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Childhood Non-Hodgkin Lymphoma Treatment (PDQ®)

Health Professional Version

.

Published online: November 12, 2021.

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 who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

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).

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 2010, childhood cancer mortality decreased by more than 50%.[1] For NHL, the 5-year survival rate increased over the same time period from about 45% to 90% for both younger children and adolescents.[1,2] In 2020, there were an estimated 30,500 survivors of childhood and adolescent NHL in the United States.[3]

Childhood and adolescent cancer survivors require close monitoring because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on the Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

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/leukemia, diffuse large B-cell lymphoma, and primary mediastinal B-cell lymphoma).

Other rare types of pediatric NHL include the following:

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 high-income countries.[4]

The following factors affect the incidence of NHL in children and adolescents:[4]

  • Geographic location: In the United States, about 800 new cases of NHL are diagnosed each year. The incidence is approximately ten cases per 1 million people per year.
    In sub-Saharan Africa, the incidence of Epstein-Barr virus (EBV)–induced Burkitt lymphoma/leukemia is tenfold to twentyfold higher than the incidence in the United States, resulting in a much higher incidence of NHL.[5]
  • Race: The incidence of NHL is higher in White people than in African American people, and Burkitt lymphoma/leukemia is more common in non-Hispanic White people (3.2 cases/million person-years) than in Hispanic White people (2.0 cases/million person-years).[6]
  • Age: Although there is no sharp age peak, childhood NHL occurs most commonly in the second decade of life.[4] NHL occurs infrequently in children younger than 3 years [4] and is very rare in infants (1% in Berlin-Frankfurt-Münster [BFM] trials from 1986 to 2002).[7]
    The incidence of NHL is increasing overall because of a slight increase in the incidence for those aged 15 to 19 years. Conversely, the incidence of NHL in children younger than 15 years has remained constant over the past several decades.[4]
  • 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.[4,8] A review of Surveillance, Epidemiology, and End Results (SEER) Program data revealed that 2.5 cases per 1 million person-years of Burkitt lymphoma/leukemia were diagnosed in the United States between 1992 and 2008, with more cases in males than in females (3.9:1.1).[4] 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.[4]

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

Table 1. Incidence and Age Distribution of Specific Types of NHLa

Incidence of NHL per Million Person-Years
MalesFemales
Age (y) <55–910–1415–19<55–9 10–1415–19
Burkitt3.266.12.80.81.10.81.2
Lymphoblastic1.62.22.82.20.91.00.70.9
DLBCL0.51.22.56.10.60.71.44.9
Other (mostly ALCL)2.33.34.37.8b1.51.62.83.4b

ALCL = anaplastic large cell lymphoma; DLBCL = diffuse large B-cell lymphoma; NHL = non-Hodgkin lymphoma.

aAdapted from Percy et al.[4]

bIndolent and aggressive histologies (more commonly seen in adult patients) are mostly found in older adolescents.

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.[4] 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.[9]
  • Immunodeficiency: Immunodeficiency, both congenital and acquired (HIV or posttransplant immunodeficiency), increases the risk of NHL.[4] 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.[10]
  • 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.[11] The distribution of NHL subtypes differs among the DNA repair syndromes, as follows:[11]
    -

    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.[12] In this small cohort, outcomes were similar to those patients with de novo NHL who were treated with standard therapy.[12]

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 developed countries, Burkitt lymphoma/leukemia occurs in the abdomen in approximately 60% of cases, with 15% to 20% of cases arising in the head and neck.[13,14] 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.
  • Pathologic 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 will survive at least 5 years, although outcome depends on a number of factors, including clinical stage and histology.[15]

Prognostic factors for childhood NHL include the following:

Refer to the following sections of this summary 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:

Response to therapy

Response to therapy in pediatric lymphoma is one of the most important prognostic markers. Regardless of histology, pediatric NHL that is refractory to first-line therapy has a very poor prognosis,[16-20] with the exception of anaplastic large cell lymphoma.[16,21]

  • Burkitt lymphoma/leukemia: One of the most important predictive factors is response to the initial prophase treatment; poor responders (i.e., <20% resolution of disease) have an event-free survival (EFS) rate of 30%.[22,23] 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.[24]
  • 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 a decreased survival in the BFM 90-95 studies, but all patients with less than 70% reduction at the end of induction had therapy intensified.[25]

International pediatric NHL response criteria have been proposed but require prospective evaluation. The clinical utility of these new criteria are under investigation.[26]

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/leukemia: One study suggested an inferior outcome for patients with Burkitt lymphoma/leukemia who had detectable MRD after induction chemotherapy.[27] 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.[28,29]
  • 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 histologic subtypes containing small cell and/or lymphohistiocytic components.[30][Level of evidence: 2A]

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.[22,25,31-33] 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.[22,31,34]

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). Patients with morphologically involved bone marrow with more than 5% lymphoma cells are considered to have stage IV disease.

