Childhood Non-Hodgkin Lymphoma Treatment (PDQ®): Treatment - Health Professional Information [NCI]

General Information About Childhood Non-Hodgkin Lymphoma (NHL)

Dramatic improvements in survival have been achieved for children and adolescents with cancer.[1] Between 1975 and 2020, childhood cancer mortality decreased by more than 50%.[1,2,3] Between 2013 and 2019, the 5-year relative survival rate was 90% for children and adolescents younger than 20 years with NHL.[3] In 2020, there were an estimated 30,500 survivors of childhood and adolescent NHL in the United States.[4]

Childhood and adolescent cancer survivors require close monitoring because cancer therapy side effects may persist or develop months or years after treatment. For information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors, see Late Effects of Treatment for Childhood Cancer.

On the basis of immunophenotype, molecular biology, and clinical response to treatment, most NHL cases occurring in childhood and adolescence fall into three categories:

1. Aggressive mature B-cell NHL (Burkitt lymphoma, diffuse large B-cell lymphoma, and primary mediastinal B-cell lymphoma).
2. Lymphoblastic lymphoma.
3. Anaplastic large cell lymphoma.

Other rare types of pediatric NHL include the following:

• Pediatric gray zone lymphoma.
• Pediatric-type follicular lymphoma.
• Marginal zone lymphoma (including mucosa-associated lymphoid tissue [MALT] lymphoma).
• Primary central nervous system (CNS) lymphoma.
• Peripheral T-cell lymphoma.
• Cutaneous T-cell lymphoma/mycosis fungoides.

Incidence

Lymphoma (Hodgkin lymphoma and NHL) is the third most common childhood malignancy, and NHL accounts for approximately 7% of cancers in children younger than 20 years in the United States.[3]

The following factors affect the incidence of NHL in children and adolescents:[2,3]

• Geographic location: In the United States, about 1,200 new cases of NHL are diagnosed each year in children and adolescents younger than 20 years.[5] The incidence is approximately 13 cases per 1 million people per year.[2,3]

  In sub-Saharan Africa, the incidence of Epstein-Barr virus (EBV)–induced Burkitt lymphoma is tenfold to twentyfold higher than the incidence in the United States, resulting in a much higher incidence of NHL.[6]

• Race: The incidence of NHL is higher in White people than in Black people. Burkitt lymphoma is more common in non-Hispanic White people (3.2 cases/million person-years) than in Hispanic White people (2 cases/million person-years).[7]
• Age: Although there is no sharp age peak, childhood NHL occurs most commonly in the second decade of life.[2,3] NHL occurs infrequently in children younger than 3 years [2,3] and is very rare in infants (1% in Berlin-Frankfurt-Münster [BFM] trials from 1986 to 2002).[8]

  The incidence of NHL is increasing overall because of a slight increase in the incidence for patients aged 15 to 19 years. Conversely, the incidence of NHL in children younger than 15 years has remained constant over the past several decades.[3]

• Sex: Childhood NHL is more common in males than in females, with the exception of primary mediastinal B-cell lymphoma, in which the incidence is almost the same in males and females.[9,10] According to data from the National Childhood Cancer Registry from 2016 to 2020, the incidence of Burkitt lymphoma was 2.4 cases per 1 million children and adolescents younger than 20 years. Males have a higher incidence of Burkitt lymphoma than females (3.8 cases vs. 0.9 cases per 1 million).[3] The incidence of diffuse large B-cell lymphoma increases with age in both males and females. The incidence of lymphoblastic lymphoma remains relatively constant across ages for both males and females.[9]

The incidence and age distribution of histological types of NHL according to sex is described in Table 1.

Table 1. Incidence and Age Distribution of Specific Types of NHL^a

​	Incidence of NHL per Million Person-Years
​	Males				Females
ALCL = anaplastic large cell lymphoma; DLBCL = diffuse large B-cell lymphoma; NHL = non-Hodgkin lymphoma.
a Adapted from Percy et al.[9]
b Indolent and aggressive histologies (more commonly seen in adult patients) are mostly found in older adolescents.
Age (y)	<5	5–9	10–14	15–19	<5	5–9	10–14	15–19
Burkitt	3.2	6	6.1	2.8	0.8	1.1	0.8	1.2
Lymphoblastic	1.6	2.2	2.8	2.2	0.9	1.0	0.7	0.9
DLBCL	0.5	1.2	2.5	6.1	0.6	0.7	1.4	4.9
Other (mostly ALCL)	2.3	3.3	4.3	7.8b	1.5	1.6	2.8	3.4b

Risk Factors

Relatively little data on the epidemiology of childhood NHL have been published. However, known risk factors include the following:

• EBV: EBV is associated with most cases of NHL occurring in the immunodeficient population.[9] Almost all endemic Burkitt lymphoma/leukemia in Africa is associated with EBV. However, approximately 15% of cases in Europe and the United States will have EBV detectable in the tumor tissue.[11]
• Immunodeficiency: Immunodeficiency, both congenital and acquired (HIV or posttransplant immunodeficiency), increases the risk of NHL.[9] U.S. transplant and cancer registries show that posttransplant lymphoproliferative disease (PTLD) accounts for about 3% of all pediatric NHL diagnoses; 65% of PTLDs are diffuse large B-cell lymphoma histology, and 9% are Burkitt histology.[12]
• DNA repair syndromes: The incidence of NHL is increased in patients with DNA repair syndromes, including ataxia-telangiectasia, Nijmegen breakage syndrome, and constitutional mismatch repair deficiency.[13] The distribution of NHL subtypes differs among the DNA repair syndromes, as follows:[13]
  • For patients with ataxia-telangiectasia, mature B-cell NHL accounts for most of the NHL cases.
  • For patients with Nijmegen breakage syndrome, mature B-cell NHL is the most common lymphoma. However, T-cell lymphoblastic lymphoma and peripheral T-cell lymphoma are each observed in approximately 20% of cases.
  • For patients with constitutional mismatch repair deficiency, most cases are T-cell lymphoblastic lymphoma.
• Previous neoplasm: NHL presenting as a subsequent neoplasm is rare in pediatrics. A retrospective review of the German Childhood Cancer Registry identified 2,968 children who were newly diagnosed with cancer, 11 (0.3%) of whom were later diagnosed with NHL as a subsequent neoplasm before age 19 years.[14] In this small cohort, outcomes were similar to those of patients with de novo NHL who were treated with standard therapy.[14]

Anatomy

Unlike adults with NHL who present most often with nodal disease, children typically have extranodal disease involving the mediastinum, abdomen, and/or head and neck, as well as the bone marrow or CNS. In high-income countries, Burkitt lymphoma occurs in the abdomen in approximately 60% of cases, with 15% to 20% of cases arising in the head and neck.[15,16] This high incidence of extranodal disease substantiates the use of the Murphy staging system for pediatric NHL, instead of the Ann Arbor staging system.

Diagnostic Evaluation

The following tests and procedures are used to diagnose childhood NHL:

• History and physical examination.
• Pathological examination of tumor cells.
  • Immunophenotyping by immunohistochemistry and/or flow cytometry.
  • Cytogenetics and/or fluorescence in situ hybridization (FISH).
• Bone marrow biopsy and aspiration.
• Lumbar puncture with cerebrospinal fluid (CSF) cytology.
• Total-body imaging (e.g., computed tomography scan, positron emission tomography, and magnetic resonance imaging).
• Measurement of serum electrolytes, lactate dehydrogenase (LDH), uric acid, blood urea nitrogen (BUN), and creatinine.
• Liver function tests.

Prognosis and Prognostic Factors for Childhood NHL

In high-income countries and with current treatments, more than 80% of children and adolescents with NHL survive at least 5 years, although outcome depends on a number of factors, including clinical stage and histology.[17]

Prognostic factors for childhood NHL include the following:

• Response to therapy.
• Stage at diagnosis/presence of minimal disseminated disease (MDD).
• Sites of disease at diagnosis.
• Age.
• Immune response to tumor.

For more information about the tumor biology and genomic alterations associated with each type of NHL, some of which are being evaluated as potential prognostic biomarkers, see the following sections:

• Aggressive mature B-cell lymphoma.
  • Burkitt lymphoma.
  • Diffuse large B-cell lymphoma.
  • Primary mediastinal B-cell lymphoma.
• Lymphoblastic lymphoma.
• Anaplastic large cell lymphoma.

Response to therapy

Regardless of histology, pediatric patients with NHL that is refractory to first-line therapy have a very poor prognosis,[18,19,20,21,22] with the exception of patients with anaplastic large cell lymphoma.[18,23] As opposed to other hematologic malignancies, it has been difficult to demonstrate the prognostic value of early response to therapy in pediatric NHL.

• Burkitt lymphoma: Historically, response to the initial prophase treatment was considered an important predictive factor. Poor responders (i.e., <20% resolution of disease) had an event-free survival (EFS) rate of 30%.[24,25] However, poor response to initial treatment was not found to be an adverse prognostic factor in the Inter B-NHL Ritux 2010 (NCT01516580) trial, in which patients were treated with more effective therapy.[26]
• Lymphoblastic lymphoma: The presence of a residual mediastinal mass at day 33 or at the end of induction was not found to be associated with decreased survival in the BFM 90-95 studies. However, all patients with less than 70% reduction at the end of induction had therapy intensified.[27]

International pediatric NHL response criteria have been proposed but require prospective evaluation. The clinical utility of these new criteria are under investigation.[28]

In contrast to the prognostic value of minimal residual disease (MRD) in patients with acute leukemia, the prognostic value of MRD after therapy is initiated remains uncertain and requires further investigation in pediatric patients with NHL.

• Burkitt lymphoma: One study suggested an inferior outcome for patients with Burkitt lymphoma who had detectable MRD after induction chemotherapy.[29] However, other studies found that detectable MRD at the end of induction was not prognostic, possibly because of the low number of relapses in patients with disease detected in the blood or bone marrow at diagnosis.[30,31]
• Anaplastic large cell lymphoma: A retrospective analysis of a collaborative European study showed that after induction, MRD-negative patients had a relapse risk of approximately 20% and an overall survival (OS) rate of approximately 90%. By contrast, MRD-positive patients had a relapse risk of 81% and an OS rate of 65% (P < .001). The presence of MRD is significantly associated with uncommon histological subtypes containing small cell and/or lymphohistiocytic components.[32][Level of evidence B4]

Stage at diagnosis/minimal disseminated disease (MDD)

In general, patients with low-stage disease (i.e., single extra-abdominal/extrathoracic tumor or totally resected intra-abdominal tumor) have an excellent prognosis (5-year survival rate of approximately 90%), regardless of histology.[24,27,33,34,35] Apart from this finding, the outcome by clinical stage, using appropriate therapy on the basis of risk stratification, does not differ significantly.

A surrogate for tumor burden, specifically elevated levels of LDH, has been shown to be prognostic in many studies.[24,33,36]

Patients with morphologically involved bone marrow with more than 5% lymphoma cells are considered to have stage IV disease. MDD is generally defined as submicroscopic bone marrow involvement that is present at diagnosis. MDD is generally detected by sensitive methods such as flow cytometry or reverse transcription–polymerase chain reaction (RT-PCR).

• Burkitt lymphoma: The role of MDD remains to be defined. One study suggested that MDD is predictive of outcome,[37,38] while another study did not.[30]
• T-cell lymphoblastic lymphoma: A Children's Oncology Group (COG) study (A5971 [NCT00004228]) demonstrated a 2-year EFS rate of 91% for patients who had an MDD level by flow cytometry lower than 1% (n = 73), compared with 68% if the MDD level exceeded 1% (n = 26), and 52% if the MDD was 5% and higher (n = 9).[39]

  An Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) study used an MDD cutoff level of 3% by flow cytometry. The study observed a 5-year EFS rate of 60% for patients with MDD greater than 3% versus 83% for the remaining patients (P = .04).[40]

  The largest experience with MDD for T-cell lymphoblastic lymphoma (n = 273) is from the COG AALL0434 (NCT00408005) study, in which MDD had no prognostic impact. Patients with bone marrow MDD levels of less than 1% had an EFS rate of 82.4% compared with 89.5% for those with MDD levels of 1% or higher (P = .3084).[41]

• Anaplastic large cell lymphoma: Multiple studies have found that the presence of MDD using molecular diagnostic methods to detect the NPM::ALK gene transcript is associated with increased risk of treatment failure.[32][Level of evidence B4]; [42,43,44,45,46,47] MDD is commonly quantified by normalizing the number of NPM::ALK transcripts to 10⁴ copies of ABL1, with 10 normalized copy number (NCN) NPM::ALK transcripts being the most common cut point to compare the prognostic impact of MDD.[42,43,44]NPM::ALK transcript levels in blood and bone marrow are comparable.[42,45] Examples of studies with MDD results include the following:
  • Among 74 patients treated on the NHL-BFM-95 and ALCL99 (NCT00006455) trials, 16 patients with more than 10 NCNs NPM::ALK in bone marrow had a cumulative incidence of relapse of 71% (± 14%) compared with 18% (± 6%) for the 59 patients with 10 or fewer NCNs.[42] The presence of MDD was significantly higher in patients with stages III to IV disease and in patients with small cell and other uncommon histologies.[42]
  • For a cohort of 420 patients treated on the ALCL99 trial, MDD results by qualitative PCR were available for 162 patients. MDD was positive in either bone marrow or blood for 54% of patients.[45] The 10-year progression-free survival (PFS) rate was 83% for patients with negative MDD compared with 62% for patients with positive MDD. In multivariate analysis, MDD and histological subtype (small cell/lymphohistiocytic) were the two factors significantly associated with inferior outcome.
  • The ANHL12P1 (NCT01979536) study evaluated the addition of either brentuximab vedotin or crizotinib to ALCL99 trial chemotherapy. The study confirmed the poor prognosis associated with MDD (defined as >10 NCNs) in the peripheral blood at diagnosis. In each arm, approximately 40% of patients had MDD, and their 2-year EFS rate was about 60%. The remaining patients without detectable MDD had a 2-year EFS rate of approximately 85%.[46,47]
  • The prognostic significance of MDD is modified by MRD positivity after one course of chemotherapy. In a study of 180 patients, the presence of MDD was associated with a cumulative incidence of relapse of 46%, compared with a cumulative incidence of relapse of 15% for patients with no bone marrow involvement.[32][Level of evidence B4] Among 26 MDD-positive/MRD-positive patients, the cumulative incidence of relapse was significantly higher (81% ± 8%) than in the 26 MDD-positive/MRD-negative patients (31% ± 9%) and the 77 MDD-negative patients (15% ± 5%) (P < .001).
  • Digital PCR methods have been applied to evaluating MDD for patients with anaplastic large cell lymphoma to facilitate harmonization between laboratories and across studies. In a study of 91 patients, NPM::ALK MDD levels by digital PCR correlated well with estimates by quantitative PCR.[43] The 3-year EFS rate was 33% (± 11%) for the 18 patients with more than 10 NCN NPM::ALK transcripts by digital PCR, compared with 79% (± 5%) for the 73 patients with 10 or fewer NCN NPM::ALK transcripts (P < .0001).

  The presence of MDD is significantly associated with uncommon histological subtypes containing small cell and/or lymphohistiocytic components.[42]

Sites of disease at diagnosis

In pediatric NHL, some sites of disease appear to have prognostic value, including the following:

• Bone marrow and CNS: Bone marrow and CNS involvement at diagnosis usually requires more intensive therapy.[26,33,48,49] However, with appropriate risk-stratified therapy, patients with bone marrow and/or CNS involvement can achieve similar outcomes to patients without bone marrow and/or CNS involvement.[26]
• Head and neck: For patients with mature B-cell NHL, OS is comparable to that observed for patients with primary tumors at other sites. Head and neck primary tumors are associated with higher rates of disseminated and CNS disease and lower rates of LDH levels that were more than twofold higher than the upper limit of normal. Childhood NHL of the head and neck site was not associated with inferior OS.[16]
• Mediastinum: Mediastinal involvement in children and adolescents with nonlymphoblastic NHL results in an inferior outcome.[17,24,33,36] In children and young adults with primary mediastinal B-cell lymphoma, series have reported 3-year EFS rates of 50% to 70%.[33,36,50] However, studies using the dose-adjusted (DA)–EPOCH protocol (etoposide, prednisone, vincristine, and doxorubicin) with rituximab have reported EFS rates higher than 80%.[51,52]
• Viscera: For anaplastic large cell lymphoma, a retrospective study by the European Intergroup for Childhood NHL (EICNHL) found a high-risk group of patients defined by involvement of mediastinum, skin, or viscera.[49] In a subsequent study analysis from EICNHL using biological risk factors, the clinical risk features were not found to be significant.[53] In the CCG-5941 (NCT00002590) study for patients with anaplastic large cell lymphoma, these clinical risk factors could not be confirmed. Only bone marrow involvement predicted inferior PFS.[54][Level of evidence B4]
• Bone: Although previously thought to be a poor prognostic site, patients with NHL arising in bone have an excellent prognosis, regardless of histology.[55,56]
• Skin: The prognostic implication of skin involvement is limited to anaplastic large cell lymphoma and depends on whether the disease is localized to skin. Patients with ALK-negative, skin-limited anaplastic large cell lymphoma appear to have an excellent prognosis. However, studies from EICNHL and the COG have demonstrated that skin involvement in systemic anaplastic large cell lymphoma does not appear to have positive prognostic value.[53,54]
• Testicle: Testicular involvement does not affect prognosis.[27,57]

Age

NHL in infants is rare (1% in BFM trials from 1986 to 2002).[8] In this retrospective review, the outcome for infants was inferior compared with the outcome for older patients with NHL.[8]

Adolescents have also been reported to have outcomes inferior to those of younger children.[15,17,58] This adverse effect of age appears to be most pronounced for adolescents with diffuse large B-cell lymphoma and, to a lesser degree, T-cell lymphoblastic lymphoma.[17,58] Conversely, for patients with Burkitt lymphoma, adolescent age (≥15 years) was not an independent risk factor for inferior outcome.[26,36] Adolescents with mature B-cell lymphoma who are treated using pediatric protocols have a superior outcome compared with those treated with adult regimens (EFS rates, 88% vs. 66%).[59][Level of evidence C2]

Immune response to tumor

An immune response against the ALK protein (i.e., anti-ALK antibody titer) may correlate with lower clinical stage and predicted relapse risk but not OS.[60] A study by the EICNHL, which combined the level of anti-ALK antibody with MDD, demonstrated that patients with newly diagnosed anaplastic large cell lymphoma could be stratified into three risk groups, with the following PFS rates:[53]

• 28% for the high-risk group (MDD positive and antibody titer ≤1/750).
• 68% for the intermediate-risk group (all remaining patients).
• 93% for the low-risk group (MDD negative and antibody titer >1/750) (P < .0001).

In a cohort of Japanese patients with anaplastic large cell lymphoma who were treated on the ALCL99 (NCT00006455) study, comparable results were obtained for a three-category risk classification algorithm.[44] For a cohort of 180 patients with anaplastic large cell lymphoma who were treated on several European studies, low anti-ALK antibody titer retained prognostic significance in a multivariate analysis, along with MDD, MRD, and uncommon histology (small cell and others).[32][Level of evidence B4]

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48. Williams D, Mori T, Reiter A, et al.: Central nervous system involvement in anaplastic large cell lymphoma in childhood: results from a multicentre European and Japanese study. Pediatr Blood Cancer 60 (10): E118-21, 2013.
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50. Gerrard M, Waxman IM, Sposto R, et al.: Outcome and pathologic classification of children and adolescents with mediastinal large B-cell lymphoma treated with FAB/LMB96 mature B-NHL therapy. Blood 121 (2): 278-85, 2013.
51. Dunleavy K, Pittaluga S, Maeda LS, et al.: Dose-adjusted EPOCH-rituximab therapy in primary mediastinal B-cell lymphoma. N Engl J Med 368 (15): 1408-16, 2013.
52. Giulino-Roth L, O'Donohue T, Chen Z, et al.: Outcomes of adults and children with primary mediastinal B-cell lymphoma treated with dose-adjusted EPOCH-R. Br J Haematol 179 (5): 739-747, 2017.
53. Mussolin L, Damm-Welk C, Pillon M, et al.: Use of minimal disseminated disease and immunity to NPM-ALK antigen to stratify ALK-positive ALCL patients with different prognosis. Leukemia 27 (2): 416-22, 2013.
54. Lowe EJ, Sposto R, Perkins SL, et al.: Intensive chemotherapy for systemic anaplastic large cell lymphoma in children and adolescents: final results of Children's Cancer Group Study 5941. Pediatr Blood Cancer 52 (3): 335-9, 2009.
55. Lones MA, Perkins SL, Sposto R, et al.: Non-Hodgkin's lymphoma arising in bone in children and adolescents is associated with an excellent outcome: a Children's Cancer Group report. J Clin Oncol 20 (9): 2293-301, 2002.
56. Zhao XF, Young KH, Frank D, et al.: Pediatric primary bone lymphoma-diffuse large B-cell lymphoma: morphologic and immunohistochemical characteristics of 10 cases. Am J Clin Pathol 127 (1): 47-54, 2007.
57. Dalle JH, Mechinaud F, Michon J, et al.: Testicular disease in childhood B-cell non-Hodgkin's lymphoma: the French Society of Pediatric Oncology experience. J Clin Oncol 19 (9): 2397-403, 2001.
58. Burkhardt B, Oschlies I, Klapper W, et al.: Non-Hodgkin's lymphoma in adolescents: experiences in 378 adolescent NHL patients treated according to pediatric NHL-BFM protocols. Leukemia 25 (1): 153-60, 2011.
59. Gupta S, Alexander S, Pole JD, et al.: Superior outcomes with paediatric protocols in adolescents and young adults with aggressive B-cell non-Hodgkin lymphoma. Br J Haematol 196 (3): 743-752, 2022.
60. Ait-Tahar K, Damm-Welk C, Burkhardt B, et al.: Correlation of the autoantibody response to the ALK oncoantigen in pediatric anaplastic lymphoma kinase-positive anaplastic large cell lymphoma with tumor dissemination and relapse risk. Blood 115 (16): 3314-9, 2010.

Histopathologic and Molecular Classification of Childhood NHL

In children, non-Hodgkin lymphoma (NHL) is distinct from the more common forms of lymphoma observed in adults. While lymphomas in adults are more commonly low or intermediate grade, almost all NHL that occurs in children is high grade.[1,2] The World Health Organization (WHO) classifies NHL according to the following features:[2,3]

• Phenotype (i.e., B-lineage, T-lineage, or natural killer [NK] cell lineage).
• Cell differentiation (i.e., precursor vs. mature).

