TKIs approved by the FDA for use in children with CML—dasatinib and nilotinib.
Evidence (dasatinib in children):
Evidence (nilotinib in children):
An initial study (NCT01077544 [CAMN107A2120]) of 11 patients evaluated pharmacokinetic, safety, and preliminary efficacy data; a second study (NCT01844765 [CAMN107A2203; AAML1321]) of 58 patients evaluated efficacy and safety. Data from both studies were combined for a pooled-data analysis of 69 patients, which included 25 patients with newly diagnosed CML and 44 patients with resistant or intolerant CML. Both studies utilized a dose of 230 mg/m2 given twice daily (rounded to the nearest 50 mg; maximum dose, 400 mg).[
A safe pediatric dose has not yet been established for other TKIs (e.g., bosutinib and ponatinib).
Discontinuation of TKI therapy
Discontinuation of TKI treatment is an accepted strategy for adults with CML who meet strict criteria related to their duration of treatment and to their response to treatment. Guidelines for discontinuation of TKIs have been developed by both the European LeukemiaNet (ELN) and the U.S. National Comprehensive Cancer Network (NCCN).[
These guidelines specify close monitoring of BCR::ABL1 transcript levels after TKI discontinuation. Loss of major molecular response (MMR or MR3) (BCR::ABL1 transcript level ≤0.1% IS) is generally used as the trigger for re-initiation of TKI therapy.
Loss of MMR is most likely to occur within the first 6 months of TKI discontinuation. Loss of MMR occurs much less frequently more than 1 year after TKI discontinuation. A meta-analysis included 3,105 adult patients who initiated a first attempt at TKI discontinuation. The study found that the probability of molecular recurrence was 35% after 0 to 6 months, 8% after 6 to 12 months, 3% after 12 to 18 months, and 3% after 18 to 24 months.[
There is limited data regarding TKI discontinuation in children with CML. This limited experience is explained, in part, by the low incidence of CML in children. In addition, only a minority of children with CML who are treated with TKIs meet the criteria for TKI discontinuation. For example, among patients enrolled on the International Chronic Myeloid Leukemia Pediatric Study (I-CML-Ped [NCT01281735]), only 9% of children with CML who were treated with TKIs met the criteria for TKI discontinuation.[
TKI withdrawal syndrome is observed in approximately 20% to 30% of adults when TKI therapy is discontinued.[
Among the 18 children who stopped taking imatinib, 9 (50%) eventually resumed treatment.[
Treatment Options under Clinical Evaluation
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
Treatment of Recurrent or Refractory Childhood CML
Treatment options for children with recurrent or refractory CML may include the following:
In children who develop a hematologic or cytogenetic relapse during treatment with imatinib or who have an inadequate initial response to imatinib, determination of BCR::ABL1 kinase domain mutation status should be considered to help guide subsequent therapy. Depending on the patient's mutation status, alternative kinase inhibitors such as dasatinib or nilotinib can be considered on the basis of the adult and pediatric experience with these agents.[
Evidence (dasatinib in children with resistant or intolerant CML):
Evidence (nilotinib in children with resistant or intolerant CML):
Dasatinib and nilotinib are active against many BCR::ABL1 gene fusion mutations that confer resistance to imatinib, although the agents are ineffective in patients with the T315I mutation. In the presence of the T315I mutation, which is resistant to all FDA-approved kinase inhibitors, an allogeneic transplant should be considered. Ponatinib, the BCR::ABL1 protein fusion inhibitor that is effective against the T315I mutation in adults, has not been prospectively studied in the pediatric population.
The question of whether a pediatric patient with CML should receive an allogeneic transplant when multiple TKIs are available remains unanswered; however, reports suggest that PFS does not improve when using HSCT, compared with the sustained use of imatinib.[
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.
References:
While the issues of long-term complications of cancer and its treatment cross many disease categories, several important issues related to the treatment of myeloid malignancies are worth emphasizing. For more information, see Late Effects of Treatment for Childhood Cancer.
Selected studies of the late effects of AML therapy in adult survivors who were not treated with hematopoietic stem cell transplant (HSCT) include the following:
Renal, gastrointestinal, and hepatic late adverse effects have been reported to be rare for children undergoing chemotherapy only for treatment of AML.[
Selected studies of the late effects of AML therapy in adult survivors who were treated with HSCT include the following:
New therapeutic approaches to reduce long-term adverse sequelae are needed, especially for reducing the late sequelae associated with myeloablative HSCT.
Important resources for details on follow-up and risks for survivors of cancer have been developed, including the COG's Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers and the National Comprehensive Cancer Network's Guidelines for Acute Myeloid Leukemia. Furthermore, having access to past medical history that can be shared with subsequent medical providers has become increasingly recognized as important for cancer survivors.
References:
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
General Information About Childhood Acute Myeloid Leukemia (AML)
Added hypodiploidy as a genetic abnormality associated with an unfavorable prognosis. Also added text to state that hypodiploidy is defined as a modal chromosome number of less than or equal to 45. In a retrospective cohort analysis, the International Berlin-Frankfurt-Münster AML Study Group aimed to characterize hypodiploidy in pediatric patients with AML (cited Hammer et al. as reference 111).
Treatment of Childhood AML
Added text about the results of the Children's Oncology Group (COG) AML1031 trial, which showed that sorafenib improved the event-free survival of pediatric patients with de novo AML and high-allelic ratio FLT3 internal tandem duplication mutations (cited Pollard et al. as reference 36).
Acute Promyelocytic Leukemia (APL)
Added text to state that in the COG AAML1331 trial, patients with standard-risk APL had idarubicin eliminated from the induction cycle. Mitoxantrone, high-dose cytarabine, and idarubicin were eliminated from the consolidation cycles. Mercaptopurine and methotrexate were eliminated from the maintenance cycles. Intrathecal doses of cytarabine were also eliminated.
Myelodysplastic Syndromes (MDS)
Added text to state that in one retrospective analysis, only the revised International Prognostic Scoring System (R-IPSS) very poor–risk subgroup, defined as having complex cytogenetics, was found to have a significant adverse prognostic impact on overall survival and relapse risk after transplant (cited Yamamoto et al. as reference 34).
Added text about the R-IPSS prognostic groups and associated cytogenetic abnormalities.
Chronic Myelogenous Leukemia (CML)
Added Discontinuation of TKI therapy as a new subsection.
Survivorship and Adverse Late Sequelae
Added text about the results of a Childhood Cancer Survivor Study cohort analysis that examined the long-term mortality and health statuses of 856 children previously treated for AML, with or without hematopoietic stem cell transplantation, between 1970 and 1999 (cited Turcotte et al. as reference 14).
This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood acute myeloid leukemia and other myeloid malignancies. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment are:
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
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PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."
The preferred citation for this PDQ summary is:
PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/leukemia/hp/child-aml-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389454]
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Last Revised: 2023-06-14
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