On the basis of the WHO classification, most NHL cases in childhood and adolescence fall into the following three categories:

1. Aggressive mature B-cell NHL: The most common types are Burkitt lymphoma, diffuse large B-cell lymphoma, and primary mediastinal B-cell lymphoma. Less common entities included in the WHO 2017 classification that occur in children include high-grade B-cell lymphoma with 11q aberrations, high-grade B-cell lymphoma–not otherwise specified, and large B-cell lymphoma with IRF4 rearrangement.[3,4]

   Compared with treatments for adults, aggressive Burkitt regimens in pediatrics have been used to treat patients with both Burkitt lymphoma and large B-cell histologies, resulting in no difference in outcome based on histology.[5,6,7,8,9] The exception is for patients with primary mediastinal B-cell lymphoma, who have had inferior outcomes with these regimens.[5,6,7,8,10]

   Historically, for patients with pediatric Burkitt lymphoma, secondary cytogenetic abnormalities, other than MYC rearrangement, have been associated with an inferior outcome,[11,12] and cytogenetic abnormalities involving gain of 7q or deletion of 13q may be associated with an inferior outcome on the FAB/LMB-96 chemotherapy protocol.[12,13] For pediatric patients with diffuse large B-cell lymphoma and chromosomal rearrangement at MYC (8q24), outcomes may be worse.[12]

   Results from the Inter-B-NHL Ritux 2010 (NCT01516580) phase III trial showed that the addition of rituximab to chemotherapy for patients with aggressive mature B-cell NHL improved event-free survival (EFS) rates, from 82% to 94%. The small number of treatment failures, resulting from a high EFS rate, make it challenging to confirm these previously identified candidate prognostic biomarkers.[14]

   Large B-cell lymphoma with IRF4 rearrangements is included in the WHO 2017 classification as a provisional entity.[4] Large B-cell lymphoma with IRF4 cases have a translocation that juxtaposes the IRF4 oncogene next to one of the immunoglobulin loci and has been associated with a favorable prognosis compared with diffuse large B-cell lymphoma cases lacking this finding.[15,16]

   For more information about the tumor biology and genomic alterations, see the sections on Tumor biology (Genomics of Burkitt lymphoma), Tumor biology (Genomics of diffuse large B-cell lymphoma), and Tumor biology (Genomics of primary mediastinal B-cell lymphoma).

2. Lymphoblastic lymphoma: This is primarily precursor T-cell lymphoma and, less frequently, precursor B-cell lymphoma.

   For more information about the tumor biology and genomic alterations, see the Tumor Biology (Genomics of lymphoblastic lymphoma) section.

3. Anaplastic large cell lymphoma: Anaplastic large cell lymphoma is classified as a mature peripheral T-cell lymphoma. The null-cell variant of anaplastic large cell lymphoma is considered to be the same disease in which the cells have lost most of the T-cell antigens.

   In adults, patients with ALK-negative disease have an inferior outcome. However, in children, the difference in outcome between patients with ALK-positive and ALK-negative disease has not been demonstrated.[17,18,19] In a series of 375 children and adolescents with systemic ALK-positive anaplastic large cell lymphoma enrolled on the ALCL99 (NCT00006455) study, the presence of a small cell or lymphohistiocytic component was observed in 32% of patients. This finding was significantly associated with a high risk of failure in the multivariate analysis, controlling for clinical characteristics.[20] With longer follow-up, presence of the small cell/lymphohistiocytic pattern maintained its prognostic significance on multivariate analysis.[21]

   In the COG-ANHL0131 (NCT00059839) study, despite a different chemotherapy backbone, patients with the small cell variant of anaplastic large cell lymphoma, as well as other histological variants, had a significantly increased risk of failure.[19]

   For more information about the tumor biology and genomic alterations, see the Tumor Biology (Genomics of anaplastic large cell lymphoma) section.

WHO Classification for NHL

The WHO classification is the most widely used NHL classification and is shown in Table 2, with immunophenotype and common clinical and molecular findings in pediatric NHL.[1,2,3]

Table 2. Major Histopathological Categories of Non-Hodgkin Lymphoma in Children and Adolescents^a

WHO Classification		Immunophenotype	Clinical Presentation	Chromosome Abnormalities	Genes Affected
CNS = central nervous system; TdT = terminal deoxynucleotidyl transferase; WHO = World Health Organization; + = positive.
a Adapted from Percy et al.[1]
Burkitt lymphoma		Mature B cell	Intra-abdominal (sporadic), head and neck (non-jaw, sporadic), jaw (endemic), bone marrow, CNS	t(8;14)(q24;q32), t(2;8)(p11;q24), t(8;22)(q24;q11)	MYC,TCF3,ID3,CCND3,TP53
High-grade B-cell lymphoma with 11q aberrations		Mature B cell	Nodal	11q alteration, noMYC rearrangement
Large B-cell lymphoma withIRF4rearrangement		Mature B cell	Nodal (typically head and neck)	CrypticIRF1rearrangement withIGHlocus	IRF4
Diffuse large B-cell lymphoma		Mature B cell	Nodal, abdominal, bone, primary CNS (when associated with immunodeficiency), mediastinal	No consistent cytogenetic abnormality identified
Primary mediastinal (thymic) large B-cell lymphoma		Mature B cell, often CD30+	Mediastinal, but may also have other nodal or extranodal disease (i.e., abdominal, often kidney)	9p and 2p gains	CIITA,TNFAIP3,SOCS1,PTPN11,STAT6
ALK-positive large B-cell lymphoma			Generalized lymphadenopathy, bone marrow in 25%	t(2;5)(p23;q35); less common variant translocations involvingALK	ALK,NPM
T-lymphoblastic leukemia/lymphoma		T lymphoblasts (TdT, CD2, CD3, CD7, CD4, CD8)	Mediastinal mass, bone marrow
B-lymphoblastic leukemia/lymphoma		B lymphoblasts (CD19, CD79a, CD22, CD10, TdT)	Skin, soft tissue, bone, lymph nodes, bone marrow
Pediatric-type follicular lymphoma		Mature B cell	Nodal (typically head and neck)		TNFRSF14,MAP2K1
Pediatric nodal marginal zone lymphoma		Mature B cell	Nodal (typically head and neck)

Other types of lymphoma, such as the nonanaplastic large cell peripheral T-cell lymphomas (including T/NK lymphomas), cutaneous lymphomas, and indolent B-cell lymphomas (e.g., follicular lymphoma and marginal zone lymphoma), are more commonly seen in adults and rarely occur in children. The WHO classification has designated pediatric-type follicular lymphoma and pediatric nodal marginal zone lymphoma as distinct entities from the counterparts observed in adults.[3]

For more information about the treatment of NHL in adult patients, see the following summaries:

• B-Cell Non-Hodgkin Lymphoma Treatment.
• Peripheral T-Cell Non-Hodgkin Lymphoma Treatment.
• Non-Hodgkin Lymphoma Treatment During Pregnancy.
• Primary CNS Lymphoma Treatment.
• Mycosis Fungoides and Other Cutaneous T-Cell Lymphomas Treatment.

References:

1. Percy CL, Smith MA, Linet M, et al.: Lymphomas and reticuloendothelial neoplasms. In: Ries LA, Smith MA, Gurney JG, et al., eds.: Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. National Cancer Institute, SEER Program, 1999. NIH Pub.No. 99-4649, pp 35-50. Also available online. Last accessed December 22, 2023.
2. Swerdlow SH, Campo E, Pileri SA, et al.: The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 127 (20): 2375-90, 2016.
3. Alaggio R, Amador C, Anagnostopoulos I, et al.: The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms. Leukemia 36 (7): 1720-1748, 2022.
4. Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th rev. ed. International Agency for Research on Cancer, 2017.
5. Burkhardt B, Zimmermann M, Oschlies I, et al.: The impact of age and gender on biology, clinical features and treatment outcome of non-Hodgkin lymphoma in childhood and adolescence. Br J Haematol 131 (1): 39-49, 2005.
6. Cairo MS, Sposto R, Gerrard M, et al.: Advanced stage, increased lactate dehydrogenase, and primary site, but not adolescent age (≥ 15 years), are associated with an increased risk of treatment failure in children and adolescents with mature B-cell non-Hodgkin's lymphoma: results of the FAB LMB 96 study. J Clin Oncol 30 (4): 387-93, 2012.
7. Patte C, Auperin A, Gerrard M, et al.: Results of the randomized international FAB/LMB96 trial for intermediate risk B-cell non-Hodgkin lymphoma in children and adolescents: it is possible to reduce treatment for the early responding patients. Blood 109 (7): 2773-80, 2007.
8. Woessmann W, Seidemann K, Mann G, et al.: The impact of the methotrexate administration schedule and dose in the treatment of children and adolescents with B-cell neoplasms: a report of the BFM Group Study NHL-BFM95. Blood 105 (3): 948-58, 2005.
9. Gerrard M, Cairo MS, Weston C, et al.: Excellent survival following two courses of COPAD chemotherapy in children and adolescents with resected localized B-cell non-Hodgkin's lymphoma: results of the FAB/LMB 96 international study. Br J Haematol 141 (6): 840-7, 2008.
10. Gerrard M, Waxman IM, Sposto R, et al.: Outcome and pathologic classification of children and adolescents with mediastinal large B-cell lymphoma treated with FAB/LMB96 mature B-NHL therapy. Blood 121 (2): 278-85, 2013.
11. Onciu M, Schlette E, Zhou Y, et al.: Secondary chromosomal abnormalities predict outcome in pediatric and adult high-stage Burkitt lymphoma. Cancer 107 (5): 1084-92, 2006.
12. Poirel HA, Cairo MS, Heerema NA, et al.: Specific cytogenetic abnormalities are associated with a significantly inferior outcome in children and adolescents with mature B-cell non-Hodgkin's lymphoma: results of the FAB/LMB 96 international study. Leukemia 23 (2): 323-31, 2009.
13. Nelson M, Perkins SL, Dave BJ, et al.: An increased frequency of 13q deletions detected by fluorescence in situ hybridization and its impact on survival in children and adolescents with Burkitt lymphoma: results from the Children's Oncology Group study CCG-5961. Br J Haematol 148 (4): 600-10, 2010.
14. Minard-Colin V, Aupérin A, Pillon M, et al.: Rituximab for High-Risk, Mature B-Cell Non-Hodgkin's Lymphoma in Children. N Engl J Med 382 (23): 2207-2219, 2020.
15. Salaverria I, Philipp C, Oschlies I, et al.: Translocations activating IRF4 identify a subtype of germinal center-derived B-cell lymphoma affecting predominantly children and young adults. Blood 118 (1): 139-47, 2011.
16. Au-Yeung RKH, Arias Padilla L, Zimmermann M, et al.: Experience with provisional WHO-entities large B-cell lymphoma with IRF4-rearrangement and Burkitt-like lymphoma with 11q aberration in paediatric patients of the NHL-BFM group. Br J Haematol 190 (5): 753-763, 2020.
17. Stein H, Foss HD, Dürkop H, et al.: CD30(+) anaplastic large cell lymphoma: a review of its histopathologic, genetic, and clinical features. Blood 96 (12): 3681-95, 2000.
18. Brugières L, Le Deley MC, Rosolen A, et al.: Impact of the methotrexate administration dose on the need for intrathecal treatment in children and adolescents with anaplastic large-cell lymphoma: results of a randomized trial of the EICNHL Group. J Clin Oncol 27 (6): 897-903, 2009.
19. Alexander S, Kraveka JM, Weitzman S, et al.: Advanced stage anaplastic large cell lymphoma in children and adolescents: results of ANHL0131, a randomized phase III trial of APO versus a modified regimen with vinblastine: a report from the children's oncology group. Pediatr Blood Cancer 61 (12): 2236-42, 2014.
20. Lamant L, McCarthy K, d'Amore E, et al.: Prognostic impact of morphologic and phenotypic features of childhood ALK-positive anaplastic large-cell lymphoma: results of the ALCL99 study. J Clin Oncol 29 (35): 4669-76, 2011.
21. Mussolin L, Le Deley MC, Carraro E, et al.: Prognostic Factors in Childhood Anaplastic Large Cell Lymphoma: Long Term Results of the International ALCL99 Trial. Cancers (Basel) 12 (10): , 2020.

Stage Information for Childhood NHL

The Ann Arbor staging system is used for all lymphomas in adults and for Hodgkin lymphoma in pediatrics. However, the Ann Arbor staging system has less prognostic value in pediatric non-Hodgkin lymphoma (NHL), primarily because of the high incidence of extranodal disease. Therefore, the most widely used staging schema for childhood NHL is that of the St. Jude Children's Research Hospital (Murphy Staging).[1] A new staging system defines bone marrow and central nervous system (CNS) involvement using modern techniques to document the presence of malignant cells. However, the basic definitions of bone marrow and CNS disease are essentially the same. The clinical utility of this staging system is under investigation.[2]

Role of Radiographic Imaging in Childhood NHL

Radiographic imaging is essential in the staging of patients with NHL. Ultrasonography may be the preferred method for assessment of an abdominal mass, but computed tomography (CT) scan and magnetic resonance imaging (MRI) have been used for staging.

The role of functional imaging in pediatric NHL is evolving and still being refined. Gallium scans have been replaced by fluorine F 18-fludeoxyglucose positron emission tomography (PET) scanning, which is now routinely performed at many centers.[3] A review of the revised International Workshop Criteria comparing CT imaging alone or CT together with PET imaging demonstrated that the combination of CT and PET imaging was more accurate than CT imaging alone.[4,5]

While the International Working Group (formerly called the International Harmonization Project for PET) response criteria have been attempted in adults, the prognostic value of PET scanning for staging pediatric NHL remains under investigation.[3,6,7] Data support that PET identifies more abnormalities than does CT scanning,[8] but it is unclear whether this should be used to upstage pediatric patients and change therapy. The International Working Group has updated their response criteria for malignant lymphoma to include PET, immunohistochemistry, and flow cytometry data.[5,9]

St. Jude Children's Research Hospital (Murphy) Staging

Stage I childhood NHL

In stage I childhood NHL, a single tumor or nodal area is involved, excluding the abdomen and mediastinum.

Stage II childhood NHL

In stage II childhood NHL, disease extent is limited to a single tumor with regional node involvement, two or more tumors or nodal areas involved on one side of the diaphragm, or a primary gastrointestinal tract tumor (completely resected) with or without regional node involvement.

Stage III childhood NHL

In stage III childhood NHL, tumors or involved lymph node areas occur on both sides of the diaphragm. Stage III NHL also includes any primary intrathoracic (mediastinal, pleural, or thymic) disease, extensive primary intra-abdominal disease, or any paraspinal or epidural tumors.

Stage IV childhood NHL

In stage IV childhood NHL, tumors involve the bone marrow and/or CNS, regardless of other sites of involvement.

Bone marrow involvement has been defined as 5% or more malignant cells in an otherwise normal bone marrow, with normal peripheral blood counts and smears. Patients with lymphoblastic lymphoma who have more than 25% malignant cells in the bone marrow are usually considered to have leukemia and may be appropriately treated on leukemia clinical trials.

CNS disease in lymphoblastic lymphoma is defined by criteria similar to that used for acute lymphocytic leukemia (i.e., white blood cell count of at least 5/μL and malignant cells in the cerebrospinal fluid [CSF]). For other types of NHL, the definition of CNS disease is any malignant cell present in the CSF regardless of cell count. The Berlin-Frankfurt-Münster group analyzed the prevalence of CNS involvement in more than 2,300 pediatric patients with NHL. Overall, CNS involvement was diagnosed in 6% of patients. CNS involvement (percentage of patients) according to NHL subtype was as follows:[10]

• Burkitt lymphoma: 8.8%.
• Precursor B-cell lymphoblastic lymphoma: 5.4%.
• T-cell lymphoblastic lymphoma: 3.2%.
• Anaplastic large cell lymphoma: 3.3%.
• Diffuse large B-cell lymphoma: 2.6%.
• Primary mediastinal large B-cell lymphoma: 0%.

References:

1. Murphy SB, Fairclough DL, Hutchison RE, et al.: Non-Hodgkin's lymphomas of childhood: an analysis of the histology, staging, and response to treatment of 338 cases at a single institution. J Clin Oncol 7 (2): 186-93, 1989.
2. Rosolen A, Perkins SL, Pinkerton CR, et al.: Revised International Pediatric Non-Hodgkin Lymphoma Staging System. J Clin Oncol 33 (18): 2112-8, 2015.
3. Juweid ME, Stroobants S, Hoekstra OS, et al.: Use of positron emission tomography for response assessment of lymphoma: consensus of the Imaging Subcommittee of International Harmonization Project in Lymphoma. J Clin Oncol 25 (5): 571-8, 2007.
4. Brepoels L, Stroobants S, De Wever W, et al.: Hodgkin lymphoma: Response assessment by revised International Workshop Criteria. Leuk Lymphoma 48 (8): 1539-47, 2007.
5. Cheson BD, Pfistner B, Juweid ME, et al.: Revised response criteria for malignant lymphoma. J Clin Oncol 25 (5): 579-86, 2007.
6. Cheson BD: The International Harmonization Project for response criteria in lymphoma clinical trials. Hematol Oncol Clin North Am 21 (5): 841-54, 2007.
7. Bakhshi S, Radhakrishnan V, Sharma P, et al.: Pediatric nonlymphoblastic non-Hodgkin lymphoma: baseline, interim, and posttreatment PET/CT versus contrast-enhanced CT for evaluation--a prospective study. Radiology 262 (3): 956-68, 2012.
8. Cheng G, Servaes S, Zhuang H: Value of (18)F-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography scan versus diagnostic contrast computed tomography in initial staging of pediatric patients with lymphoma. Leuk Lymphoma 54 (4): 737-42, 2013.
9. Cheson BD, Fisher RI, Barrington SF, et al.: Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol 32 (27): 3059-68, 2014.
10. Salzburg J, Burkhardt B, Zimmermann M, et al.: Prevalence, clinical pattern, and outcome of CNS involvement in childhood and adolescent non-Hodgkin's lymphoma differ by non-Hodgkin's lymphoma subtype: a Berlin-Frankfurt-Munster Group Report. J Clin Oncol 25 (25): 3915-22, 2007.

Treatment Option Overview for Childhood NHL

Many of the advancements in childhood cancer survival have been made by using combinations of known and/or new agents to improve the best available, accepted therapy. Clinical trials in pediatrics are designed to compare potentially better therapy with currently accepted standard therapy. This comparison may be done in a randomized study of two treatment arms or by evaluating a single new treatment and comparing the results with those previously obtained with standard therapy.

All children with non-Hodgkin lymphoma (NHL) should consider enrolling in a clinical trial. Treatment planning by a multidisciplinary team of cancer specialists with experience treating tumors of childhood is strongly recommended to determine, coordinate, and implement treatment to achieve optimal survival. Children with NHL should be referred for treatment by a multidisciplinary team of pediatric oncologists at an institution with experience in treating pediatric cancers. Information about ongoing National Cancer Institute (NCI)–supported clinical trials is available from the NCI website.

NHL in children is generally considered to be widely disseminated at diagnosis, even when the tumor is apparently localized. As a result, combination chemotherapy is recommended for most patients.[1] Exceptions to this treatment strategy include the following:

• Peripheral T-cell lymphoma that is limited to the skin, including anaplastic large cell lymphoma.
• Indolent mature B-cell lymphomas.
• Pediatric-type follicular lymphoma.
• Posttransplant lymphoproliferative disease (when immunosuppression can be safely decreased).

In contrast to the treatment of adults with NHL, the use of radiation therapy is limited in children with NHL. Study results include the following:

• Early studies demonstrated that the routine use of radiation had no benefit for patients with low-stage (I or II) NHL.[2]
• Studies have demonstrated that prophylactic central nervous system (CNS) radiation can be omitted in patients with pediatric NHL.[3,4,5,6]
• For patients with anaplastic large cell lymphoma and B-cell NHL who present with CNS disease, radiation can also be eliminated.[5,6]

Radiation therapy may have a role in treating patients who have not had a complete response to chemotherapy. Data to support limiting the use of radiation therapy in the treatment of pediatric NHL come from the Childhood Cancer Survivor Study.[7] This analysis demonstrated that radiation exposure was a significant risk factor for subsequent neoplasms and death in long-term survivors.

The treatment of NHL in childhood and adolescence has historically been based on the histological subtype of the disease. A study by the Children's Cancer Group demonstrated that the outcomes for patients with lymphoblastic lymphoma were superior with longer acute lymphoblastic leukemia–like therapy, while patients with nonlymphoblastic NHL (Burkitt lymphoma) had superior outcomes with short, intensive, pulsed therapy. The outcomes for patients with large cell lymphoma were similar with either approach.[8]

Outcomes for children and adolescents with recurrent NHL remain very poor, with the exception of patients with anaplastic large cell lymphoma.[9,10,11,12,13,14] Patients or families who desire additional disease-directed therapy should consider entering trials of novel therapeutic approaches. Regardless of whether a decision is made to pursue disease-directed therapy at the time of progression, palliative care remains a central focus of management. This ensures that quality of life is maximized while attempting to reduce symptoms and stress related to terminal illness.

Table 3 describes the treatment options for newly diagnosed and recurrent childhood NHL.

Table 3. Treatment Options for Childhood Non-Hodgkin Lymphoma (NHL)

Treatment Group			Treatment Options
CAR = chimeric antigen receptor; CNS = central nervous system; EBV = Epstein-Barr virus; MALT = mucosa-associated lymphoid tissue; PTLD = posttransplant lymphoproliferative disease; HSCT = hematopoietic stem cell transplant.
Mature B-cell NHL:
	Burkitt lymphoma	Newly diagnosed	Surgery(for stage I and II only)
			Chemotherapy with or without rituximab
		Recurrent or refractory	Chemotherapy with or without rituximab
			Allogeneic or autologous HSCT
			CAR T-cell therapy
	Diffuse large B-cell lymphoma	Newly diagnosed	Surgery(for stage I and II only)
			Chemotherapy with or without rituximab
		Recurrent or refractory	Chemotherapy with or without rituximab
			Allogeneic or autologous HSCT
			CAR T-cell therapy
	Primary mediastinal B-cell lymphoma		Chemotherapy and rituximab
Lymphoblastic lymphoma		Newly diagnosed	Chemotherapy
			Cranial radiation therapy for overt CNS disease only
		Recurrent or refractory	Nelarabine or nelarabine-containing chemotherapy regimens
			Chemotherapy
			Bortezomib with chemotherapy
			Allogeneic HSCT
Anaplastic large cell lymphoma		Newly diagnosed	Surgery followed by chemotherapy(for stage I)
			Chemotherapy
		Recurrent or refractory	Chemotherapy, brentuximab, and/or ALK inhibitors (e.g., crizotinib or alectinib)
			Allogeneic or autologous HSCT
Lymphoproliferative disease associated with immunodeficiency:
	Lymphoproliferative disease associated with primary immunodeficiency		Chemotherapy with or without rituximab
			Allogeneic HSCT
	NHL associated with DNA repair defect syndromes		Chemotherapy
	HIV-associated NHL		Chemotherapy with or without rituximab
	PTLD		Surgery and reduction of immunosuppressive therapy, if possible
			Rituximab alone
			Standard or slightly modified chemotherapy with or without rituximab
			Low-dose chemotherapy with or without rituximab
Rare NHL:
	Pediatric-type follicular lymphoma		Surgery only
			Chemotherapy with or without rituximab
	Marginal zone lymphoma		Surgery only
			Radiation therapy
			Rituximab with or without chemotherapy
			Antibiotic therapy, for MALT lymphoma
	Primary CNS lymphoma		Chemotherapy and rituximab
			Radiation therapy
	Peripheral T-cell lymphoma		Chemotherapy
			Radiation therapy
			Allogeneic or autologous HSCT
	Cutaneous T-cell lymphoma		No standard treatments have been established
	Mycosis fungoides		No standard treatments have been established

Medical Emergencies

The most common potentially life-threatening clinical situations, seen in patients with lymphoblastic lymphoma and Burkitt lymphoma, are the following:

• Mediastinal masses.
• Tumor lysis syndrome.

Mediastinal masses

Patients with large mediastinal masses are at risk of tracheal compression, superior vena caval compression, large pleural and pericardial effusions, and right and left ventricular outflow compression. Thus, cardiac or respiratory arrest is a significant risk, particularly if the patient is placed in a supine position for procedures such as computed tomography (CT) or echocardiography scans.[15] Most of these procedures can be performed with patients on their side or prone.

Because of the risk of complications from general anesthesia or heavy sedation, a careful physiological and radiographic evaluation of the patient should be completed, and the least invasive procedure should be used to establish the diagnosis of lymphoma.[16,17] The following procedures may be used:

• Bone marrow aspirate and biopsy.
• Thoracentesis. If a pleural or pericardial effusion is present, a cytological diagnosis is frequently possible using thoracentesis, with confirmation of the diagnosis and cell lineage by flow cytometry.
• Lymph node biopsy. In children who present with peripheral adenopathy, a lymph node biopsy performed under local anesthesia and with the patient in an upright position may be possible.[18]

In situations when the above procedures do not yield a diagnosis, the use of a CT-guided core-needle biopsy should be considered. This procedure can frequently be performed using light sedation and local anesthesia before more invasive procedures are undertaken. Care should be taken to keep patients out of a supine position. Mediastinoscopy, anterior mediastinotomy, or thoracoscopy are the procedures of choice when other diagnostic modalities fail to establish the diagnosis. A formal thoracotomy is rarely, if ever, indicated for the diagnosis or treatment of childhood lymphoma.

Occasionally, it will not be possible to perform a diagnostic operative procedure because of the risk of complications from general anesthesia or heavy sedation. In these situations, preoperative treatment with steroids or, less commonly, localized radiation therapy should be considered. Because preoperative treatment may affect the ability to obtain an accurate tissue diagnosis, a diagnostic biopsy should be done as soon as the risk of complications from general anesthesia or heavy sedation is reduced.

Tumor lysis syndrome

Tumor lysis syndrome results from rapid breakdown of malignant cells, causing several metabolic abnormalities, most notably hyperuricemia, hyperkalemia, and hyperphosphatemia. Patients may present with tumor lysis syndrome before the start of therapy.

Hyperhydration and allopurinol or rasburicase (urate oxidase) are essential components of therapy in all patients, except those with the most limited disease.[19,20,21,22,23,24] In patients with G6PD deficiency, rasburicase may cause hemolysis or methemoglobinuria and should be avoided. An initial prephase consisting of low-dose cyclophosphamide and vincristine does not obviate the need for allopurinol or rasburicase and hydration.

Hyperuricemia and tumor lysis syndrome, particularly when associated with ureteral obstruction, frequently result in life-threatening complications.

Tumor Surveillance

Although the use of positron emission tomography (PET) to assess rapidity of response to therapy appears to have prognostic value in Hodgkin lymphoma and some types of NHL observed in adult patients, it remains under investigation in pediatric NHL. To date, there are insufficient data for pediatric NHL to support a finding that early response to therapy assessed by PET has prognostic value.

Diagnosing relapsed disease solely based on imaging requires caution because false-positive results are common.[25,26,27,28] Data also demonstrate that PET scanning can produce false-negative results.[29] A study of young adults with primary mediastinal B-cell lymphoma demonstrated that 9 of 12 patients who had residual mediastinal masses at the end of therapy had positive PET scans. Seven of these nine patients had the masses resected, but no viable tumor was found.[30] Before changes in therapy are undertaken based on residual masses noted by imaging, even if the PET scan is positive, a biopsy to prove residual disease is warranted.[28]

References:

1. Sandlund JT, Downing JR, Crist WM: Non-Hodgkin's lymphoma in childhood. N Engl J Med 334 (19): 1238-48, 1996.
2. Link MP, Shuster JJ, Donaldson SS, et al.: Treatment of children and young adults with early-stage non-Hodgkin's lymphoma. N Engl J Med 337 (18): 1259-66, 1997.
3. Burkhardt B, Woessmann W, Zimmermann M, et al.: Impact of cranial radiotherapy on central nervous system prophylaxis in children and adolescents with central nervous system-negative stage III or IV lymphoblastic lymphoma. J Clin Oncol 24 (3): 491-9, 2006.
4. Sandlund JT, Pui CH, Zhou Y, et al.: Effective treatment of advanced-stage childhood lymphoblastic lymphoma without prophylactic cranial irradiation: results of St Jude NHL13 study. Leukemia 23 (6): 1127-30, 2009.
5. Seidemann K, Tiemann M, Schrappe M, et al.: Short-pulse B-non-Hodgkin lymphoma-type chemotherapy is efficacious treatment for pediatric anaplastic large cell lymphoma: a report of the Berlin-Frankfurt-Münster Group Trial NHL-BFM 90. Blood 97 (12): 3699-706, 2001.
6. Cairo MS, Gerrard M, Sposto R, et al.: Results of a randomized international study of high-risk central nervous system B non-Hodgkin lymphoma and B acute lymphoblastic leukemia in children and adolescents. Blood 109 (7): 2736-43, 2007.
7. Bluhm EC, Ronckers C, Hayashi RJ, et al.: Cause-specific mortality and second cancer incidence after non-Hodgkin lymphoma: a report from the Childhood Cancer Survivor Study. Blood 111 (8): 4014-21, 2008.
8. Anderson JR, Jenkin RD, Wilson JF, et al.: Long-term follow-up of patients treated with COMP or LSA2L2 therapy for childhood non-Hodgkin's lymphoma: a report of CCG-551 from the Childrens Cancer Group. J Clin Oncol 11 (6): 1024-32, 1993.
9. Brugières L, Pacquement H, Le Deley MC, et al.: Single-drug vinblastine as salvage treatment for refractory or relapsed anaplastic large-cell lymphoma: a report from the French Society of Pediatric Oncology. J Clin Oncol 27 (30): 5056-61, 2009.
10. Mori T, Takimoto T, Katano N, et al.: Recurrent childhood anaplastic large cell lymphoma: a retrospective analysis of registered cases in Japan. Br J Haematol 132 (5): 594-7, 2006.
11. Woessmann W, Zimmermann M, Lenhard M, et al.: Relapsed or refractory anaplastic large-cell lymphoma in children and adolescents after Berlin-Frankfurt-Muenster (BFM)-type first-line therapy: a BFM-group study. J Clin Oncol 29 (22): 3065-71, 2011.
12. Mossé YP, Lim MS, Voss SD, et al.: Safety and activity of crizotinib for paediatric patients with refractory solid tumours or anaplastic large-cell lymphoma: a Children's Oncology Group phase 1 consortium study. Lancet Oncol 14 (6): 472-80, 2013.
13. Pro B, Advani R, Brice P, et al.: Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study. J Clin Oncol 30 (18): 2190-6, 2012.
14. Knörr F, Brugières L, Pillon M, et al.: Stem Cell Transplantation and Vinblastine Monotherapy for Relapsed Pediatric Anaplastic Large Cell Lymphoma: Results of the International, Prospective ALCL-Relapse Trial. J Clin Oncol 38 (34): 3999-4009, 2020.
15. Azizkhan RG, Dudgeon DL, Buck JR, et al.: Life-threatening airway obstruction as a complication to the management of mediastinal masses in children. J Pediatr Surg 20 (6): 816-22, 1985.
16. King DR, Patrick LE, Ginn-Pease ME, et al.: Pulmonary function is compromised in children with mediastinal lymphoma. J Pediatr Surg 32 (2): 294-9; discussion 299-300, 1997.
17. Shamberger RC, Holzman RS, Griscom NT, et al.: Prospective evaluation by computed tomography and pulmonary function tests of children with mediastinal masses. Surgery 118 (3): 468-71, 1995.
18. Prakash UB, Abel MD, Hubmayr RD: Mediastinal mass and tracheal obstruction during general anesthesia. Mayo Clin Proc 63 (10): 1004-11, 1988.
19. Pui CH, Mahmoud HH, Wiley JM, et al.: Recombinant urate oxidase for the prophylaxis or treatment of hyperuricemia in patients With leukemia or lymphoma. J Clin Oncol 19 (3): 697-704, 2001.
20. Goldman SC, Holcenberg JS, Finklestein JZ, et al.: A randomized comparison between rasburicase and allopurinol in children with lymphoma or leukemia at high risk for tumor lysis. Blood 97 (10): 2998-3003, 2001.
21. Cairo MS, Bishop M: Tumour lysis syndrome: new therapeutic strategies and classification. Br J Haematol 127 (1): 3-11, 2004.
22. Cairo MS, Coiffier B, Reiter A, et al.: Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensus. Br J Haematol 149 (4): 578-86, 2010.
23. Galardy PJ, Hochberg J, Perkins SL, et al.: Rasburicase in the prevention of laboratory/clinical tumour lysis syndrome in children with advanced mature B-NHL: a Children's Oncology Group Report. Br J Haematol 163 (3): 365-72, 2013.
24. Coiffier B, Altman A, Pui CH, et al.: Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review. J Clin Oncol 26 (16): 2767-78, 2008.
25. Rhodes MM, Delbeke D, Whitlock JA, et al.: Utility of FDG-PET/CT in follow-up of children treated for Hodgkin and non-Hodgkin lymphoma. J Pediatr Hematol Oncol 28 (5): 300-6, 2006.
26. Nakatani K, Nakamoto Y, Watanabe K, et al.: Roles and limitations of FDG PET in pediatric non-Hodgkin lymphoma. Clin Nucl Med 37 (7): 656-62, 2012.
27. Ulaner GA, Lilienstein J, Gönen M, et al.: False-Positive [18F]fluorodeoxyglucose-avid lymph nodes on positron emission tomography-computed tomography after allogeneic but not autologous stem-cell transplantation in patients with lymphoma. J Clin Oncol 32 (1): 51-6, 2014.
28. Bhojwani D, McCarville MB, Choi JK, et al.: The role of FDG-PET/CT in the evaluation of residual disease in paediatric non-Hodgkin lymphoma. Br J Haematol 168 (6): 845-53, 2015.
29. Picardi M, De Renzo A, Pane F, et al.: Randomized comparison of consolidation radiation versus observation in bulky Hodgkin's lymphoma with post-chemotherapy negative positron emission tomography scans. Leuk Lymphoma 48 (9): 1721-7, 2007.
30. Dunleavy K, Pittaluga S, Maeda LS, et al.: Dose-adjusted EPOCH-rituximab therapy in primary mediastinal B-cell lymphoma. N Engl J Med 368 (15): 1408-16, 2013.

Special Considerations for the Treatment of Children With Cancer

Cancer in children and adolescents is rare, although the overall incidence has been slowly increasing since 1975.[1] Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the following health care professionals and others to ensure that children receive the treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life:

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

For 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 and adolescents with cancer.[2] At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate is offered to most patients and families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with current standard therapy. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing NCI-supported clinical trials is available from the NCI website.

References:

1. Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014.
2. American Academy of Pediatrics: Standards for pediatric cancer centers. Pediatrics 134 (2): 410-4, 2014. Also available online. Last accessed December 15, 2023.

Aggressive Mature B-Cell NHL

Burkitt Lymphoma

Incidence

In the United States, Burkitt lymphoma accounts for about 40% of childhood non-Hodgkin lymphoma (NHL) cases and exhibits a consistent, aggressive clinical behavior.[1] The overall incidence of Burkitt lymphoma in the United States is 2.4 cases per 1 million person-years and is higher among boys than girls (3.8 vs. 0.9).[2,3] For more information about the incidence of Burkitt lymphoma by age and sex distribution, see Table 1.

Clinical presentation

The most common primary sites of disease are the abdomen and the lymphatic tissue of Waldeyer ring.[4] Other sites of involvement include testes, bone, skin, bone marrow, and central nervous system (CNS). While lung involvement does not tend to occur, pleural and peritoneal spread are seen.[4]

Tumor biology

Genomics of Burkitt lymphoma

The malignant cells of Burkitt lymphoma show a mature B-cell phenotype and are negative for the enzyme terminal deoxynucleotidyl transferase. These malignant cells usually express surface immunoglobulin (Ig), most bearing a clonal surface IgM with either kappa or lambda light chains. A variety of additional B-cell markers (e.g., CD19, CD20, CD22) are usually present, and most childhood Burkitt lymphomas express CD10.[1]

Burkitt lymphoma expresses a characteristic chromosomal translocation, usually t(8;14) and more rarely t(8;22) or t(2;8). Each of these translocations juxtaposes the MYC oncogene and the immunoglobulin locus (IG, mostly the IGH locus) regulatory elements, resulting in the inappropriate expression of MYC, a gene involved in cellular proliferation.[5,6] The presence of one of the variant translocations t(2;8) or t(8;22) does not appear to affect response or outcome.[7,8]

Mapping of IGH-translocation breakpoints demonstrated that IG::MYC translocations in sporadic Burkitt lymphoma most commonly occur through aberrant class-switch recombination and less commonly through somatic hypervariant. Translocations resulting from aberrant variable, diversity, and joining (VDJ) gene segment recombinations are rare.[9] These findings are consistent with a germinal center derivation of Burkitt lymphoma.

While MYC translocations are present in all Burkitt lymphoma, cooperating genomic alterations appear to be required for lymphoma development. Some of the more commonly observed recurring variants that have been identified in Burkitt lymphoma in pediatric and adult cases are listed below. The clinical significance of these variants for pediatric Burkitt lymphoma remains to be elucidated.

• Activating variants in the transcription factor TCF3 and inactivating variants in its negative regulator ID3 are observed in approximately 70% of Burkitt lymphoma cases.[9,10,11,12,13]
• TP53 variants are observed in one-third to one-half of cases.[10,12]
• CCND3 variants are commonly observed in sporadic Burkitt lymphoma (approximately 40% of cases) but are rare in endemic Burkitt lymphoma.[10,12]
• Mutually exclusive variants in SMARCA4 and ARID1A,[9] components of the SWItch/Sucrose Non-Fermentable (SWI/SNF) complex, are observed in more than one-half of pediatric Burkitt lymphoma cases.[8]
• Variants in MYC itself are observed in approximately one-half of Burkitt lymphoma cases and appear to enhance tumorigenesis, in part, by increasing MYC stability.[9,10,14]
• Variants and altered DNA methylation result in dysregulation of sphingosine-1-phosphate signaling in a subset of Burkitt lymphoma. Genes contributing to this include RHOA, which is altered in approximately 10% of cases, and, less commonly, GNA13, GNA11, and GNA12.[8,10,11]

A study that compared the genomic landscape of endemic Burkitt lymphoma with the genomics of sporadic Burkitt lymphoma found the expected high rate of Epstein-Barr virus (EBV) positivity in endemic cases, with much lower rates in sporadic cases. There was general similarity between the patterns of variants for endemic and sporadic cases and for EBV-positive and EBV-negative cases. However, EBV-positive cases showed significantly lower variant rates for selected genes/pathways, including SMARCA4, CCND3, TP53, and apoptosis.[8]

Cytogenetic evidence of MYC rearrangement is the gold standard for diagnosis of Burkitt lymphoma. For cases in which cytogenetic analysis is not available, the World Health Organization (WHO) has recommended that the Burkitt-like diagnosis be reserved for lymphoma resembling Burkitt lymphoma or with more pleomorphism, large cells, and a proliferation fraction (i.e., MIB-1 or Ki-67 immunostaining) of 99% or greater.[1] BCL2 staining by immunohistochemistry is variable. The absence of a translocation involving the BCL2 gene does not preclude the diagnosis of Burkitt lymphoma and has no clinical implications.[15]

Genomics of Burkitt-like lymphoma/high-grade B-cell lymphoma with 11q aberrations

Burkitt-like lymphoma with 11q aberration was added as a provisional entity in the 2017 revised WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues.[16] In the 5th edition of the WHO classification, this entity was renamed high-grade B-cell lymphoma with 11q aberrations.[17] In this entity, MYC rearrangement is absent, and the characteristic chromosome 11q finding (detected cytogenetically and/or with copy-number DNA arrays) is 11q23.2-q23.3 gain/amplification and 11q24.1-qter loss.[18,19]

• In a study of 102 lymphomas that morphologically resembled Burkitt lymphoma, diffuse large B-cell lymphoma, and high-grade B-cell lymphoma, unclassifiable, 13 cases (13%) lacked a MYC rearrangement but were positive for 11q proximal gain and telomeric loss by fluorescence in situ hybridization.[20]
• Most patients with high-grade B-cell lymphoma with 11q aberrations present in the adolescent and young adult age range with localized nodal disease.[19,20] Head and neck involvement is the most common presentation, although presentation in other nodal areas, as well as in the abdomen, can occur.
• Cases show a very high proliferative index and can show a focal starry sky pattern.[19,20]
• Outcomes appear highly favorable in the small number of cases identified.[19,20]
• The variant landscape of high-grade B-cell lymphoma with 11q aberrations is distinct from that of Burkitt lymphoma. Variants commonly observed in Burkitt lymphoma (e.g., ID3, TCF3, and CCND3) are uncommon in high-grade B-cell lymphoma with 11q aberrations.[18] Conversely, variants in GNA13 appear to be common (up to 50%) in patients with high-grade B-cell lymphoma with 11q aberrations and are less common in patients with Burkitt lymphoma.

Prognostic factors

For information about prognostic factors for Burkitt lymphoma, see the Prognosis and Prognostic Factors for Childhood NHL section.

Standard treatment options for Burkitt lymphoma

The treatment of Burkitt lymphoma is the same as treatment for diffuse large B-cell lymphoma, and the following discussion is pertinent to both types of childhood NHL.

Unlike mature B-lineage NHL seen in adult patients, there is no difference in outcome based on histology in pediatric patients (Burkitt lymphoma or diffuse large B-cell lymphoma). Pediatric Burkitt lymphoma and diffuse large B-cell lymphoma are clinically very aggressive, and patients are treated with very intensive regimens.[21,22,23,24,25,26]

Tumor lysis syndrome is often present at diagnosis or after initiation of treatment. This emergent clinical situation should be anticipated and addressed before treatment is started. For more information, see the Tumor lysis syndrome section.

Current treatment strategies are based on risk stratification, as described in Table 4. Involvement of the bone marrow may lead to confusion about whether the patient has lymphoma or leukemia. Traditionally, patients with more than 25% marrow blasts are classified as having mature B-cell leukemia, and those with fewer than 25% marrow blasts are classified as having lymphoma. It is not clear whether these arbitrary definitions are biologically distinct, but there is no question that patients with leukemic involvement should be treated with protocols designed for Burkitt lymphoma.[21,23,26]

Table 4. FAB/LMB and BFM Staging Schemas for B-cell NHL

​	Stratum	Disease Manifestation
ALL = acute lymphoblastic leukemia; BFM = Berlin-Frankfurt-Münster; CNS= central nervous system; FAB = French-American-British; LDH = lactate dehydrogenase; LMB = Lymphome Malins de Burkitt; NHL = non-Hodgkin lymphoma.
a Based on results of the FAB/LMB-96 study, a serum LDH level more than twice the upper limit of normal has been used to define a group B high-risk group in the international B-cell NHL studyANHL1131 (NCT01516567).[22]
COG-C5961 (FAB/LMB-96);[22,23,27]COG-ANHL1131 (Inter-B-NHL Ritux 2010) [26]	A	Completely resected stage I and abdominal stage II
	Ba	Multiple extra-abdominal sites
		Nonresected stage I and II, III, IV (marrow <25% blasts, no CNS disease); epidural masses (stage III Murphy staging) are treated as group B unless there is evidence of dural invasion
	C	Mature B-cell ALL (>25% blasts in marrow) and/or CNS disease
BFM Group[28]	R1	Completely resected stage I and abdominal stage II
	R2	Nonresected stage I or II and stage III with LDH <500 IU/L
	R3	Stage III with LDH 500–999 IU/L
		Stage IV, B-ALL (>25% blasts), no CNS disease, and LDH <1,000 IU/L
	R4	Stage III, IV, B-cell ALL with LDH >1,000 IU/L
		Any CNS disease

The following studies have contributed to the development of current treatment regimens for pediatric patients with Burkitt lymphoma and diffuse large B-cell lymphoma.

Evidence (chemotherapy):

1. Berlin-Frankfurt-Münster (BFM) studies
   1. Localized disease (R1 and R2 groups): The BFM group has treated risk group R1 patients with two cycles of multiagent chemotherapy (GER-GPOH-NHL-BFM-90 and GER-GPOH-NHL-BFM-95).[21,28] R2 patients received a cytoreductive phase followed by five cycles of chemotherapy.[21,28]
      • Event-free survival (EFS) rates with best therapy in the NHL-BFM-95 study were higher than 95% for R1 and R2 group patients.[21]
   2. Advanced/disseminated disease (R3 and R4 groups): In the NHL-BFM-95 study, the EFS rate was 93% with best therapy.[21]
      • Inferior outcome was observed for patients with CNS disease at presentation (3-year EFS rate, 70%).[28]
2. French Society of Pediatric Oncology Lymphome Malins de Burkitt (LMB) and French-American British (FAB) studies
   1. Localized disease (group A): Patients who received two cycles of multiagent chemotherapy, without intrathecal chemotherapy or rituximab, had excellent outcomes (COG-C5961 [FAB/LMB-96]).[27][Level of evidence B4]
   2. Advanced disease (group B):
      • The 3-year EFS rate was 90% for stage III patients and 86% for stage IV (CNS-negative and nonleukemic) patients.
      • Patients with a lactate dehydrogenase (LDH) level more than twice the upper limit of normal had an EFS rate of 86% compared with 96% in those with lower LDH levels.
   3. Disseminated disease (group C):
      • Patients with leukemic disease only, and no CNS disease, had a 3-year EFS rate of 90%, while patients with CNS disease at presentation had a 3-year EFS rate of 70%.
      • Patients with combined marrow and CNS disease at diagnosis had an EFS rate of only 61%.
      • This study identified the response to prophase reduction as the most significant prognostic factor. Patients with poorly responding disease (i.e., <20% resolution of disease) had an EFS rate of 30%.

Both the BFM and FAB/LMB studies demonstrated that omission of craniospinal irradiation, even in patients presenting with CNS disease, does not affect outcome (COG-C5961 [FAB/LMB-96] and NHL-BFM-90 [GER-GPOH-NHL-BFM-90]).[21,22,23,28]

Evidence (rituximab):

1. In a phase II study performed by the BFM group, single-agent rituximab showed activity in pediatric patients with Burkitt lymphoma.[29][Level of evidence B4]
2. A Children's Oncology Group (COG) pilot study (COG-ANHL01P1) added rituximab to baseline chemotherapy with FAB/LMB-96 therapy in patients with stage III and stage IV B-cell NHL.[30,31,32]; [24][Level of evidence C1]
   • Compared with chemotherapy-only protocols, toxicity was similar with the addition of rituximab, despite a trend toward higher peak levels of rituximab in younger patients.
3. An international randomized phase III trial (COG-ANHL1131) evaluated the benefit of adding rituximab to standard therapy for Group B patients with high levels of LDH and Group C patients. The study was closed early because of the superior outcomes observed for the patients who received rituximab.[26] This study led to the European Medicines Agency and U.S. Food and Drug Administration approval of rituximab for the treatment of pediatric patients with B-cell lymphoma.
   • For patients in the rituximab arm, the EFS rate was 94% for this high-risk group of patients (stage III with elevated LDH and stage IV), compared with 82% for patients who received standard therapy (hazard ratio, 0.32; 95% confidence interval [CI], 0.15–0.66; one-sided P = .00096).
   • Refractory disease or relapse/progression was observed in 15% of patients who received standard therapy, compared with 3% of patients who received rituximab.
   • Toxic mortality occurred in 2% of patients in each arm.
   • For patients who received rituximab, there was no difference in outcome based on age, histology (diffuse large B-cell lymphoma vs. Burkitt lymphoma), stage, and response to low-dose cyclophosphamide, vincristine, and prednisone (COP regimen).
   • A prespecified, secondary aim of the study was to evaluate the immune effects of rituximab therapy in pediatric patients after the completion of intensive therapy.[33] Patients in the rituximab group were significantly more likely to have low IgG, IgA, and IgM serum concentrations 1 month after the end of therapy than patients in the chemotherapy-only group. Low IgG levels persisted for 1 year after the start of therapy for patients who received rituximab. No fatal infections were observed in the follow-up period. However, a small number of patients who had all received rituximab had severe infections.

Standard treatment options for Burkitt lymphoma and diffuse large B-cell lymphoma are described in Table 5.

Table 5. Standard Treatment Options for Burkitt Lymphoma and Diffuse Large B-cell Lymphoma

Trial	Stratum	Disease Manifestations	Treatment
ALL = acute lymphoblastic leukemia; BFM = Berlin-Frankfurt-Münster; CNS = central nervous system; COG = Children's Oncology Group; FAB = French-American-British; LDH = lactate dehydrogenase; LMB = Lymphome Malins de Burkitt; NHL = non-Hodgkin lymphoma; POG = Pediatric Oncology Group.
COG-C5961(FAB/LMB-96)[22,27]COG-ANHL01[31,32];[24][Level of evidence C1] COG-ANHL1131 (Inter-B-NHL Ritux 2010)[26]	A	Completely resected stage I and abdominal stage II	Two cycles of chemotherapy[27]
	B	Multiple extra-abdominal sites	Prephase + four cycles of chemotherapy (reduced-intensity arm)[22,34]
		Nonresected stage I and II, III (normal LDH)
		Stage III (elevated LDH), marrow <25% blasts, no stage IV CNS disease	Prephase + four cycles of chemotherapy (reduced-intensity arm) + six doses of rituximab[26]
	C	Mature B-cell ALL (>25% blasts in marrow) and/or stage IV CNS disease	Prephase + six cycles of chemotherapy (full-intensity arm) and only two maintenance cycles + six doses of rituximab[26]
GER-GPOH-NHL-BFM-95[21]	R1	Completely resected stage I and abdominal stage II	Two cycles of chemotherapy
	R2	Nonresected stage I/II and stage III with LDH <500 IU/L	Prephase + four cycles of chemotherapy (4-hour methotrexate infusion)

Treatment options for recurrent or refractory Burkitt lymphoma

There is no standard treatment option for patients with recurrent or progressive disease. For patients with recurrent or refractory aggressive mature B-cell NHL, survival rates range between 10% and 50%. In the largest series, the survival rate was about 20%.[23,35,36]; [37][Level of evidence C1] Three large retrospective multivariable analyses identified the following prognostic factors:

• For improved survival:
  • Duration of complete remission of more than 6 months.[38,39]
  • Normal LDH levels at initial diagnosis.[38,39]
  • One site of disease at relapse.[38]
  • No failure in bone marrow.[39]
  • Diffuse large B-cell lymphoma histology.[38]
  • Complete remission before hematopoietic stem cell transplant (HSCT).[37][Level of evidence C1]
  • Reinduction with intensive continuous therapy before HSCT.[37][Level of evidence C1]
• For inferior survival:
  • Progression during initial therapy.[37][Level of evidence C1]
  • Rituximab during initial therapy.[37][Level of evidence C1]

Treatment options for recurrent or refractory Burkitt lymphoma and diffuse large B-cell lymphoma include the following:

1. R-ICE regimen (rituximab plus ifosfamide, carboplatin, and etoposide [ICE]).[40]
2. CYVE regimen (high-dose cytarabine and etoposide) for relapsed group A and group B disease.[38]
3. Allogeneic or autologous HSCT.[41,42,43]
4. Bispecific antibody (anti-CD20, anti-CD3).[44]
5. Chimeric antigen receptor (CAR) T-cell therapy.[45]
6. R-VICI regimen (rituximab, vincristine, idarubicin, ifosfamide, carboplatin, and dexamethasone).[37][Level of evidence C1]

Chemoresistance makes remission difficult to achieve.

Evidence (treatment of recurrent or refractory Burkitt lymphoma):

1. A study from the United Kingdom for children with relapsed or refractory mature B-cell NHL and B-cell acute lymphoblastic leukemia reported the following:[46]
   • The most favorable outcomes occurred in patients who received rituximab and an autologous HSCT.
   • However, the study could not distinguish whether this relationship reflected that children who survived were those who remained well enough to tolerate chemotherapy and rituximab, achieved a response, and were eligible for transplant.
2. In a COG study of 20 patients with relapsed/refractory B-cell NHL (Burkitt lymphoma [n = 14] and diffuse large B-cell lymphoma) who were treated with R-ICE, the following was observed:[40][Level of evidence C1]
   • A complete remission/partial remission rate of 60%.
3. The Japanese Pediatric Leukemia/Lymphoma Study Group performed a phase II study using R-ICE to treat 28 pediatric patients with relapsed/refractory B-cell NHL.[47]
   • The investigators observed a complete and partial response rate of 70%.
4. A retrospective review of patients with relapsed disease treated in the LMB-89, LMB-96, and LMB-2001 trials were analyzed. Group A and group B patients received the CYVE regimen as initial salvage therapy, and group C patients received ICE with or without rituximab.[38]
   • The complete and partial remission rate was 64%; 2 of 3 group A patients responded, 19 of 29 group B patients responded, and 3 of 5 group C patients responded.
5. A retrospective review of patients with relapsed Burkitt lymphoma treated initially with BFM therapy noted that patients who were treated before the year 2000 had significantly inferior outcomes compared with those who were treated after 2000. The 5-year overall survival (OS) rates were 11% for those treated before the year 2000, compared with 27% for those treated after 2000. The 75 patients treated after 2000 were analyzed further, with the following results:[37][Level of evidence C1]
   • Of the 75 patients, 29 (41%) had leukemic involvement.
   • Median time to relapse was 0.4 years after diagnosis. More than one-third of patients relapsed during initial treatment.
   • Reinduction therapy was variable; 65% of patients proceeded to either autologous or allogeneic HSCT.
   • Reinduction with intensive continuous chemotherapy with R-VICI therapy before HSCT improved survival (4-year OS rate, 67%).
   • Initial disease risk category was prognostic: Low-risk patients (R1/R2) had improved survival (4-year OS rate, 50%), compared with high-risk patients (R3/R4; 4-year OS rate, 21%).
   • First-line therapy was also prognostic: 25 of 28 patients with progression during first-line therapy died, and 9 of 10 patients who were treated with front-line rituximab died.
   • Complete remission before HSCT was prognostic (4-year OS rate, 63%).
6. There are limited data for CAR T-cell therapy in pediatric patients with Burkitt lymphoma and diffuse large B-cell lymphoma. A single-center experience included 23 children with relapsed or refractory Burkitt lymphoma who were treated sequentially with three CAR T cells (CD19, CD22, and CD20). Patients were followed every 2 weeks, and they received subsequent CAR T cells if CAR T cells were not detectable in the blood or there was evidence of disease progression.[45]
   • The 18-month complete response and PFS rates were 78%.
   • These results may be due to short (1 week) CAR T-cell manufacture time and/or sequential antigen targeting.
   • The sustained complete response rates were 39% (9 of 23) for CD19 CAR T cells, 38% (5 of 13) for CD22 CAR T cells, and 50% (3 of 6) for CD20 CAR T cells.
   • The median follow-up was only 17 months.

If remission can be achieved, high-dose therapy plus HSCT remains the best option for survival. Patients not in remission at the time of transplant fare significantly worse.[38,41,46,48,49,50] The very poor outcome of patients whose disease is refractory to salvage chemotherapy suggests that a nonexperimental transplant option should not be pursued in these patients.[41,49,50] If a complete remission was reported, survival ranges between 30% to 75%, albeit all series have a small number of patients (i.e., fewer than 40).[41,46,47,49,51] The benefit of autologous versus allogeneic HSCT remains unclear.[36,41,51,52]; [48][Level of evidence B4]; [53][Level of evidence C2]

For more information about transplant, see Pediatric Autologous Hematopoietic Stem Cell Transplant, Pediatric Allogeneic Hematopoietic Stem Cell Transplant, and Pediatric Hematopoietic Stem Cell Transplant and Cellular Therapy for Cancer.

Evidence (HSCT therapy):

1. An analysis of data from the Center for International Blood and Marrow Transplant Research demonstrated the following:[41]
   • No difference in outcome using either autologous or allogeneic donor stem cell sources.
   • The 2-year EFS rates were 50% for patients with diffuse large B-cell lymphoma and 30% for patients with Burkitt lymphoma who survived to undergo a transplant.
   • Some graft-versus-lymphoma effect has been implied by the lower relapse rate in the allogeneic HSCT patients. However, that effect was balanced by the higher treatment-related mortality.
2. A small, single-center, prospective study used autologous transplant followed by reduced-intensity allogeneic HSCT to treat patients with relapsed NHL.[42]
   • The study reported an EFS rate of 60%.

Treatment options under clinical evaluation for Burkitt leukemia

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.

Diffuse Large B-Cell Lymphoma

Primary mediastinal B-cell lymphoma, previously considered a subtype of diffuse large B-cell lymphoma, is now a separate entity in the WHO classification. For more information, see the Primary Mediastinal B-cell Lymphoma section.

Incidence

Diffuse large B-cell lymphoma is an aggressive mature B-cell neoplasm that represents 10% to 20% of pediatric NHL cases.[54,55] Diffuse large B-cell lymphoma occurs more frequently during the second decade of life than during the first decade.[55,56] For more information on the incidence of diffuse large B-cell lymphoma by age and sex distribution, see Table 1.

Clinical presentation

Pediatric diffuse large B-cell lymphoma may present in a manner clinically similar to that of Burkitt lymphoma, although more often it is localized, and less often it involves the bone marrow or CNS.[54,56] For more information, see the Clinical presentation section in the Burkitt lymphoma section.

Tumor biology

Genomics of diffuse large B-cell lymphoma

Gene expression profiling of diffuse large B-cell lymphoma in adults has defined molecular subtypes. These subtypes are based on the suspected cell of origin, including germinal center B cell (GCB), activated B cell (ABC), and 10% to 15% of cases that remain unclassifiable. Current comprehensive molecular profiling of diffuse large B-cell lymphoma in adults has led to the proposal of additional subclassification beyond the cell of origin. This additional subclassification is based on genetic variants and copy number variations.[57,58] Diffuse large B-cell lymphoma in children and adolescents differs biologically from diffuse large B-cell lymphoma in adults in the following ways:

• Most pediatric diffuse large B-cell lymphoma cases have a germinal center B-cell phenotype, as assessed by immunohistochemical analysis of selected proteins found in normal germinal center B cells, such as the BCL6 gene product and CD10.[7,59,60,61] The age at which the favorable germinal center subtype changes to the less favorable nongerminal center subtype was shown to be a continuous variable.[62]
• Pediatric diffuse large B-cell lymphoma rarely demonstrates the t(14;18) translocation involving the IGH gene and the BCL2 gene that is seen in adults.[59]
• As many as 30% of patients younger than 14 years with diffuse large B-cell lymphoma will have a gene signature similar to Burkitt lymphoma.[63,64]
• In contrast to adult diffuse large B-cell lymphoma, pediatric cases show a high frequency of abnormalities at the MYC locus (chromosome 8q24), with approximately one-third of pediatric cases showing MYC rearrangement and approximately one-half of the nonrearranged cases showing MYC gain or amplification.[64,65]
• One report included 31 pediatric patients with diffuse large B-cell lymphoma, NOS. Most patients (n = 21) showed a germinal center phenotype, and the genomic alterations resembled those of adult germinal center B-cell diffuse large B-cell lymphoma (GCB-DLBCL) (e.g., SOCS1 and KMT2D variants). Among this group of patients, MYC rearrangements were detected in 3 patients, and 5 of 25 cases were EBV positive (4 with the activated B-cell phenotype).[61]

Large B-cell lymphoma with IRF4 rearrangement (LBCL-IRF4) is a distinct entity in the 5th edition of the WHO classification of lymphoid neoplasms.[66]

• LBCL-IRF4 cases have a translocation that juxtaposes the IRF4 oncogene next to one of the immunoglobulin loci.
• In one report, diffuse large B-cell lymphoma cases with an IRF4 translocation were significantly more frequent in children than in adults with diffuse large B-cell lymphoma or follicular lymphoma (15% vs. 2%). One study of 32 pediatric cases of diffuse large B-cell lymphoma or follicular lymphoma found 2 (6%) with IRF4 translocations.[67] A second study of 34 cases of pediatric follicular lymphoma or diffuse large B-cell lymphoma found 7 cases (21%) with IRF translocations. Most of these cases occurred in the adolescent age range.[20]
• LBCL-IRF4 cases are primarily germinal center–derived B-cell lymphomas. They commonly present with nodal involvement of the head and neck (particularly the Waldeyer ring) and less commonly in the gastrointestinal tract.[20,61,68,69,70]
• LBCL-IRF4 shows strong IRF4 expression. In a study of 17 cases, the most frequently altered genes were CARD11 (35%) and CCND3 (24%).
• LBCL-IRF4 appears to be a low stage at diagnosis and is associated with a favorable prognosis compared with diffuse large B-cell lymphoma cases lacking this abnormality.[20,61,68]

High-grade B-cell lymphoma, NOS, is defined as a clinically aggressive B-cell lymphoma that lacks MYC plus BCL2 and/or BCL6 rearrangements. In addition, this entity does not meet criteria for diffuse large B-cell lymphoma, NOS, or Burkitt lymphoma.[71]

• High-grade B-cell lymphoma, NOS, is a biologically heterogeneous disease. In a study of eight cases of pediatric high-grade B-cell lymphoma, NOS, four had variant profiles similar to that of Burkitt lymphoma (e.g., MYC rearrangements and variants in CCND3, ID3, and DDX3X).[61] The remaining cases lacked MYC rearrangements and had variant profiles closer to GCB-DLBCL (e.g., TNFRSF14, CARD11 and EZH2 variants), and lacked MYC translocations.

Prognostic factors

For information about prognostic factors for diffuse large B-cell lymphoma, see the Prognosis and Prognostic Factors for Childhood NHL section.

Treatment options for diffuse large B-cell lymphoma

As with Burkitt lymphoma, current treatment strategies are based on risk stratification, as described in Table 5. The treatment of diffuse large B-cell lymphoma is the same as the treatment of Burkitt lymphoma. For information about the treatment of diffuse large B-cell lymphoma, see the Standard treatment options for Burkitt lymphoma section.

Treatment options for recurrent or refractory diffuse large B-cell lymphoma

The treatment of recurrent diffuse large B-cell lymphoma is the same as the treatment of recurrent Burkitt lymphoma. For more information, see the Treatment options for recurrent or refractory Burkitt lymphoma section.

Treatment options under clinical evaluation for diffuse large B-cell lymphoma

Information about 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.

Primary Mediastinal B-Cell Lymphoma

Incidence

In the pediatric population, primary mediastinal B-cell lymphoma is predominantly seen in older adolescents, accounting for 1% to 2% of all pediatric NHL cases.[56,72,73,74]

Clinical presentation

As the name suggests, primary mediastinal B-cell lymphoma occurs in the mediastinum. The tumor can be locally invasive (e.g., pericardial and lung extension), and it can be associated with superior vena cava syndrome. The tumor can disseminate outside the thoracic cavity with nodal and extranodal involvement, with predilection to the kidneys. However, CNS and marrow involvement are exceedingly rare.[75]

Tumor biology

Genomics of primary mediastinal B-cell lymphoma

Primary mediastinal B-cell lymphoma was previously considered a subtype of diffuse large B-cell lymphoma, but is now a separate entity in the World Health Organization (WHO) classification.[17] These tumors arise in the mediastinum from thymic B cells and show a diffuse large cell proliferation with sclerosis that compartmentalizes neoplastic cells.

Primary mediastinal B-cell lymphoma can be very difficult to distinguish morphologically from the following types of lymphoma:

• Diffuse large B-cell lymphoma: Cell surface markers in primary mediastinal B-cell lymphoma are similar to the ones seen in diffuse large B-cell lymphoma (i.e., CD19, CD20, CD22, CD79a, and PAX-5). However, primary mediastinal B-cell lymphoma may display cytoplasmic immunoglobulins, and CD30 expression is commonly present.[76]
• Hodgkin lymphoma: Primary mediastinal B-cell lymphoma may be difficult to distinguish from Hodgkin lymphoma clinically and morphologically, especially with small mediastinal biopsies because of extensive sclerosis and necrosis.

Primary mediastinal B-cell lymphoma has distinctive gene expression and variant profiles compared with diffuse large B-cell lymphoma. However, its gene expression and variant profiles have features similar to those seen in Hodgkin lymphoma.[77,78,79] Primary mediastinal B-cell lymphoma is also associated with a distinctive constellation of chromosomal aberrations compared with other NHL subtypes. Because primary mediastinal B-cell lymphoma is primarily a cancer of adolescents and young adults, the genomic findings are presented without regard to age.

• Multiple genomic alterations contribute to immune evasion in primary mediastinal B-cell lymphoma:
  • Structural rearrangements and copy number gains at chromosome 9p24 are common in primary mediastinal B-cell lymphoma. This region encodes the immune checkpoint genes CD274 (PDL1) and PDCD1LG2. The genomic alterations lead to increased expression of these checkpoint proteins.[79,80,81,82,83]
  • Genomic alterations in CIITA, which is the master transcriptional regulator of major histocompatibility complex (MHC) class II expression, are common in primary mediastinal B-cell lymphoma. These alterations lead to loss of MHC class II expression.[79,83,84]
  • Approximately 50% of primary mediastinal B-cell lymphoma cases show variants or focal copy number losses in B2M, the gene that encodes beta-2-microglobulin (the invariant chain of the MHC class I). These alterations lead to reduced expression of MHC class I.[79,83]
• Genomic alterations involving genes of the JAK-STAT pathway are observed in most cases of primary mediastinal B-cell lymphoma.[85]
  • STAT6 is altered in approximately 40% of primary mediastinal B-cell lymphoma cases.[79,83]
  • The chromosome 9p region that shows gains and amplification in primary mediastinal B-cell lymphoma encodes JAK2, which activates the STAT pathway.[73,74]
  • SOCS1, a negative regulator of JAK-STAT signaling, is inactivated in approximately 50% to 60% of primary mediastinal B-cell lymphoma cases by either variant or gene deletion.[79,83,86,87]
  • The IL4R gene shows activating variants in approximately 20% to 30% of primary mediastinal B-cell lymphoma cases. IL4R activation leads to increased JAK-STAT pathway activity.[79,83,85]
• Genomic alterations leading to NF-ĸB activation are also common in primary mediastinal B-cell lymphoma. These include copy number gains and amplifications at 2p16.1, a region that encodes BCL11A and REL.[73,74,79,83] Genes encoding negative regulators of NF-kB signaling (e.g., TNFAIP3 and NFKBIE) show inactivating variants in primary mediastinal B-cell lymphoma.[79,83]
• Other genes that are altered in primary mediastinal B-cell lymphoma include ZNF217, XPO1, and EZH2.[79,83]

Prognostic factors

For information on prognostic factors for primary mediastinal B-cell lymphoma, see the Prognosis and Prognostic Factors for Childhood NHL section.

Treatment options for primary mediastinal B-cell lymphoma

Treatment options for primary mediastinal B-cell lymphoma include the following:

1. Dose-adjusted etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and rituximab (DA-EPOCH-R).
2. Lymphomes Malins B (LMB)–based chemotherapy plus rituximab.

Pediatric and adolescent patients with stage III primary mediastinal large B-cell lymphoma fared significantly worse on the FAB/LMB-96 (NCT00002757) study, with a 5-year EFS rate of 66%, compared with 85% for adolescents with nonmediastinal diffuse large B-cell lymphoma.[88][Level of evidence B4] Similarly, in the NHL-BFM-95 trial, patients with primary mediastinal B-cell lymphoma had an EFS rate of 50% at 3 years.[21] However, a study of young adults treated with DA-EPOCH-R showed excellent disease-free survival rates.[89]

Evidence (DA-EPOCH-R):

1. A single-arm study in young adults used the DA-EPOCH-R regimen (usually six cycles) with filgrastim and no radiation therapy.[89][Level of evidence B4]
   • The 5-year EFS rate was 93%, and the OS rate was 97%.
   • At short-term follow-up, there was no evidence of cardiac toxicity, despite a high cumulative dose of doxorubicin for those who received most of the anthracycline-dose escalations.
   • An important finding in this study was the prognostic value of end-of-therapy imaging. Nine of 12 patients who had residual mediastinal masses at the end of therapy had positive positron emission tomography scans. Seven of these nine patients had the masses resected, but no viable tumor was found.
   • A concern for using this regimen is the significantly higher cumulative doses of alkylating agents and anthracyclines administered than those used in previous regimens.
2. A multicenter retrospective study of 38 pediatric patients (aged <21 years) and 118 adult patients treated with DA-EPOCH-R observed the following:[90]
   • Pediatric patients had a 3-year EFS rate of 81% and a 3-year OS rate of 91%. These results were not significantly different from the results observed in adults.
3. A prospective international study included 46 patients (aged <18 years) who were treated with DA-EPOCH-R. The study demonstrated the following results:[91]
   • The 4-year EFS rate was 70%, and the 3-year OS rate was 85%.
   • These outcomes were lower than those in other studies that treated patients with DA-EPOCH-R and were not statistically different from the results of the FAB/LMB-96 (NCT00002757) trial, when a Burkitt lymphoma therapy was used.
   • The ability to dose escalate and the adverse events were similar to what has been reported in adult patients.

Evidence (LMB-based chemotherapy plus rituximab):

1. The French prospective LMB2001 study reported the outcomes of patients with primary mediastinal B-cell lymphoma who were treated with LMB-based chemotherapy without radiation therapy. There were 773 patients with B-cell NHL, including 42 patients with primary mediastinal B-cell lymphoma, treated between 2001 and 2012. In 2008, the investigators recommended treating all patients with primary mediastinal B-cell lymphoma with rituximab on day 1 of each course. Additionally, patients with bulky mediastinal adenopathy (>10 cm) and/or high LDH serum level (>2N on the Institution upper limit value), and/or lomboaortic nodes were assigned to Group C1 therapy. After 2010, patients with primary mediastinal B-cell lymphoma were treated with a hybrid Group B/C therapy. In total, 21 of 42 patients received rituximab. Nineteen patients were treated with Group B therapy, 18 with Group C therapy, and 5 with Group B/C therapy. The median follow-up was 7.1 years for the entire cohort, 10.6 years for patients who did not receive rituximab, and 6.4 years for patients treated with rituximab.[92]
   • The 5-year EFS rate was 88.1% (95% CI, 75%–94.8%) for the whole cohort.
     • The 5-year EFS rate was 81% (95% CI, 60%–92.3%) for patients who did not receive rituximab.
     • The 5-year EFS rate was 95.2% (95% CI, 77.3%–99.2%) for patients who received rituximab.
   • The 5-year OS rate was 95.2% for the whole cohort.
     • The 5-year OS rate was 90.5% for patients who did not receive rituximab.
     • The 5-year OS rate was 100% for patients who received rituximab.

Treatment options for recurrent or refractory primary mediastinal B-cell lymphoma

The U.S. Food and Drug Administration granted accelerated approval of pembrolizumab for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma or who have relapsed after two or more previous lines of therapy. The approval was based on data from 53 patients (median age, 33 years; range, 20–61 years). The overall response rate was 41%, which included 12% complete responses and 29% partial responses.[93]

Treatment options under clinical evaluation for primary mediastinal B-cell lymphoma

Information about 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:

• ANHL1931 (NCT04759586) (Nivolumab in Combination With Chemo-Immunotherapy for the Treatment of Newly Diagnosed Primary Mediastinal B-Cell Lymphoma): This phase III trial compares the effects of nivolumab combined with chemo-immunotherapy versus chemo-immunotherapy alone in treating patients with newly diagnosed primary mediastinal B-cell lymphoma. Patients treated with R-CHOP (rituximab with doxorubicin, cyclophosphamide, vincristine, and prednisone) or who have biopsy-proven, end-of-therapy disease are permitted to undergo consolidative radiation therapy.

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65. Poirel HA, Cairo MS, Heerema NA, et al.: Specific cytogenetic abnormalities are associated with a significantly inferior outcome in children and adolescents with mature B-cell non-Hodgkin's lymphoma: results of the FAB/LMB 96 international study. Leukemia 23 (2): 323-31, 2009.
66. Pittaluga S, Harris NL, Siebert R, et al.: Large B-cell lymphoma with IRF4 rearrangement. In: Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th rev. ed. International Agency for Research on Cancer, 2017, pp 280-1.
67. Chisholm KM, Mohlman J, Liew M, et al.: IRF4 translocation status in pediatric follicular and diffuse large B-cell lymphoma patients enrolled in Children's Oncology Group trials. Pediatr Blood Cancer 66 (8): e27770, 2019.
68. Salaverria I, Philipp C, Oschlies I, et al.: Translocations activating IRF4 identify a subtype of germinal center-derived B-cell lymphoma affecting predominantly children and young adults. Blood 118 (1): 139-47, 2011.
69. Liu Q, Salaverria I, Pittaluga S, et al.: Follicular lymphomas in children and young adults: a comparison of the pediatric variant with usual follicular lymphoma. Am J Surg Pathol 37 (3): 333-43, 2013.
70. Jiang XN, Yu F, Xue T, et al.: IRF4 rearrangement may predict favorable prognosis in children and young adults with primary head and neck large B-cell lymphoma. Cancer Med 12 (9): 10684-10693, 2023.
71. Kluin PM, Harris NL, Stein H, et al.: High-grade B-cell lymphoma. In: Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th rev. ed. International Agency for Research on Cancer, 2017, pp 335-41.
72. Seidemann K, Tiemann M, Lauterbach I, et al.: Primary mediastinal large B-cell lymphoma with sclerosis in pediatric and adolescent patients: treatment and results from three therapeutic studies of the Berlin-Frankfurt-Münster Group. J Clin Oncol 21 (9): 1782-9, 2003.
73. Bea S, Zettl A, Wright G, et al.: Diffuse large B-cell lymphoma subgroups have distinct genetic profiles that influence tumor biology and improve gene-expression-based survival prediction. Blood 106 (9): 3183-90, 2005.
74. Oschlies I, Burkhardt B, Salaverria I, et al.: Clinical, pathological and genetic features of primary mediastinal large B-cell lymphomas and mediastinal gray zone lymphomas in children. Haematologica 96 (2): 262-8, 2011.
75. Jaffe ES, Harris NL, Stein H, et al.: Primary mediastinal (thymic) large B-cell lymphoma. In: Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th rev. ed. International Agency for Research on Cancer, 2017, pp 314-6.
76. Jaffe ES, Harris NL, Stein H, et al.: Introduction and overview of the classification of the lymphoid neoplasms. In: Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. International Agency for Research on Cancer, 2008, pp 157-66.
77. Rosenwald A, Wright G, Leroy K, et al.: Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma. J Exp Med 198 (6): 851-62, 2003.
78. Savage KJ, Monti S, Kutok JL, et al.: The molecular signature of mediastinal large B-cell lymphoma differs from that of other diffuse large B-cell lymphomas and shares features with classical Hodgkin lymphoma. Blood 102 (12): 3871-9, 2003.
79. Mottok A, Hung SS, Chavez EA, et al.: Integrative genomic analysis identifies key pathogenic mechanisms in primary mediastinal large B-cell lymphoma. Blood 134 (10): 802-813, 2019.
80. Green MR, Monti S, Rodig SJ, et al.: Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Blood 116 (17): 3268-77, 2010.
81. Twa DD, Chan FC, Ben-Neriah S, et al.: Genomic rearrangements involving programmed death ligands are recurrent in primary mediastinal large B-cell lymphoma. Blood 123 (13): 2062-5, 2014.
82. Chong LC, Twa DD, Mottok A, et al.: Comprehensive characterization of programmed death ligand structural rearrangements in B-cell non-Hodgkin lymphomas. Blood 128 (9): 1206-13, 2016.
83. Chapuy B, Stewart C, Dunford AJ, et al.: Genomic analyses of PMBL reveal new drivers and mechanisms of sensitivity to PD-1 blockade. Blood 134 (26): 2369-2382, 2019.
84. Mottok A, Woolcock B, Chan FC, et al.: Genomic Alterations in CIITA Are Frequent in Primary Mediastinal Large B Cell Lymphoma and Are Associated with Diminished MHC Class II Expression. Cell Rep 13 (7): 1418-1431, 2015.
85. Viganò E, Gunawardana J, Mottok A, et al.: Somatic IL4R mutations in primary mediastinal large B-cell lymphoma lead to constitutive JAK-STAT signaling activation. Blood 131 (18): 2036-2046, 2018.
86. Melzner I, Bucur AJ, Brüderlein S, et al.: Biallelic mutation of SOCS-1 impairs JAK2 degradation and sustains phospho-JAK2 action in the MedB-1 mediastinal lymphoma line. Blood 105 (6): 2535-42, 2005.
87. Mestre C, Rubio-Moscardo F, Rosenwald A, et al.: Homozygous deletion of SOCS1 in primary mediastinal B-cell lymphoma detected by CGH to BAC microarrays. Leukemia 19 (6): 1082-4, 2005.
88. Gerrard M, Waxman IM, Sposto R, et al.: Outcome and pathologic classification of children and adolescents with mediastinal large B-cell lymphoma treated with FAB/LMB96 mature B-NHL therapy. Blood 121 (2): 278-85, 2013.
89. Dunleavy K, Pittaluga S, Maeda LS, et al.: Dose-adjusted EPOCH-rituximab therapy in primary mediastinal B-cell lymphoma. N Engl J Med 368 (15): 1408-16, 2013.
90. Giulino-Roth L, O'Donohue T, Chen Z, et al.: Outcomes of adults and children with primary mediastinal B-cell lymphoma treated with dose-adjusted EPOCH-R. Br J Haematol 179 (5): 739-747, 2017.
91. Burke GAA, Minard-Colin V, Aupérin A, et al.: Dose-Adjusted Etoposide, Doxorubicin, and Cyclophosphamide With Vincristine and Prednisone Plus Rituximab Therapy in Children and Adolescents With Primary Mediastinal B-Cell Lymphoma: A Multicenter Phase II Trial. J Clin Oncol 39 (33): 3716-3724, 2021.
92. Dourthe ME, Phulpin A, Auperin A, et al.: Rituximab in addition to LMB-based chemotherapy regimen in children and adolescents with primary mediastinal large B-cell lymphoma: results of the French LMB2001 prospective study. Haematologica 107 (9): 2173-2182, 2022.
93. Zinzani PL, Ribrag V, Moskowitz CH, et al.: Safety and tolerability of pembrolizumab in patients with relapsed/refractory primary mediastinal large B-cell lymphoma. Blood 130 (3): 267-270, 2017.

Lymphoblastic Lymphoma

Incidence

Lymphoblastic lymphoma comprises approximately 20% of childhood non-Hodgkin lymphoma (NHL) cases.[1,2] For more information about the incidence of lymphoblastic lymphoma by age and sex distribution, see Table 1.

Clinical Presentation

As many as 75% of patients with T-cell lymphoblastic lymphoma will present with an anterior mediastinal mass, which may manifest as dyspnea, wheezing, stridor, dysphagia, or swelling of the head and neck.

Pleural and/or pericardial effusions may be present. Involvement of lymph nodes, usually above the diaphragm, may be a prominent feature. There may also be involvement of bone, skin, bone marrow, central nervous system (CNS), abdominal organs (but rarely bowel), and, occasionally, other sites such as lymphoid tissue of Waldeyer ring, testes, or subcutaneous tissue. Abdominal involvement is less common in T-cell lymphoblastic lymphoma than in Burkitt lymphoma.

Involvement of the bone marrow may lead to confusion about whether the patient has lymphoma with bone marrow involvement or leukemia with extramedullary disease. Traditionally, patients with more than 25% marrow blasts are considered to have T-cell acute lymphoblastic leukemia (ALL), and those with fewer than 25% marrow blasts are considered to have stage IV T-cell lymphoblastic lymphoma. The World Health Organization (WHO) classifies lymphoblastic lymphoma as the same disease as ALL.[3] The debate centers on whether they truly represent the same disease.[4] It is not yet clear whether these arbitrary definitions are biologically distinct or relevant for treatment design.

B-cell lymphoblastic lymphoma is more often localized nodal disease, but it can present with extranodal disease (e.g., isolated testicular or cutaneous disease).[5,6]

Tumor Biology

Genomics of lymphoblastic lymphoma

Lymphoblastic lymphomas are usually positive for terminal deoxynucleotidyl transferase. More than 75% of cases have a T-cell immunophenotype and the remaining cases have a precursor B-cell phenotype.[5]

As opposed to pediatric T-cell acute lymphoblastic leukemia (T-ALL), the molecular biology and chromosomal abnormalities of pediatric lymphoblastic lymphoma are not as well characterized. Many genomic alterations that occur in T-ALL also occur in T-cell lymphoblastic lymphoma. Examples include the following:

• NOTCH1 and FBXW7 variants (which also induce NOTCH pathway signaling) are common in T-ALL.[7]NOTCH1 and FBXW7 variants are also observed in approximately 60% to 65% and 15% to 25% of T-cell lymphoblastic lymphoma cases, respectively.[8,9,10,11]
• CDKN2A at chromosome 9p21 is commonly altered in both T-ALL and in T-cell lymphoblastic lymphoma, with approximately three-fourths of each showing deletions of this gene locus.[7,11]
• Loss of heterozygosity at chromosome 6q is observed in approximately 15% of T-ALL cases.[11]
• PTEN variants are observed in approximately 15% of T-ALL cases and in a comparable percentage of T-lymphoblastic lymphoma cases.[7,10,11]
• KMT2D variants are observed in approximately 10% of T-lymphoblastic lymphoma cases.[11] Other genes associated with epigenetics that are altered in T-ALL include PHF6 and KMT2C.

For the genomic alterations described above, NOTCH1 and FBXW7 variants may confer a more favorable prognosis for patients with T-cell lymphoblastic lymphoma. In contrast, loss of heterozygosity at chromosome 6q, PTEN variants, and KMT2D variants may be associated with an inferior prognosis.[8,9,10,11,12] For example, one study noted that the presence of a KMT2D and/or PTEN variant was associated with a high risk of relapse in patients with wild-type NOTCH1 or FBXW7, but these variants were not associated with an increased risk of relapse in patients with variants in NOTCH1 or FBXW7.[11] Studies with larger numbers of patients are needed to better define the critical genomic determinants of outcome for patients with T-cell lymphoblastic lymphoma.

There have been few studies of the genomic characteristics of B-lymphoblastic lymphoma. One report described copy number alterations for pediatric B-lymphoblastic lymphoma cases. The study noted that some gene deletions that are common in B-ALL (e.g., CDKN2A, IKZF1, and PAX5) appeared to occur with appreciable frequency in B-lymphoblastic lymphoma.[4]

Prognostic Factors

For information about prognostic factors for lymphoblastic lymphoma, see the Prognosis and Prognostic Factors for Childhood NHL section.

Standard Treatment Options for Lymphoblastic Lymphoma

Low-stage (stage I or stage II) lymphoblastic lymphoma is primarily a B-cell disease. Treatment with short, pulsed chemotherapy (i.e., doxorubicin, cyclophosphamide, vincristine, and prednisone [CHOP]), followed by 6 months of maintenance therapy, produces a disease-free survival (DFS) rate of about 60% and an overall survival (OS) rate exceeding 90%.[13,14] However, the use of an ALL treatment approach, consisting of induction, consolidation, and maintenance therapy for a total of 24 months, has produced DFS rates higher than 90% in children with low-stage lymphoblastic lymphoma.[6,15,16]

Patients with high-stage (stage III or stage IV) lymphoblastic lymphoma, most often T-cell disease, have DFS rates higher than 80%.[15,16,17] Mediastinal involvement is common, but radiation therapy is not necessary for patients with mediastinal masses, except in the emergency treatment of symptomatic superior vena cava obstruction or airway obstruction. In these cases, either corticosteroid therapy or low-dose radiation therapy is usually given. For more information, see the Mediastinal masses section.

The following studies have contributed to the development of current treatment regimens for pediatric patients with lymphoblastic lymphoma.

The Pediatric Oncology Group conducted a trial to test the effectiveness of high-dose methotrexate in the treatment of patients with T-cell ALL and T-cell lymphoblastic lymphoma. In the lymphoma patients (n = 66), high-dose methotrexate did not demonstrate a benefit, with a 5-year event-free survival (EFS) rate of 88%.[18][Level of evidence A1] Of note, all of these patients received prophylactic cranial radiation therapy, even though other studies have shown that it is not required for patients with T-cell lymphoblastic lymphoma.[16,17] In this study, the benefit of adding the cardioprotectant dexrazoxane was tested in a randomized fashion. The addition of dexrazoxane did not affect patient outcomes, and it provided cardioprotective benefits, as demonstrated by echocardiographic and laboratory assessments.[19][Level of evidence B4]

In the NHL-BFM-90 study, the 5-year DFS rate was 90%, and there was no difference in outcome between patients with stage III and stage IV disease.[15] Patients with precursor B-cell lymphoblastic lymphoma appeared to have similar results using the same therapy.[2] All patients received prophylactic cranial radiation therapy. In the NHL-BFM-95 study, the amount of daunorubicin and asparaginase in induction was reduced and patients did not receive prophylactic cranial radiation therapy.[16] The DFS rate in this study was similar to the rate in the NHL-BFM-90 study. However, the EFS rate was lower, at 82%, because of a higher incidence of subsequent neoplasms.[16] A single-center study reported that patients treated for lymphoblastic lymphoma had a higher incidence of subsequent neoplasms than did patients treated for other pediatric NHL.[20] However, studies from the Children's Oncology Group (COG) and the Childhood Cancer Survivor Study Group did not support this finding.[17,21,22,23]

Evidence for chemotherapy (low-stage treatment regimens for lymphoblastic lymphoma):

1. COG-A5971 (NCT00004228) : Stage I or stage II patients (arm A0; localized disease) received a modified Children's Cancer Group (CCG) BFM regimen and a reduced number of intrathecal treatments during the maintenance phase.[6]
   • In 56 patients, the 5-year EFS rate was 90%, and the OS rate was 96%.

Evidence for chemotherapy (high-stage treatment regimens for lymphoblastic lymphoma):

1. GER-GPOH-NHL-BFM-95: Only CNS-positive patients received CNS radiation therapy. The treatment duration for patients with T-cell and B-cell precursor lymphoblastic lymphoma was 24 months.[15,16]
   • The 5-year DFS rate was 88%, and the OS rate was 85%.
2. COG-A5971 (NCT00004228) : This trial evaluated two strategies for CNS prophylaxis, without the use of CNS irradiation, for patients with stage III and stage IV lymphoblastic lymphoma. Patients were randomly assigned to receive either high-dose methotrexate during the interim maintenance phase (BFM-95) or intrathecal chemotherapy throughout the maintenance phase (CCG-BFM).[17][Level of evidence A1]
   • First randomization:
     • Arm A1 (disseminated disease, no CNS disease): Modified CCG-BFM regimen without intensification. No high-dose methotrexate was administered during the interim maintenance phase, but intrathecal therapy was administered throughout the maintenance phase.
     • Arm B1 (disseminated disease, no CNS disease): GER-GPOH-NHL-BFM-95 regimen without intensification and without intrathecal therapy during the maintenance phase.
   • Second randomization:
     • Arm A2 (disseminated disease, no CNS disease): Modified CCG-BFM regimen (arm A1) with intensified induction and delayed intensification.
     • Arm B2 (disseminated disease, no CNS disease): GER-GPOH-NHL-BFM-95 regimen (arm B1) with intensified induction and delayed intensification. Patients with CNS disease were nonrandomly treated on arm B2 with the addition of radiation therapy.

   Equivalent outcomes were observed for patients treated on arms A1, B1, A2, and B2. The 5-year EFS rates were 81%, 80%, 84%, and 80%, respectively. The OS rates were 84%, 88%, 85%, and 85%, respectively. Patients with CNS disease at diagnosis had a 5-year EFS rate of 63% and an OS rate of 81%.

3. COG AALL0434 (NCT00408005): In this trial, patients with stages II to IV T-cell lymphoblastic lymphoma received COG-augmented, BFM-backbone therapy with Capizzi methotrexate and intrathecal chemotherapy through the maintenance phase. No patients with CNS disease received cranial radiation therapy because patients with CNS3 disease were not eligible. Patients with less than 1% minimal disseminated disease (MDD) in their bone marrow at diagnosis, assessed by flow cytometry, were nonrandomly assigned to treatment without nelarabine. Patients with greater than 1% MDD were randomly assigned to receive treatment with or without nelarabine.[23]
   • The overall 4-year DFS rate was 85%, and the OS rate was 89%.
   • There was no difference in DFS observed between standard-risk and high-risk patients. Disease stage and MDD status at diagnosis also did not demonstrate differences in EFS.
   • Although nelarabine was beneficial in patients with T-ALL, there was no statistical difference in outcome for patients with NHL who did or did not receive nelarabine. This result may be explained by small numbers of randomized NHL patients or lower CNS relapse rates in NHL patients (i.e., 1.4%).
4. COG AALL1231 (NCT02112916): Patients who were newly diagnosed with T-cell lymphoblastic lymphoma were treated with the AALL0434 backbone, with some treatment modifications. Dexamethasone was given instead of prednisone in the induction and maintenance phases, and two additional pegaspargase doses were given during the induction and delayed intensification phases. Patients were randomly assigned to receive treatment with or without bortezomib (four doses in induction and four doses in delayed intensification).[24]
   • There was an increased rate of toxic deaths in the AALL1231 trial (4%), compared with the AALL0434 trial (2%).
   • Patients who received bortezomib had statistically significantly better 4-year EFS rates than those who did not receive bortezomib (EFS rates, 86% vs. 76%; P = .04). However, patients in the bortezomib arm had EFS and OS rates similar to patients in both arms of the AALL0434 trial, who were treated with and without nelarabine.
   • The poorer-than-expected outcome for patients treated without bortezomib cannot be explained solely by an increased toxic death rate. Despite more intensive therapy in the AALL1231 trial than in the AALL0434 trial, more relapses were observed in AALL1231.

Treatment Options for Recurrent or Refractory Lymphoblastic Lymphoma

For patients with recurrent or refractory lymphoblastic lymphoma, survival rates range from 10% to 40%.[21,25]; [26][Level of evidence B4]; [27,28][Level of evidence C1] As in patients with Burkitt lymphoma, chemoresistant disease is common.

There are no standard treatment options for patients with recurrent or refractory disease.

Treatment options for recurrent or refractory lymphoblastic lymphoma include the following:

1. Nelarabine or nelarabine-containing chemotherapy regimens (nelarabine, cyclophosphamide, and etoposide).[29,30,31]
2. ICE regimen (ifosfamide, carboplatin, and etoposide).[32]
3. Bortezomib with block 1 (four-drug induction), block 2 (cyclophosphamide, etoposide, and high-dose methotrexate), and block 3 (high-dose cytarabine and PEG-asparaginase).[33]
4. Allogeneic hematopoietic stem cell transplant (HSCT).[34,35]

Evidence (treatment of recurrent or refractory lymphoblastic lymphoma):

1. A COG phase II study of nelarabine (compound 506U78) as a single agent demonstrated a response rate of 40%.[29]
2. A phase IV multicenter study of patients with recurrent or refractory T-cell leukemia/lymphoma (n = 28, 11 lymphoma) were treated with single-agent nelarabine.[30]
   • A complete response rate of 36% was observed.
3. Three small series have treated patients with recurrent or refractory T-cell leukemia/lymphoma using nelarabine, cyclophosphamide, and etoposide.[31,36,37]
   1. One study treated 27 patients.[31]
      • A partial/complete response rate of 85% was observed.
      • However, 13% of patients developed greater than grade 3 neurotoxicity, and three patients died of neurotoxicity.
      • Of the four lymphoma patients, one patient achieved a partial remission, but all patients eventually had disease progression.
   2. The second study treated seven patients.[36]
      • The partial/complete response rate was 100%.
      • Of the two lymphoma patients, both achieved partial responses but later progressed.
   3. The third study treated ten patients.[37]
      • Forty-four percent of the patients had any response (complete response, complete response with incomplete platelet recovery, or partial response), and the complete response rate was 33%.
      • Two of ten patients had severe peripheral neuropathy.
4. On the AALL07P1 (NCT00873093) trial, ten patients with T-cell lymphoblastic lymphoma in first relapse were treated with bortezomib added to a four-drug induction regimen.[33]
   • Seven patients had a response; one patient had a complete response, two patients had unconfirmed complete responses, and four patients had partial responses.
5. A BFM study showed an OS rate of 14% for patients relapsing after BFM front-line therapy. All patients who survived had undergone an allogeneic HSCT.[28]
6. A Center for International Blood and Marrow Transplant Research analysis demonstrated that the EFS rate was significantly worse when an autologous (4%) versus allogeneic (40%) donor stem cell source was used. All treatment failures resulted from progressive disease.[34]

Treatment Options Under Clinical Evaluation for Lymphoblastic Lymphoma

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.

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35. Naik S, Martinez CA, Omer B, et al.: Allogeneic hematopoietic stem cell transplant for relapsed and refractory non-Hodgkin lymphoma in pediatric patients. Blood Adv 3 (18): 2689-2695, 2019.
36. Commander LA, Seif AE, Insogna IG, et al.: Salvage therapy with nelarabine, etoposide, and cyclophosphamide in relapsed/refractory paediatric T-cell lymphoblastic leukaemia and lymphoma. Br J Haematol 150 (3): 345-51, 2010.
37. Whitlock JA, Malvar J, Dalla-Pozza L, et al.: Nelarabine, etoposide, and cyclophosphamide in relapsed pediatric T-acute lymphoblastic leukemia and T-lymphoblastic lymphoma (study T2008-002 NECTAR). Pediatr Blood Cancer 69 (11): e29901, 2022.

Anaplastic Large Cell Lymphoma

Incidence

Anaplastic large cell lymphoma accounts for approximately 10% of childhood non-Hodgkin lymphoma (NHL) cases.[1] For more information about the incidence of anaplastic large cell lymphoma by age and sex distribution, see Table 1.

Clinical Presentation

Clinically, systemic anaplastic large cell lymphoma has a broad range of presentations. These include involvement of lymph nodes and a variety of extranodal sites, particularly skin and bone and, less often, gastrointestinal tract, lung, pleura, and muscle. Involvement of the central nervous system (CNS) and bone marrow is uncommon.

Anaplastic large cell lymphoma is often associated with systemic symptoms (e.g., fever, weight loss) and a prolonged waxing and waning course, making diagnosis difficult and often delayed. Patients with anaplastic large cell lymphoma may present with signs and symptoms consistent with hemophagocytic lymphohistiocytosis.[2]

There is a subgroup of patients with anaplastic large cell lymphoma who have leukemic peripheral blood involvement. These patients usually exhibit significant respiratory distress with diffuse lung infiltrates or pleural effusions and have hepatosplenomegaly.[3,4]

Tumor Biology

Genomics of anaplastic large cell lymphoma

While mature T cell is the predominant immunophenotype of anaplastic large cell lymphoma, null-cell disease (i.e., no T-cell, B-cell, or natural killer-cell surface antigen expression) does occur. The World Health Organization (WHO) classifies anaplastic large cell lymphoma as a subtype of peripheral T-cell lymphoma.[5,6]

All anaplastic large cell lymphoma cases are CD30-positive. More than 90% of pediatric anaplastic large cell lymphoma cases have a chromosomal rearrangement involving the ALK gene. About 85% of these chromosomal rearrangements will be t(2;5)(p23;q35), leading to the expression of the NPM::ALK fusion protein. The other 15% of cases are composed of variant ALK translocations.[7] The anti-ALK immunohistochemical staining pattern is quite specific for the type of ALK translocation. Cytoplasm and nuclear ALK staining is associated with NPM::ALK fusion proteins, whereas cytoplasmic staining of ALK is only associated with the variant ALK translocations, as shown in Table 6.[8]

Table 6. VariantALKTranslocation and Associated Partner Chromosome Location and Frequency^a

Gene Fusion	Partner Chromosome Location	Frequency of Gene Fusion
a Adapted from Tsuyama et al.[8]
NPM::ALK	5q36.1	Approximately 80%
TPM3::ALK	1p23	Approximately 15%
ALO17::ALK	17q25.3	Rare
ATIC::ALK	2q35	Rare
CLTC::ALK	17q23	Rare
MSN::ALK	Xp11.1	Rare
MYH9::ALK	22q13.1	Rare
TFG::ALK	3q12.2	Rare
TPM4::ALK	19p13	Rare
TRAF1::ALK	9q33.2	Rare

In adults, ALK-positive anaplastic large cell lymphoma is viewed differently from other peripheral T-cell lymphomas because prognosis tends to be superior.[9] Also, adult patients with ALK-negative anaplastic large cell lymphoma have an inferior outcome compared with patients who have ALK-positive disease.[10] In children, however, this difference in outcome between ALK-positive and ALK-negative disease has not been demonstrated. In addition, no correlation has been found between outcome and the specific ALK-translocation type.[11,12,13]

One European series included 375 children and adolescents with systemic ALK-positive anaplastic large cell lymphoma. The presence of a small cell or lymphohistiocytic component was observed in 32% of patients, and it was significantly associated with a high risk of failure in the multivariate analysis, controlling for clinical characteristics (hazard ratio, 2.0; P = .002).[12] The prognostic implication of the small cell variant of anaplastic large cell lymphoma was also shown in the COG-ANHL0131 (NCT00059839) study, despite using a different chemotherapy backbone.[13]

Prognostic Factors

For information on prognostic factors for anaplastic large cell lymphoma, see the Prognosis and Prognostic Factors for Childhood NHL section.

Standard Treatment Options for Anaplastic Large Cell Lymphoma

Children and adolescents with high-stage (stage III or IV) anaplastic large cell lymphoma have a disease-free survival rate of approximately 60% to 75%.[14,15,16,17,18,19]

It is unclear which treatment strategy is best for patients with anaplastic large cell lymphoma. Current data do not suggest superiority of one treatment regimen over another for these standard treatment options.

Commonly used treatment regimens include the following:

1. POG-8314/POG-8719/POG 9219: Three cycles of chemotherapy (no radiation or maintenance therapy) for stage I and stage II disease.[20]
2. GER-GPOH-NHL-BFM-90: Prephase plus three cycles of chemotherapy (only for completely resected disease).[15]
3. APO regimen: Doxorubicin, prednisone, and vincristine.[16] This regimen can be administered in the outpatient setting. The duration of therapy is 52 weeks, and the cumulative dose of doxorubicin is 300 mg/m². No alkylator therapy is given.
4. FRE-IGR-ALCL99: Dexamethasone, cyclophosphamide, ifosfamide, etoposide, doxorubicin, intravenous (IV) methotrexate (3 g/m² in one study arm), cytarabine, prednisolone, and vinblastine.[21] This regimen usually requires hospitalization for administration. The total duration of therapy is 5 months, and the cumulative dose of doxorubicin is 150 mg/m².

Evidence (treatment of anaplastic large cell lymphoma):

1. The POG-9219 study for patients with low-stage lymphoma used three cycles of doxorubicin, cyclophosphamide, vincristine, and prednisone (CHOP).[20]
   • The 5-year event-free survival (EFS) rate was 88% for patients with large cell lymphoma (anaplastic large cell lymphoma and diffuse large B-cell lymphoma).
2. The FRE-IGR-ALCL99 trial used three cycles of chemotherapy after cytoreductive prophase for patients with stage I, completely resected disease. The therapy for patients without complete resection was the same as the therapy for patients with disseminated disease.[22][Level of evidence B4]
   • Only 6 of 36 patients with stage I disease had complete resections. No treatment failures were reported for these 6 patients.
   • The 3-year EFS (77%) and overall survival (OS) (97%) rates for patients without complete resections were not statistically different from the outcomes for patients with higher-stage disease.
3. The German Berlin-Frankfurt-Münster (BFM) group used six cycles of intensive pulsed therapy, similar to their B-cell NHL therapy (GER-GPOH-NHL-BFM-90 [NHL-BFM-90]).[15,23,24]; [21][Level of evidence A1] Building on these results, the European Intergroup for Childhood NHL group conducted the FRE-IGR-ALCL99 study (based on the GER-GPOH-NHL-BFM-90 regimen).
   • First, this randomized study demonstrated that methotrexate 1 g/m² infused over 24 hours plus intrathecal methotrexate and methotrexate 3 g/m² infused over 3 hours without intrathecal methotrexate yielded similar outcomes.[23][Level of evidence A3] However, methotrexate 3 g/m² over 3 hours had less toxicity than methotrexate 1 g/m² over 24 hours.[23]; [21][Level of evidence B1]
   • Second, patients in the FRE-IGR-ALCL99 trial were randomly assigned to receive either limited vinblastine or prolonged (1 year) vinblastine exposure. Patients who received the vinblastine-plus-chemotherapy regimen had a better EFS rate in the first year after therapy (91%) than did those who did not receive vinblastine (74%). However, after 2 years of follow-up, the EFS rate was 73% for both groups.[24][Level of evidence B1] This suggests that the longer therapy in the vinblastine group delayed, but did not prevent, relapse.
4. The COG-ANHL0131 (NCT00059839) trial showed that the addition of vinblastine to the doxorubicin, prednisone, and vincristine (APO) regimen increased toxicity, but did not improve the survival of patients with anaplastic large cell lymphoma.[13]
5. The earlier Pediatric Oncology Group (POG) trial (POG-9317) demonstrated no benefit of adding methotrexate and high-dose cytarabine to 52 weeks of the APO regimen.[16]
6. The Italian Association of Pediatric Hematology/Oncology group used a leukemia-like regimen for 24 months in the LNH-92 trial. The results of this study were similar to those of studies that used other regimens, although the duration of first remission was prolonged by the longer therapy.[17]
7. The CCG-5941 study tested an approach similar to that used in the LNH-92 trial, with more intensive induction and consolidation with maintenance for a total duration of therapy of 1 year. Similar outcomes and similar significant increase in hematologic toxicity were observed.[18][Level of evidence B4]
8. One arm of the COG ANHL12P1 (NCT01979536) study added brentuximab vedotin to the ALCL99 trial chemotherapy backbone, and 68 patients were enrolled.[25]
   • Patients who received the brentuximab vedotin–containing regimen had a 2-year EFS rate of 79% (95% confidence interval [CI], 67%–87%) and an OS rate of 97% (95% CI, 88%–99%). Patients who received the ALCL99 trial therapy without brentuximab vedotin had an estimated 5-year progression-free survival (PFS) rate of approximately 70%.
   • All events occurred after completion of therapy, with median time from diagnosis to relapse of 7.5 months (range, 5.5–22.0 months).
   • The addition of brentuximab vedotin to ALCL99 trial chemotherapy produced toxicity similar to what was observed in the ALCL99 trial.
   • This study confirmed the poor prognosis associated with minimal disseminated disease (MDD) in the peripheral blood at diagnosis. Patients with MDD (n = 22; 37%) had a 5-year EFS rate of 57.8%, compared with patients without MDD (n = 37; 63%) who had a 5-year EFS rate of 84.9%.
9. The second arm of the COG ANHL12P1 study added crizotinib to the ALCL99 trial chemotherapy backbone, and 66 patients were enrolled.[26]
   • Patients who received the crizotinib-containing regimen had a 2-year EFS rate of 76.8% (95% CI, 68.5%–88.1%) and a 2-year OS rate of 95.2% (95% CI, 85.7%–98.4%). Patients who received ALCL99 trial therapy without crizotinib had an estimated 5-year PFS rate of approximately 70%.
   • All events occurred after completion of therapy, with median time from diagnosis to relapse of 7.4 months (range, 4.2–28.9 months).
   • The addition of crizotinib produced an unexpectedly high rate of thromboembolic events. Eleven of the first 41 patients (26.8%; 95% CI, 14.2%–42.9%) experienced grade 2 or higher thromboembolic adverse events. Among 25 patients enrolled after instituting mandatory prophylactic anticoagulation, 2 patients (8%) experienced grade 2 or higher thromboembolic events. Given the high rate of thromboembolic events, the authors recommend not using crizotinib with ALCL99 trial chemotherapy.
   • Patients with MDD in the peripheral blood at diagnosis (n = 20) had a 5-year EFS rate of 58.1%, while patients without MDD (n = 37) had a 5-year EFS rate of 85.6%.

CNS involvement in patients with anaplastic large cell lymphoma is rare at diagnosis. In an international study of systemic childhood anaplastic large cell lymphoma, 12 of 463 patients (2.6%) had CNS involvement, 3 of whom had isolated CNS disease (primary CNS lymphoma). For the CNS-positive group who received multiagent chemotherapy, including high-dose methotrexate, cytarabine, and intrathecal treatment, the EFS rate was 50% (95% CI, 25%–75%), and the OS rate was 74% (95% CI, 45%–91%) at a median follow-up of 4.1 years. The role of cranial radiation therapy has been difficult to assess.[27]

Treatment Options for Recurrent or Refractory Anaplastic Large Cell Lymphoma

Unlike mature B-cell or lymphoblastic lymphoma, the survival rates for patients with recurrent or refractory anaplastic large cell lymphoma are 40% to 60%.[28,29,30,31]

There is no standard approach for the treatment of recurrent or refractory anaplastic large cell lymphoma.

Treatment options for recurrent or refractory anaplastic large cell lymphoma include the following:

1. ICE regimen (ifosfamide, carboplatin, and etoposide).[32]
2. Vinblastine.[33]
3. Brentuximab vedotin.[34]; [35][Level of evidence B4]
4. Crizotinib [36] and other ALK inhibitors (e.g., alectinib and ceritinib).[37,38]
5. Allogeneic or autologous hematopoietic stem cell transplant (HSCT).[39,40,41]

Although remissions can be achieved with single-agent therapy (e.g., vinblastine, brentuximab vedotin, or crizotinib), CNS progressions after therapy have been observed in patients with recurrent anaplastic large cell lymphoma. A large retrospective review of a study database found that the incidence of CNS involvement at relapse is about 4%. The median time to relapse with CNS involvement was 8 months for 26 patients. The 3-year OS rate after relapse was about 50%.[42]

Chemotherapy, followed by autologous or allogeneic HSCT, if remission can be achieved, has been used in this setting.[29,30,39,40,43]

Evidence (chemotherapy and targeted therapy):

1. Vinblastine is active as a single agent in patients with recurrent or refractory anaplastic large cell lymphoma.
   1. In one study, patients with recurrent or refractory anaplastic large cell lymphoma were treated with vinblastine alone, and the following was observed:[33][Level of evidence C1]
      • Vinblastine induced complete remission in 25 of 30 evaluable patients (83%).
      • Nine of these 25 patients remained in complete remission, with a median follow-up of 7 years from the end of treatment.
2. ALK kinase inhibitors are highly active in patients with recurrent anaplastic large cell lymphoma that express the NPM::ALK fusion protein.
   1. Crizotinib, a kinase inhibitor that blocks the activity of the NPM::ALK fusion protein, has been evaluated in children and adults with relapsed/refractory anaplastic large cell lymphoma.[44]
      • Of 26 patients with anaplastic large cell lymphoma who were treated with crizotinib on a pediatric phase I study with a phase II extension, 21 patients achieved complete responses.[36,45][Level of evidence B4]
      • Although complete responses are common, the duration of therapy remains unclear.[46][Level of evidence C2]
      • The most common adverse event was neutropenia.[45]
   2. Alectinib is a second-generation ALK inhibitor that showed superiority over crizotinib in phase III studies for patients with ALK variants and non-small cell lung cancer.[47]
      • In a study of ten patients with relapsed/refractory anaplastic large cell lymphoma, eight achieved objective responses, with six complete responses. Five patients achieved durable remissions (397–925 days at the time of the report) to alectinib as a single agent.[37]
   3. Ceritinib, an orally administered, second-generation ALK inhibitor, has been shown to be safe and effective in pediatric patients with ALK-positive tumors whose cancer relapsed. In a phase I dose-finding study, eight patients with anaplastic large cell lymphoma were evaluable for response.[38]
      • Twenty-five percent of the patients achieved a complete response, and 50% achieved a partial response.
3. Brentuximab vedotin has been evaluated in adults with anaplastic large cell lymphoma.
   1. In a phase II study of adults and adolescents with CD30-positive cancers, patients received a dose of 1.8 mg/kg of brentuximab vedotin every 3 weeks for approximately 1 year. The median age of patients was 52 years (range, 14–76 years). Sixteen of 58 patients (28%) had ALK-positive anaplastic large cell lymphoma, and 42 of 58 patients (72%) had ALK-negative anaplastic large cell lymphoma.[34]
      • Complete remission rates of approximately 55% to 60% and partial remission rates of 29% were observed.[34]
      • For the 38 patients who achieved a complete remission (28 ALK-negative patients, 10 ALK-positive patients), the 5-year PFS rate was 79%, and the OS rate was 57%. PFS was similar for ALK-positive and ALK-negative patients.[48]
      • Sixteen patients (11 ALK-negative patients, 5 ALK-positive patients) remained in remission without the start of new therapy other than consolidative HSCT at 5 or more years from the end of treatment with brentuximab vedotin. Of the five ALK-positive patients who remained in remission, four received an allogeneic HSCT, and one received no therapy other than brentuximab vedotin.[48]
4. Brentuximab vedotin has been evaluated in children with recurrent or refractory anaplastic large cell lymphoma.
   1. In a phase II study, 17 patients (median age, 11 years) were treated with brentuximab vedotin at a dose of 1.8 mg/kg every 21 days. Twelve patients were ALK positive and five were ALK negative. After treatment with brentuximab vedotin, nine patients then received either autologous or allogeneic transplant.[35][Level of evidence B4]
      • The overall response rate was 53% (9 of 17 patients), with a complete response rate of 41% (7 of 17 patients), a partial response rate of 12% (2 of 17 patients), a stable disease rate of 29% (5 of 17 patients), and a progressive disease rate of 18% (3 of 17 patients).
      • The median EFS was 4.8 months.
      • The OS rate was 93.3% at 24 months.

Evidence (autologous vs. allogeneic HSCT):

1. A retrospective study of patients with relapsed or refractory anaplastic large cell lymphoma who received BFM-type first-line therapy, reinduction chemotherapy, followed by autologous HSCT reported the following:[30][Level of evidence B4]
   • A 5-year EFS rate of 59% and an OS rate of 77%. However, the outcomes were poor for patients with bone marrow or CNS involvement, relapse during first-line therapy, or CD3-positive anaplastic large cell lymphoma. These patients may benefit from allogeneic transplant.
2. In a European prospective study of patients with relapsed or refractory anaplastic large cell lymphoma, primary refractory patients received aggressive multiagent chemotherapy and underwent allogeneic HSCT. Relapsed patients with CD3-positive disease received less-intense multiagent chemotherapy and allogeneic HSCT (recommended therapy) or autologous HSCT if no donors were available. Relapsed patients with CD3-negative disease (<1 year from diagnosis) received less-aggressive chemotherapy and autologous HSCT. Relapsed patients with CD3-negative disease (>1 year from diagnosis) received single-agent vinblastine for 2 years.[31] The study demonstrated the following results:
   • For the entire cohort, the 5-year EFS rate was approximately 50%, and the OS rate was 77%.
   • For patients with refractory disease or early relapse, reinduction with multiagent chemotherapy followed by allogeneic HSCT achieved the best results (i.e., long-term EFS rate, 65%).
   • Patients who received autologous HSCT fared much worse (i.e., long-term EFS rate, 25%).
   • Patients who had a late relapse (>1 year from diagnosis) were treated with vinblastine for 2 years and achieved a 5-year EFS rate of 81%.
3. Several additional studies suggest that allogeneic HSCT may result in better outcomes for patients with refractory/relapsed anaplastic large cell lymphoma.[39,41,43,49]

Treatment Options Under Clinical Evaluation for Anaplastic Large Cell Lymphoma

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

• APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified in a patient's tumor (refractory or recurrent). Children and adolescents aged 1 to 21 years are eligible for the trial.

  Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.

• NCT03703050 (Nivolumab for Pediatric and Adult Relapsing/Refractory ALK-Positive Anaplastic Large Cell Lymphoma, for Evaluation of Response in Patients With Progressive Disease [Cohort 1] or as Consolidative Immunotherapy in Patients in Complete Remission After Relapse [Cohort 2] [NIVO-ALCL]): ALK-positive anaplastic large cell lymphoma commonly expresses PD-L1,[50,51] and two patients with ALK-positive anaplastic large cell lymphoma treated with the checkpoint inhibitor nivolumab achieved complete responses.[52,53] Further clinical evaluation is needed to define the role of checkpoint blockade for children with ALK-positive anaplastic large cell lymphoma.

Current Clinical Trials

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

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41. Naik S, Martinez CA, Omer B, et al.: Allogeneic hematopoietic stem cell transplant for relapsed and refractory non-Hodgkin lymphoma in pediatric patients. Blood Adv 3 (18): 2689-2695, 2019.
42. Del Baldo G, Abbas R, Woessmann W, et al.: Neuro-meningeal relapse in anaplastic large-cell lymphoma: incidence, risk factors and prognosis - a report from the European intergroup for childhood non-Hodgkin lymphoma. Br J Haematol 192 (6): 1039-1048, 2021.
43. Woessmann W, Peters C, Lenhard M, et al.: Allogeneic haematopoietic stem cell transplantation in relapsed or refractory anaplastic large cell lymphoma of children and adolescents--a Berlin-Frankfurt-Münster group report. Br J Haematol 133 (2): 176-82, 2006.
44. Gambacorti-Passerini C, Messa C, Pogliani EM: Crizotinib in anaplastic large-cell lymphoma. N Engl J Med 364 (8): 775-6, 2011.
45. Mossé YP, Voss SD, Lim MS, et al.: Targeting ALK With Crizotinib in Pediatric Anaplastic Large Cell Lymphoma and Inflammatory Myofibroblastic Tumor: A Children's Oncology Group Study. J Clin Oncol 35 (28): 3215-3221, 2017.
46. Gambacorti-Passerini C, Mussolin L, Brugieres L: Abrupt Relapse of ALK-Positive Lymphoma after Discontinuation of Crizotinib. N Engl J Med 374 (1): 95-6, 2016.
47. Peters S, Camidge DR, Shaw AT, et al.: Alectinib versus Crizotinib in Untreated ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med 377 (9): 829-838, 2017.
48. Pro B, Advani R, Brice P, et al.: Five-year results of brentuximab vedotin in patients with relapsed or refractory systemic anaplastic large cell lymphoma. Blood 130 (25): 2709-2717, 2017.
49. Fukano R, Mori T, Kobayashi R, et al.: Haematopoietic stem cell transplantation for relapsed or refractory anaplastic large cell lymphoma: a study of children and adolescents in Japan. Br J Haematol 168 (4): 557-63, 2015.
50. Panjwani PK, Charu V, DeLisser M, et al.: Programmed death-1 ligands PD-L1 and PD-L2 show distinctive and restricted patterns of expression in lymphoma subtypes. Hum Pathol 71: 91-99, 2018.
51. Shen J, Li S, Medeiros LJ, et al.: PD-L1 expression is associated with ALK positivity and STAT3 activation, but not outcome in patients with systemic anaplastic large cell lymphoma. Mod Pathol 33 (3): 324-333, 2020.
52. Hebart H, Lang P, Woessmann W: Nivolumab for Refractory Anaplastic Large Cell Lymphoma: A Case Report. Ann Intern Med 165 (8): 607-608, 2016.
53. Rigaud C, Abbou S, Minard-Colin V, et al.: Efficacy of nivolumab in a patient with systemic refractory ALK+ anaplastic large cell lymphoma. Pediatr Blood Cancer 65 (4): , 2018.

Lymphoproliferative Disease Associated With Immunodeficiency in Children

Incidence

The incidence of lymphoproliferative disease or lymphoma is 100-fold higher in immunocompromised children than in the general population. The causes of such immune deficiencies include the following:

• A genetically inherited defect (primary immunodeficiency).
• Secondary to HIV infection.
• Iatrogenic disorders after transplant (solid organ transplant or allogeneic hematopoietic stem cell transplant [HSCT]). Epstein-Barr virus (EBV) is associated with most of these tumors, but some tumors are not associated with any infectious agent.
• Iatrogenic disorders from chemotherapy.

Clinical Presentation

Non-Hodgkin lymphoma (NHL) associated with immunodeficiency is usually aggressive. Most cases occur in extralymphatic sites and have a higher incidence of primary central nervous system (CNS) involvement.[1,2,3,4]

Lymphoproliferative Disease Associated With Primary Immunodeficiency

Lymphoproliferative disease observed in primary immunodeficiency usually shows an aggressive mature B-cell phenotype and large cell histology.[2] Mature T-cell lymphoma and anaplastic large cell lymphoma have been observed.[2] Children with primary immunodeficiency and NHL are more likely to have high-stage (stage III or stage IV) disease and present with symptoms related to extranodal disease, particularly in the gastrointestinal tract and CNS.[2]

Treatment options for lymphoproliferative disease associated with primary immunodeficiency

Treatment options for lymphoproliferative disease associated with primary immunodeficiency include the following:

1. Chemotherapy with or without rituximab.
2. Allogeneic hematopoietic stem cell transplant (HSCT).

Patients with primary immunodeficiency can achieve complete and durable remissions with standard chemotherapy regimens for NHL, although toxicity is increased.[2]; [5][Level of evidence C1] Recurrences in these patients are common and may not represent the same clonal disease.[6] Immunologic correction through allogeneic HSCT is often required to prevent recurrences.

NHL Associated With DNA Repair Defect Syndromes

The incidence of NHL is increased in patients with DNA repair syndromes, including ataxia-telangiectasia, Nijmegen breakage syndrome, and constitutional mismatch repair deficiency. Aggressive mature B-cell NHL accounts for most NHL seen in patients with ataxia-telangiectasia (84%) and Nijmegen breakage syndrome (46%), while T-cell lymphoblastic lymphoma (81%) is observed in patients with constitutional mismatch repair deficiency.[5]

Treatment options for NHL associated with DNA repair defect syndromes

Patients with DNA repair defects are particularly difficult to treat.[7,8] Overall survival rates at 5 and 10 years are poor, at 40% to 60%.[5,9]

Treatment options for NHL associated with DNA repair defect syndromes include the following:

1. Chemotherapy.
   • Cytotoxic agents produce much more toxicity and greatly increase the risk of subsequent neoplasms in these patients. One review reported that dose reduction of chemotherapeutic drugs was effective and reduced toxic effects, but did not prevent subsequent neoplasms (10-year incidence rate, 25%).[9]

HIV-Associated NHL

NHL in children with HIV often presents with fever, weight loss, and symptoms related to extranodal disease, such as abdominal pain or CNS symptoms.[1] Most childhood HIV-related NHL is of mature B-cell phenotype but with a spectrum, including primary effusion lymphoma, primary CNS lymphoma, mucosa-associated lymphoid tissue (MALT), Burkitt lymphoma, and diffuse large B-cell lymphoma.[10,11]

HIV-associated NHL can be broadly grouped into the following three subcategories:

1. Systemic (nodal and extranodal). Approximately 80% of all NHL in HIV patients is considered to be systemic.[1]
2. Primary CNS lymphoma.
3. Body cavity–based lymphoma, also referred to as primary effusion lymphoma. Primary effusion lymphoma, a unique lymphomatous effusion associated with human herpesvirus 8 (HHV-8) or Kaposi sarcoma herpesvirus infection, is primarily observed in adults infected with HIV but has been reported in HIV-infected children.[12]

Highly active antiretroviral therapy has decreased the incidence of NHL in HIV-positive individuals, particularly for primary CNS lymphoma cases.[13,14]

Treatment options for HIV-associated NHL

Treatment options for HIV-associated NHL include the following:

1. Chemotherapy with or without rituximab.

In the era of highly active antiretroviral therapy, children with HIV and NHL are treated with standard chemotherapy regimens for NHL. However, the prevention (using prophylaxis) and early detection of infection is warranted.[1,13,14] Although the number of pediatric patients with HIV-associated NHL is too small to perform meaningful clinical trials, studies of adult patients support the addition of rituximab to standard treatment regimens.[15] Treatment of recurrent disease is based on histology using standard approaches.

Posttransplant Lymphoproliferative Disease (PTLD)

PTLD represents a spectrum of clinically and morphologically heterogeneous lymphoid proliferations. Essentially all PTLDs after HSCT are associated with EBV, but EBV-negative PTLD can be seen after solid organ transplant.[3] While most PTLDs are of B-cell phenotype, approximately 10% are mature (peripheral) T-cell lymphomas.[16] The B-cell stimulation by EBV may result in multiple clones of proliferating B cells. Both polymorphic and monomorphic histologies may be present in a patient, even within the same lesion of PTLD.[17] Thus, histology of a single biopsied site may not be representative of the entire disease process.

The World Health Organization (WHO) has classified PTLD into the following three subtypes:[16]

• Early lesion: Early lesions show germinal center expansion, but tissue architecture remains normal.
• Polymorphic PTLD: Presence of infiltrating T cells, disruption of nodal architecture, and necrosis distinguish polymorphic PTLD from early lesions.
• Monomorphic PTLD: Histologies observed in patients with the monomorphic subtype are like those observed in NHL, with diffuse large B-cell lymphoma being the most common histology, followed by Burkitt lymphoma, myeloma, plasmacytoma, and Hodgkin-like PTLD rarely occur in patients with this subtype. T-cell PTLD is seen in about 10% of PTLD cases, may be EBV positive or EBV negative, and is usually of the mature T-cell subtype.[16]

EBV lymphoproliferative disease posttransplant may manifest as isolated hepatitis, lymphoid interstitial pneumonitis, meningoencephalitis, or an infectious mononucleosis-like syndrome. The definition of PTLD is frequently limited to lymphomatous lesions (low stage or high stage), which are often extranodal (frequently in the allograft).[3] PTLD may less commonly present as a rapidly progressive, high-stage disease that clinically resembles septic shock, and these patients have a poor prognosis. However, the use of rituximab and low-dose chemotherapy may improve outcomes in these patients.[18,19] U.S. transplant and cancer registries show that PTLD accounts for about 3% of all pediatric NHL diagnoses; 65% of PTLDs have diffuse large B-cell lymphoma histology, and 9% of PTLDs have Burkitt histology.[20]

Treatment options for PTLD

Treatment options for PTLD include the following:

1. For localized resectable disease, surgical resection and, if possible, reduction of immunosuppressive therapy.
2. Rituximab therapy alone.[21]
3. Standard or slightly modified lymphoma-specific chemotherapy regimens for the specific histology, with or without rituximab for B-cell PTLD.[22,23,24]
4. For EBV-positive B-cell PTLD, low-dose chemotherapy with or without rituximab.[19]; [25][Level of evidence C2]

First-line therapy for patients with PTLD is to reduce immunosuppressive therapy as much as possible.[25,26] However, this may not be possible because of the increased risk of organ rejection or graft-versus-host disease (GVHD).

Rituximab, an anti-CD20 antibody, has been used in the posttransplant setting. Rituximab as a single agent to treat PTLD after organ transplant has demonstrated efficacy in adult patients, but data are lacking in pediatric patients.

Evidence (rituximab):

1. A study of 144 children and adults who developed post-HSCT PTLD reported the following:[21][Level of evidence C1]
   • Approximately 70% of the patients who received rituximab survived.
   • Survival was also associated with reduction of immunosuppression.
   • Older age, extranodal disease, and acute GVHD were predictors of poor outcome.

For more information, see the Polymorphic Posttransplant Lymphoproliferative Disorder section in B-Cell Non-Hodgkin Lymphoma Treatment.

Low-intensity chemotherapy has been effective in patients with EBV-positive, CD20-positive B-lineage PTLD.[19,27] An event-free survival rate of 67% was demonstrated in a Children's Oncology Group study using rituximab plus cyclophosphamide and prednisone in children with PTLD after solid organ transplant in whom immune suppression was reduced.[19][Level of evidence B4] Other studies suggest that modified conventional lymphoma therapy is effective for patients who have PTLD with MYC translocations and Burkitt histology.[23,24][Level of evidence C2] Patients with T-cell or Hodgkin-like PTLD are usually treated with standard lymphoma-specific chemotherapy regimens.[28,29,30,31]

Antirejection therapy is usually decreased or discontinued when chemotherapy is given to avoid excessive toxicity. There are no data to guide the re-initiation of immunosuppressive therapy after chemotherapy treatment. There is little evidence of benefit for chemotherapy after HSCT.

Adoptive immunotherapy with either donor lymphocytes or ex vivo –generated EBV-specific cytotoxic T-lymphocytes (EBV-CTLs) has been effective in treating patients with PTLD after blood or bone marrow transplant.[32,33] To make this approach more broadly applicable, banks of off-the-shelf, third-party, allogeneic EBV-CTLs derived from healthy donors have been developed.[34,35] EBV-CTLs were evaluated in 46 patients with PTLD that had either progressed during rituximab treatment, not fully responded to rituximab treatment, or had recurred after a previous response. The following results were observed:[36]

• The lymphomas were monomorphic diffuse large B-cell lymphomas in 24 of 33 patients who underwent HSCT and in 8 of 13 patients who underwent solid organ transplants.
• EBV-CTLs were selected for having at least one HLA allele shared between the donor EBV-CTLs and the lymphoma.
• The objective response rate after one cycle of EBV-CTLs was 39% (9 complete responses [CRs] and 9 partial responses [PRs] among 46 patients). With additional cycles of therapy, 29 of 45 evaluable patients (64%) achieved CRs or sustained PRs.
• Three of five recipients with progressive disease after their first cycle of EBV-CTLs achieved CRs or durable PRs after receiving EBV-CTLs from a different donor.
• Of 11 patients with CNS involvement, 5 achieved CRs and 4 achieved durable PRs.
• Factors associated with favorable response included previous treatment with rituximab only (i.e., no prior chemotherapy or radiation therapy), absence of extranodal disease, and more extensive in vivo expansion of the EBV-CTLs.

Treatment options under clinical evaluation for PTLD

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:

• NCT03394365 (Tabelecleucel for Solid Organ or Allogeneic HSCT Participants With EBV-Positive PTLD After Failure of Rituximab or Rituximab and Chemotherapy [ALLELE]): The purpose of this study is to determine the clinical benefit and characterize the safety profile of tabelecleucel for the treatment of EBV-positive PTLD in the setting of: (1) solid organ transplant after failure of rituximab and rituximab plus chemotherapy; or (2) allogeneic HSCT after failure of rituximab.

Immunodeficiency Associated With Acute Lymphoblastic Leukemia (ALL) Therapy

An international collaboration identified 95 cases of lymphoid neoplasms after the diagnosis of ALL.[37] Of these cases, 52 were characteristic of EBV-associated lymphoproliferative disease in the setting of immunodeficiency. These 52 cases were analyzed, along with 14 additional cases identified from the literature (n = 66). All cases occurred in the maintenance phase or within 6 months of completing maintenance (median, 14 months into maintenance therapy). Treatment strategies varied, but two-thirds of the patients were event-free survivors at 5 years.

References:

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2. Seidemann K, Tiemann M, Henze G, et al.: Therapy for non-Hodgkin lymphoma in children with primary immunodeficiency: analysis of 19 patients from the BFM trials. Med Pediatr Oncol 33 (6): 536-44, 1999.
3. Loren AW, Porter DL, Stadtmauer EA, et al.: Post-transplant lymphoproliferative disorder: a review. Bone Marrow Transplant 31 (3): 145-55, 2003.
4. Jaffe ES, van Krieken JH, Onciu M, et al.: Lymphoproliferative diseases associated with primary immune disorders. In: Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th rev. ed. International Agency for Research on Cancer, 2017, pp 444-61.
5. Attarbaschi A, Carraro E, Abla O, et al.: Non-Hodgkin lymphoma and pre-existing conditions: spectrum, clinical characteristics and outcome in 213 children and adolescents. Haematologica 101 (12): 1581-1591, 2016.
6. Hoffmann T, Heilmann C, Madsen HO, et al.: Matched unrelated allogeneic bone marrow transplantation for recurrent malignant lymphoma in a patient with X-linked lymphoproliferative disease (XLP). Bone Marrow Transplant 22 (6): 603-4, 1998.
7. Sandoval C, Swift M: Treatment of lymphoid malignancies in patients with ataxia-telangiectasia. Med Pediatr Oncol 31 (6): 491-7, 1998.
8. Dembowska-Baginska B, Perek D, Brozyna A, et al.: Non-Hodgkin lymphoma (NHL) in children with Nijmegen Breakage syndrome (NBS). Pediatr Blood Cancer 52 (2): 186-90, 2009.
9. Bienemann K, Burkhardt B, Modlich S, et al.: Promising therapy results for lymphoid malignancies in children with chromosomal breakage syndromes (Ataxia teleangiectasia or Nijmegen-breakage syndrome): a retrospective survey. Br J Haematol 155 (4): 468-76, 2011.
10. Ohno Y, Kosaka T, Muraoka I, et al.: Remission of primary low-grade gastric lymphomas of the mucosa-associated lymphoid tissue type in immunocompromised pediatric patients. World J Gastroenterol 12 (16): 2625-8, 2006.
11. Fedorova A, Mlyavaya T, Alexeichik A, et al.: Successful treatment of the HIV-associated Burkitt lymphoma in a three-year-old child. Pediatr Blood Cancer 47 (1): 92-3, 2006.
12. Jaffe ES: Primary body cavity-based AIDS-related lymphomas. Evolution of a new disease entity. Am J Clin Pathol 105 (2): 141-3, 1996.
13. Kirk O, Pedersen C, Cozzi-Lepri A, et al.: Non-Hodgkin lymphoma in HIV-infected patients in the era of highly active antiretroviral therapy. Blood 98 (12): 3406-12, 2001.
14. Godot C, Patte C, Blanche S, et al.: Characteristics and prognosis of B-cell lymphoma in HIV-infected children in the HAART era. J Pediatr Hematol Oncol 34 (7): e282-8, 2012.
15. Besson C, Lancar R, Prevot S, et al.: Outcomes for HIV-associated diffuse large B-cell lymphoma in the modern combined antiretroviral therapy era. AIDS 31 (18): 2493-2501, 2017.
16. Swerdlow SH, Webber SA, Chadburn A: Post-transplant lymphoproliferative disorders. In: Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. International Agency for Research on Cancer, 2008, pp 343-9.
17. Chadburn A, Cesarman E, Liu YF, et al.: Molecular genetic analysis demonstrates that multiple posttransplantation lymphoproliferative disorders occurring in one anatomic site in a single patient represent distinct primary lymphoid neoplasms. Cancer 75 (11): 2747-56, 1995.
18. Collins MH, Montone KT, Leahey AM, et al.: Autopsy pathology of pediatric posttransplant lymphoproliferative disorder. Pediatrics 107 (6): E89, 2001.
19. Gross TG, Orjuela MA, Perkins SL, et al.: Low-dose chemotherapy and rituximab for posttransplant lymphoproliferative disease (PTLD): a Children's Oncology Group Report. Am J Transplant 12 (11): 3069-75, 2012.
20. Yanik EL, Shiels MS, Smith JM, et al.: Contribution of solid organ transplant recipients to the pediatric non-hodgkin lymphoma burden in the United States. Cancer 123 (23): 4663-4671, 2017.
21. Styczynski J, Gil L, Tridello G, et al.: Response to rituximab-based therapy and risk factor analysis in Epstein Barr Virus-related lymphoproliferative disorder after hematopoietic stem cell transplant in children and adults: a study from the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation. Clin Infect Dis 57 (6): 794-802, 2013.
22. Hayashi RJ, Kraus MD, Patel AL, et al.: Posttransplant lymphoproliferative disease in children: correlation of histology to clinical behavior. J Pediatr Hematol Oncol 23 (1): 14-8, 2001.
23. Picarsic J, Jaffe R, Mazariegos G, et al.: Post-transplant Burkitt lymphoma is a more aggressive and distinct form of post-transplant lymphoproliferative disorder. Cancer 117 (19): 4540-50, 2011.
24. Windebank K, Walwyn T, Kirk R, et al.: Post cardiac transplantation lymphoproliferative disorder presenting as t(8;14) Burkitt leukaemia/lymphoma treated with low intensity chemotherapy and rituximab. Pediatr Blood Cancer 53 (3): 392-6, 2009.
25. Gross TG, Bucuvalas JC, Park JR, et al.: Low-dose chemotherapy for Epstein-Barr virus-positive post-transplantation lymphoproliferative disease in children after solid organ transplantation. J Clin Oncol 23 (27): 6481-8, 2005.
26. Green M, Michaels MG, Webber SA, et al.: The management of Epstein-Barr virus associated post-transplant lymphoproliferative disorders in pediatric solid-organ transplant recipients. Pediatr Transplant 3 (4): 271-81, 1999.
27. Twist CJ, Hiniker SM, Gratzinger D, et al.: Treatment and outcomes in classic Hodgkin lymphoma post-transplant lymphoproliferative disorder in children. Pediatr Blood Cancer 66 (8): e27803, 2019.
28. Yang F, Li Y, Braylan R, et al.: Pediatric T-cell post-transplant lymphoproliferative disorder after solid organ transplantation. Pediatr Blood Cancer 50 (2): 415-8, 2008.
29. Williams KM, Higman MA, Chen AR, et al.: Successful treatment of a child with late-onset T-cell post-transplant lymphoproliferative disorder/lymphoma. Pediatr Blood Cancer 50 (3): 667-70, 2008.
30. Dharnidharka VR, Douglas VK, Hunger SP, et al.: Hodgkin's lymphoma after post-transplant lymphoproliferative disease in a renal transplant recipient. Pediatr Transplant 8 (1): 87-90, 2004.
31. Goyal RK, McEvoy L, Wilson DB: Hodgkin disease after renal transplantation in childhood. J Pediatr Hematol Oncol 18 (4): 392-5, 1996.
32. Papadopoulos EB, Ladanyi M, Emanuel D, et al.: Infusions of donor leukocytes to treat Epstein-Barr virus-associated lymphoproliferative disorders after allogeneic bone marrow transplantation. N Engl J Med 330 (17): 1185-91, 1994.
33. Rooney CM, Smith CA, Ng CY, et al.: Infusion of cytotoxic T cells for the prevention and treatment of Epstein-Barr virus-induced lymphoma in allogeneic transplant recipients. Blood 92 (5): 1549-55, 1998.
34. Haque T, Wilkie GM, Taylor C, et al.: Treatment of Epstein-Barr-virus-positive post-transplantation lymphoproliferative disease with partly HLA-matched allogeneic cytotoxic T cells. Lancet 360 (9331): 436-42, 2002.
35. Barker JN, Doubrovina E, Sauter C, et al.: Successful treatment of EBV-associated posttransplantation lymphoma after cord blood transplantation using third-party EBV-specific cytotoxic T lymphocytes. Blood 116 (23): 5045-9, 2010.
36. Prockop S, Doubrovina E, Suser S, et al.: Off-the-shelf EBV-specific T cell immunotherapy for rituximab-refractory EBV-associated lymphoma following transplantation. J Clin Invest 130 (2): 733-747, 2020.
37. Elitzur S, Vora A, Burkhardt B, et al.: EBV-driven lymphoid neoplasms associated with pediatric ALL maintenance therapy. Blood 141 (7): 743-755, 2023.

Rare NHL Occurring in Children

Low-grade or intermediate-grade mature B-cell lymphomas—such as small lymphocytic lymphoma, mucosa-associated lymphoid tissue (MALT) lymphoma, mantle cell lymphoma, myeloma, or follicular cell lymphoma—are rarely seen in children. The World Health Organization (WHO) classification has identified pediatric-type follicular lymphoma and pediatric nodal marginal zone lymphoma as entities separate from their adult counterparts.[1]

The Children's Oncology Group (COG) opened a registry study (COG-ANHL04B1) to learn more about the clinical and pathological features of these rare types of pediatric non-Hodgkin lymphoma (NHL). This study banks tissue for pathobiology studies and collects limited data on clinical presentation and outcome of therapy.[2]

Pediatric Gray Zone Lymphoma

Gray zone lymphomas represent a hybrid malignancy, with an unclassifiable B-cell lymphoma and classical Hodgkin lymphoma, which may present together in an initial biopsy or sequentially as a relapse.[3]

A retrospective case series study assessed the clinical characteristics and outcomes of six patients with gray zone lymphomas from Austria. The three male and three female patients ranged in age from 15 to 17 years. Two of the six patients had B symptoms and high lactate dehydrogenase (LDH) levels. All patients had mediastinal masses, and five of six patients had positive cervical/supraclavicular lymph nodes. Extranodal involvement of the pleura and lung was common. Initial therapy with B-cell NHL treatments in five patients led to a complete response (CR) in one patient and progressive disease and death in one patient. The other three patients relapsed with primarily classical Hodgkin lymphoma histology and required treatment with salvage therapy. All of these patients survived after high-dose therapies and hematopoietic stem cell transplants (HSCT). One patient who initially received Hodgkin lymphoma therapy achieved a CR and survived.[4]

Pediatric-Type Follicular Lymphoma

Pediatric-type follicular lymphoma is a disease that genetically and clinically differs from its adult counterpart and is recognized by the WHO classification as a separate entity from follicular lymphoma observed commonly in adults.[5] The genetic hallmark of adult follicular lymphoma is t(14;18)(q32;q21) involving BCL2. However, this translocation must be excluded to diagnose pediatric-type follicular lymphoma.[5,6,7,8]

Pediatric-type follicular lymphoma predominantly occurs in males, is associated with a high proliferation rate, and is more likely to be localized disease.[6,9,10] In pediatric-type follicular lymphoma, a high-grade component (i.e., grade 3 with high proliferative index such as Ki-67 expression of >30%) resembling diffuse large B-cell lymphoma can frequently be detected at initial diagnosis but does not indicate a more aggressive clinical course in children. Unlike follicular lymphoma in adults, pediatric-type follicular lymphoma does not transform to diffuse large B-cell lymphoma.[5,6,8,10,11] Limited-stage disease is observed with pediatric-type follicular lymphoma. Cervical lymph nodes and tonsils are common sites, but disease has also occurred in extranodal sites such as the testis, kidney, gastrointestinal tract, and parotid gland.[6,7,8,11,12,13,14]

Tumor biology

Genomics of pediatric-type follicular lymphoma

Pediatric-type follicular lymphoma and nodal marginal zone lymphoma are rare indolent B-cell lymphomas that are clinically and molecularly distinct from these tumor types in adults.

• The pediatric types lack BCL2 and IRF4 rearrangements, resulting in IRF4 expression.[15]
• BCL6 and MYC rearrangements are also not present in pediatric-type follicular lymphoma.[15]
• TNFSFR14 variants are common in pediatric-type follicular lymphoma. These variants appear to occur with similar frequency in adult follicular lymphoma.[10,16]
• MAP2K1 variants, which are uncommon in adults, are observed in as many as 43% of pediatric-type follicular lymphoma cases. Other genes (e.g., MAPK1 and RRAS) have been found to be altered in cases without MAP2K1 variants. This finding suggests that the MAP kinase pathway is important in the pathogenesis of pediatric-type follicular lymphoma.[17,18]
• IRF8 variants, KMT2C variants, and abnormalities in chromosome 1p have also been observed in pediatric-type follicular lymphoma.[16,19,20,21]

Treatment options for pediatric-type follicular lymphoma

Pediatric-type follicular lymphoma is rare in children, with only case reports and small case series to guide therapy. The outcomes of patients with pediatric-type follicular lymphoma are excellent, with an event-free survival (EFS) rate of about 95%.[6,8,9,10,11,13] Unlike in adult follicular lymphoma, the clinical course in pediatric patients is not dominated by relapses.[6,8,11,12]

Treatment options for pediatric-type follicular lymphoma include the following:

1. Surgery only.
2. Multiagent chemotherapy with or without rituximab.

Studies suggest that for children with stage I disease who had a complete resection, a watch-and-wait approach without chemotherapy may be indicated. Patients with higher-stage disease also have a favorable outcome with low-intensity and intermediate-intensity chemotherapy, with an EFS rate of 94% and an overall survival (OS) rate of 100% (2-year median follow-up).[2,6,9,10] Although the number of pediatric patients with pediatric follicular-type lymphoma is too small to perform meaningful clinical trials, studies of adult patients with follicular lymphoma support the addition of rituximab to standard treatment regimens.

For patients with BCL2-rearranged tumors, treatment similar to that of adult patients with follicular lymphoma is administered.

For more information, see the Follicular Lymphoma (Grades 1–3a) section in B-Cell Non-Hodgkin Lymphoma Treatment.

Marginal Zone Lymphoma (Including MALT Lymphoma)

Marginal zone lymphoma is a type of indolent lymphoma that is rare in pediatric patients. Marginal zone lymphoma can present as nodal or extranodal disease and almost always as low-stage (stage I or stage II) disease. It is unclear whether the marginal zone lymphoma that is observed in pediatric patients is clinicopathologically different from the disease that is observed in adults. Most extranodal marginal zone lymphoma in pediatrics presents as MALT lymphoma and may be associated with Helicobacter pylori (gastrointestinal) or Chlamydophila psittaci (conjunctival), previously called Chlamydia psittaci.[22,23]

Treatment options for marginal zone lymphoma (including MALT lymphoma)

Treatment options for marginal zone lymphoma (including MALT lymphoma) include the following:

1. Surgery only.
2. Radiation therapy.
3. Rituximab with or without chemotherapy.
4. Antibiotic therapy, for MALT lymphoma.

Most pediatric patients with marginal zone lymphomas require no more than local therapy involving curative surgery and/or radiation therapy.[22,24] Treatment of patients with MALT lymphoma of the gastric mucosa may also include antibiotic therapy, which is considered standard treatment in adults. However, the use of antibiotic therapy in children has not been well studied because there are so few cases.

Evidence (treatment of marginal zone lymphoma):

1. In the largest retrospective study of pediatric patients (aged 18 years or younger) with marginal zone lymphoma (N = 66), the following was reported:[25][Level of evidence C1]
   1. The overall 5-year EFS rate was 70%.
   2. The OS rate was 98%.
   3. Patients primarily fell into the following two WHO-defined groups:
      • Nodal (32%): Nearly all patients were male, with localized primary tumors in the head and neck. The treatment for all patients was resection (complete or incomplete) followed by observation. The EFS rate was 94%, and the OS rate was 100%.
      • Extranodal (67%): 57% of patients were male, and 27% of patients had a preexisting condition, which was immune compromising in most patients. The treatment options included chemotherapy, radiation, rituximab, resection, and observation. The EFS rate was 64%, and the OS rate was 97%. The only two deaths resulted from treatment-related complications of HSCT. Both patients had an underlying immunodeficiency. Of note, 9 of 12 patients with extranodal marginal zone lymphoma who were managed with resection only remained in a first continuous complete remission with no further therapy. The other 3 patients who relapsed had their disease successfully salvaged.

Although the number of pediatric patients with MALT lymphoma is too small to perform meaningful clinical trials, studies of adult patients support the use of rituximab with or without chemotherapy. For more information, see the Marginal Zone Lymphoma section in B-Cell Non-Hodgkin Lymphoma Treatment.

Intralesional interferon-alpha for conjunctival MALT lymphoma has been studied in trials.[26]

Primary Central Nervous System (CNS) Lymphoma

Other types of NHL that are rare in adults and are exceedingly rare in pediatric patients include primary CNS lymphomas. Because of the small numbers of patients, it is difficult to ascertain whether the disease observed in children is the same as the disease observed in adults.

Reports suggest that the outcome of pediatric patients with primary CNS lymphoma (OS rate, 70%–80%) may be superior to that of adults with primary CNS lymphoma.[27,28,29,30]

Most children have diffuse large B-cell lymphoma, although other histologies have been observed.

Treatment options for primary CNS lymphoma

Treatment options for primary CNS lymphoma include the following:

1. Chemotherapy and rituximab (for mature B-cell disease).
2. Radiation therapy.

Therapy with high-dose intravenous methotrexate and cytosine arabinoside is the most successful, and intrathecal chemotherapy may be needed only when malignant cells are present in the cerebrospinal fluid.[31]

There are case reports describing the administration of repeated doses of intraventricular rituximab in patients with refractory primary CNS lymphoma, with excellent results reported.[32,33] This apparently good outcome needs to be confirmed, and similar results have not been observed in adults. It is generally believed that rituximab does not cross the blood-brain barrier.

Among patients who have a partial response to induction therapy, and particularly those who are not eligible for transplant, reduced-dose whole-brain radiation therapy with a boost to residual disease may be a viable treatment approach that merits further investigation.[34,35]

For more information about treatment options for non–AIDS-related primary CNS lymphoma, see Primary CNS Lymphoma Treatment.

Peripheral T-Cell Lymphoma

Peripheral T-cell lymphoma, excluding anaplastic large cell lymphoma, is rare in children.

Mature T-cell/natural killer (NK)–cell lymphoma or peripheral T-cell lymphoma has a postthymic phenotype (e.g., terminal deoxynucleotidyl transferase negative), usually expresses CD4 or CD8, and has rearrangement of T-cell receptor genes, either alpha-beta and/or gamma-delta chains. The most common phenotype observed in children is peripheral T-cell lymphoma, not otherwise specified (NOS), although angioimmunoblastic lymphoma, enteropathy-associated lymphoma (associated with celiac disease), subcutaneous panniculitis-like lymphoma, angiocentric lymphoma, and extranodal NK/T-cell peripheral T-cell lymphoma have been reported.[36,37,38,39,40]

Extranodal NK/T-cell lymphoma is a rare subtype of NHL, constitutes between 0.2% and 1.6% of newly diagnosed cases of NHL in children and adolescents, and is closely associated with the Epstein-Barr virus (EBV).[41] The incidence varies by region. The incidence is between 3% and 10% in Asian countries and 1% in western countries.[42] The common primary tumor sites are the nasal cavity and paranasal sinuses.[43] A standard treatment for pediatric patients has not been established. A series of 34 patients were treated with chemotherapy with or without asparaginase. At a median follow-up of 54 months, patients with lower-stage (I/II) disease had 5-year EFS and OS rates of 66.2% and 94.7%, respectively, compared with 26.0% and 42.3% for patients with stage III/IV disease. For all patients, there was no statistically significant difference in outcomes between patients who received asparaginase-containing regimens and those who did not. All patients with stage I/II disease received radiation therapy, whereas only 4 of 13 patients with higher-stage disease received radiation therapy. The 5-year EFS rate was 66.7% for stage III/IV patients who received hematopoietic stem cell transplant (HSCT) and 11.1% for patients who did not receive HSCT (P = .054).[44][Level of evidence C1]

Although very rare, gamma-delta hepatosplenic T-cell lymphoma may be seen in children.[39] This tumor has also been associated with children and adolescents who have Crohn disease and have been treated with immunosuppressive therapy. This lymphoma has been fatal in all cases.[45]

Treatment options for peripheral T-cell lymphoma

Optimal therapy for peripheral T-cell lymphoma is unclear for both pediatric and adult patients.

Treatment options for peripheral T-cell lymphoma include the following:

1. Chemotherapy.
2. Radiation therapy.
3. Allogeneic or autologous HSCT.

There have been four retrospective analyses of treatment and outcome for pediatric patients with peripheral T-cell lymphoma.

Evidence (treatment of peripheral T-cell lymphoma):

1. The United Kingdom Children's Cancer Study Group (UKCCSG) examined 25 children diagnosed with peripheral T-cell lymphoma over a 20-year period and reported the following:[36]
   • A 5-year survival rate of approximately 50%.
   • The UKCCSG also observed that the use of acute lymphoblastic leukemia–like therapy, instead of NHL therapy, produced a superior outcome.
2. The COG reported on 20 patients older than 8 years who were treated on Pediatric Oncology Group NHL trials.[37]
   • Eight of ten patients with low-stage disease achieved long-term disease-free survival, compared with only four of ten patients with high-stage disease.
3. In a study of Japanese children with peripheral T-cell lymphoma (N = 21), treatment included chemotherapy (n = 18), radiation therapy (n = 2), and autologous (n = 2) and allogeneic (n = 9) HSCT.[46]
   • The 5-year OS rate was 85.2%
4. The Berlin-Frankfurt-Münster study group reported 38 cases of peripheral T-cell lymphoma acquired over a 26-year period.[39][Level of evidence C2]
   • Patients with peripheral T-cell lymphoma, NOS (n = 18), most with advanced disease (stage III [n = 10] and stage IV [n = 5]), were usually treated with anaplastic large cell lymphoma protocols and had a 10-year EFS rate of 61%.
   • Patients with NK/T-cell lymphoma (n = 9) fared poorly, with a 10-year EFS rate of 17%.
   • This series also included five patients with hepatosplenic T-cell lymphoma and five patients with subcutaneous panniculitis-like T-cell lymphoma.

For more information about the treatment of adults, see Peripheral T-Cell Non-Hodgkin Lymphoma Treatment.

Cutaneous T-Cell Lymphoma/Mycosis Fungoides

Cutaneous T-cell lymphoma

General information about cutaneous T-cell lymphoma

Primary cutaneous lymphomas are very rare in pediatric patients (1 case per 1 million person-years), but the incidence increases in adolescents and young adults. All histologies of NHL have been observed to involve the skin. More than 80% of cutaneous lymphomas are the T-cell or NK-cell phenotype.[47]

Subcutaneous panniculitic T-cell lymphomas (SPTCL) are very rare lymphomas with panniculitis-like infiltration of subcutaneous tissue by cytotoxic T-cells. SPTCL account for less than 1% of all peripheral T-cell lymphomas.[48,49,50] SPTCL can be observed with malignant T cells, expressing alpha-beta chain T-cell receptor or gamma-delta T-cell receptor rearrangements.

In adults, the gamma-delta subtype of SPTCL is associated with a more aggressive course and a worse prognosis than the alpha-beta subtype of SPTCL.[51] Morbidity and mortality are frequently related to the development of hemophagocytic syndrome, which was reported in one series of adults to occur in 17% of patients with alpha-beta SPTCL and in 45% of patients with gamma-delta SPTCL. The 5-year OS rate is 82% for patients with alpha-beta SPTCL and 11% for patients with gamma-delta SPTCL.[51]

SPTCL is heterogeneous in the pediatric age group and does not necessarily follow the course observed in adults. In a retrospective series of 18 children (median age, 11.1 years; range, 0.52–14.7 years, with 3 children aged <1 year), most presented with single or multiple subcutaneous nodules or patchy skin lesions on the limbs and/or trunk. Most of the patients also had fever, asthenia, and weight loss. Four out of five patients screened were positive for the HAVCR2 gene variant in the T-cell immunoglobulin domain and mucin domain 3 (TIM-3) lineages.[52][Level of evidence C3] Seven cases were associated with hemophagocytic syndrome, similar to 7 of 11 pediatric cases in another series.[53]; [52][Level of evidence C3]

The diagnosis of primary cutaneous anaplastic large cell lymphoma can be difficult to distinguish pathologically from more benign diseases such as lymphomatoid papulosis.[54] Primary cutaneous lymphomas are now thought to represent a spectrum of disorders, distinguished by clinical presentation.

Treatment options for cutaneous T-cell lymphoma

Because of the rarity of cutaneous T-cell lymphoma, no standard treatments have been established. Management and treatment of patients with cutaneous T-cell lymphoma should be individualized and, in some cases, watchful waiting may be appropriate. Treatment may only be necessary if hemophagocytic syndrome develops.[55]

There is no standard treatment regimen for SPTCL. Spontaneous remissions have been observed, particularly in younger children. Older children, however, may have a course of disease that is complicated by hemophagocytic syndrome. First-line treatment consists of either chemotherapy or immunomodulatory drugs. Chemotherapy was the mainstay of treatment before 2019. Immunomodulatory therapy or observational follow-up became the mainstay of treatment after this time. Immunomodulatory agents include steroids combined with cyclosporine A or ruxolitinib. In a series of 18 patients, the CR rate was 71.4% for patients treated with these immunomodulatory agents.[52][Level of evidence C3]

An oral retinoid (bexarotene) has been reported to be active against SPTCL in a series of 15 patients from three institutions.[56] In a series of 11 pediatric patients, aggressive polychemotherapy was used in all patients. Nine of 11 patients sustained clinical remission, with a median follow-up of 3.5 years.[53] Additional treatment options include high-dose steroids, bexarotene, denileukin diftitox, multiagent chemotherapy, and HSCT.[50,55,56,57,58,59,60]

Primary cutaneous anaplastic large cell lymphoma usually does not express ALK and may be treated successfully with surgical resection and/or local radiation therapy without systemic chemotherapy.[61] There are reports of surgery alone also being curative for patients with ALK-positive cutaneous anaplastic large cell lymphoma, but extensive staging and vigilant follow-up is required.[62,63]

Mycosis fungoides

General information about mycosis fungoides

Mycosis fungoides is rarely reported in children and adolescents,[64,65,66,67] accounting for about 0.5% to 7% of all cases. In a systematic review of 571 children and adolescents with mycosis fungoides, the mean age of diagnosis was 12.2 years, and the mean age at onset was 8.6 years.

Compared with adults, pediatric patients are diagnosed with an earlier stage of mycosis fungoides and have a higher rate of atypical presentations, specifically the hypopigmented variant.[66] One of the largest series of pediatric patients with mycosis fungoides (n = 71; diagnosed aged <18 years) was followed for a mean of 9.2 years (range, 1–24 years).[66]

• Sixty-nine of 71 patients had early-stage disease. The mean age of symptom onset was 8 years, and the mean age at diagnosis was 11 years. There was a mean diagnostic delay of 3 years.
• The most common presentation was hypopigmented lesions (55%), followed by folliculotropic lesions (42%) and classical mycosis fungoides (39%), alone or in combination.
• The head and neck region was more frequently involved in early-stage folliculotropic mycosis fungoides (43%), compared with nonfolliculotropic mycosis fungoides (12%) (P = .004). Pruritis was more common in folliculotropic mycosis fungoides than in nonfolliculotropic mycosis fungoides.
• CD4 predominance was seen in 73% of patients with early-stage folliculotropic mycosis fungoides, whereas CD8 predominance was seen in 49% of patients with nonfolliculotropic mycosis fungoides.
• Bacterial infection was rare in pediatric patients, in contrast to the frequency in adults.

Factors associated with worse overall 10-year survival were delay in establishing the correct diagnosis, granulomatous slack skin, granulomatous mycosis fungoides, history of organ transplant, and stage 2 disease at the time of diagnosis.[68][Level of evidence C3] For information about the treatment of adults, see Mycosis Fungoides and Other Cutaneous T-Cell Lymphomas Treatment.

Treatment options for mycosis fungoides

Mycosis fungoides in pediatric patients may respond to various therapies, including topical steroids, retinoids, radiation therapy, or phototherapy (e.g., narrowband UVB treatment [NBUVB]), but remission may not be durable.[69,70,71,72] In a retrospective series of 71 pediatric patients with mycosis fungoides, the overall response rate (CR + partial remission) was 88%. However, CR was achieved in only 40% of patients initially.[66][Level of evidence C3]

• NBUVB monotherapy was the most commonly administered treatment to pediatric patients with early-stage nonfolliculotropic mycosis fungoides. The CR rate was 63% for these patients. In contrast, pediatric patients with early-stage folliculotropic mycosis fungoides had a CR rate of 29% with NBUVB (P = .04).
• UVA-based phototherapy, such as systemic psoralen plus UVA (PUVA), bath PUVA, or UVA combined with NBUVB, were the most commonly administered treatments to patients with folliculotropic mycosis fungoides, with CR rates of 60% versus 81% for patients with nonfolliculotropic mycosis fungoides (P = .17).
• During a mean follow-up of 9.2 years, four of the patients with early-stage disease (6%) experienced progression of their disease stage. Two of these patients (both with folliculotropic mycosis fungoides) progressed to advanced-stage disease.

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Latest Updates to This Summary (04 / 30 / 2024)

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.

Editorial changes were made to this summary.

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.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood non-Hodgkin lymphoma. 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:

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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 Non-Hodgkin Lymphoma Treatment are:

• William L. Carroll, MD (Laura and Isaac Perlmutter Cancer Center at NYU Langone)
• Louis S. Constine, MD (James P. Wilmot Cancer Center at University of Rochester Medical Center)
• Alan Scott Gamis, MD, MPH (Children's Mercy Hospital)
• Thomas G. Gross, MD, PhD (National Cancer Institute)
• Michelle Hermiston, MD, PhD (University of California, San Francisco)
• Megan S. Lim, MD, PhD (University of Pennsylvania)
• Kenneth L. McClain, MD, PhD (Texas Children's Cancer Center and Hematology Service at Texas Children's Hospital)
• Arthur Kim Ritchey, MD (Children's Hospital of Pittsburgh of UPMC)
• Lisa Giulino Roth, MD (Weil Cornell Medical College)
• Nita Louise Seibel, MD (National Cancer Institute)
• Malcolm A. Smith, MD, PhD (National Cancer Institute)

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PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Non-Hodgkin Lymphoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/lymphoma/hp/child-nhl-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389181]

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Last Revised: 2024-04-30