  • Burkitt lymphoma/leukemia: The role of MDD remains to be defined. One study suggested that MDD is predictive of outcome,[35,36] while another study did not.[28]
  • 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).[37]
    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).[38]
    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).[39]
  • 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.[30][Level of evidence: 2A][40-43] MDD is commonly quantified by normalizing the number of NPM-ALK transcripts to 104 copies ABL1, with 10 normalized copy number (NCN) NPM-ALK transcripts being the most common cut point to compare the prognostic impact of MDD.[40-42] NPM-ALK transcript levels in blood and bone marrow are comparable.[40,43] 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 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.[40] 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.[40]
    • 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.[43] 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 histologic subtype (small cell/lymphohistiocytic) were the two factors significantly associated with inferior outcome.
    • 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.[30][Level of evidence: 2A] 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.[41] 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 a 3-year EFS rate of 79% (± 5%) for the 73 patients with 10 or more NCN NPM-ALK transcripts (P < .0001).
    The presence of MDD is significantly associated with uncommon histologic subtypes containing small cell and/or lymphohistiocytic components.[40]

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.[24,31,44,45] However, with appropriate risk-stratified therapy, patients with bone marrow and/or CNS involvement can achieve similar outcomes to patients without marrow and/or CNS involvement.[24]
  • 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.[14]
  • Mediastinum: Mediastinal involvement in children and adolescents with nonlymphoblastic NHL results in an inferior outcome.[15,22,31,34] In children and young adults with primary mediastinal B-cell lymphoma, series have reported 3-year EFS rates of 50% to 70%.[31,34,46] However, studies using the dose-adjusted (DA)–EPOCH protocol (etoposide, prednisone, vincristine, and doxorubicin) with rituximab have reported EFS rates higher than 80%.[47,48]
  • 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.[45] In a subsequent study analysis from EICNHL utilizing biologic risk factors, the clinical risk features were not found to be significant.[49] 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.[50][Level of evidence: 2A]
  • Bone: Although previously thought to be a poor prognostic site, patients with NHL arising in bone have an excellent prognosis, regardless of histology.[51,52]
  • 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.[49,50]
  • Testicle: Testicular involvement does not affect prognosis.[25,53]

Age

NHL in infants is rare (1% in BFM trials from 1986 to 2002).[7] In this retrospective review, the outcome for infants was inferior compared with the outcome for older patients with NHL.[7]

Adolescents have been reported to have outcomes inferior to those of younger children.[13,15,54] 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.[15,54] Conversely, for patients with Burkitt lymphoma/leukemia, adolescent age (≥15 years) was not an independent risk factor for inferior outcome.[24,34]

Immune response to tumor

An immune response against the ALK protein (i.e., anti-ALK antibody titer) appeared to correlate with lower clinical stage and predicted relapse risk but not OS.[55] 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:[49]

  • 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.[42] 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).[30][Level of evidence: 2A]

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  41. Damm-Welk C, Kutscher N, Zimmermann M, et al.: Quantification of minimal disseminated disease by quantitative polymerase chain reaction and digital polymerase chain reaction for NPM-ALK as a prognostic factor in children with anaplastic large cell lymphoma. Haematologica 105 (8): 2141-2149, 2020. [PMC free article: PMC7395281] [PubMed: 31649129]
  42. Iijima-Yamashita Y, Mori T, Nakazawa A, et al.: Prognostic impact of minimal disseminated disease and immune response to NPM-ALK in Japanese children with ALK-positive anaplastic large cell lymphoma. Int J Hematol 107 (2): 244-250, 2018. [PubMed: 29030834]
  43. 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. [PMC free article: PMC7598675] [PubMed: 32987765]
  44. 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. [PubMed: 23720354]
  45. Le Deley MC, Reiter A, Williams D, et al.: Prognostic factors in childhood anaplastic large cell lymphoma: results of a large European intergroup study. Blood 111 (3): 1560-6, 2008. [PubMed: 17957029]
  46. 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. [PMC free article: PMC3544113] [PubMed: 23149845]
  47. 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. [PMC free article: PMC4568999] [PubMed: 23574119]
  48. 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. [PMC free article: PMC6650639] [PubMed: 29082519]
  49. 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. [PubMed: 22907048]
  50. 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. [PMC free article: PMC2769495] [PubMed: 18985718]
  51. 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. [PubMed: 11981000]
  52. 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. [PubMed: 17145622]
  53. 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. [PubMed: 11331318]
  54. 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. [PubMed: 21030984]
  55. 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. [PubMed: 20185586]

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]

  • 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/leukemia, 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 Burkitt-like lymphoma with 11q alteration, high-grade B-cell lymphoma–not otherwise specified, and large B-cell lymphoma with IRF4 rearrangement (LBCL-IRF4).[3]
    Compared with treatments for adults, aggressive Burkitt regimens in pediatrics have been used to treat patients with both Burkitt lymphoma/leukemia and large B-cell histologies, resulting in no difference in outcome based on histology.[4-8] The exception is for patients with primary mediastinal B-cell lymphoma, who have had inferior outcomes with these regimens.[4-7,9]
    For patients with pediatric Burkitt lymphoma/leukemia, secondary cytogenetic abnormalities, other than MYC rearrangement, have been associated with an inferior outcome,[10,11] 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.[11,12] For pediatric patients with diffuse large B-cell lymphoma and chromosomal rearrangement at MYC (8q24), outcomes may be worse.[11]
    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.[13]
    LBCL-IRF4 is included in the WHO 2017 classification as a provisional entity.[3] LBCL-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.[14,15]
    Refer to the Tumor biology (Genomics of Burkitt lymphoma/leukemia), Tumor biology (Genomics of diffuse large B-cell lymphoma), and Tumor biology (Genomics of primary mediastinal B-cell lymphoma) sections of this summary for more information about the tumor biology and genomic alterations.
  2. Lymphoblastic lymphoma: This is primarily precursor T-cell lymphoma and, less frequently, precursor B-cell lymphoma.
    Refer to the Tumor Biology (Genomics of lymphoblastic lymphoma) section of this summary for more information about the tumor biology and genomic alterations.
  3. Anaplastic large cell lymphoma: This type includes mature peripheral T-cell/null-cell lymphomas. The null-cell variant is considered to be the same disease in which the cells have lost most of the T-cell antigens.
    In adults, ALK-negative disease has an inferior outcome; however, in children, the difference in outcome between ALK-positive and ALK-negative disease has not been demonstrated.[16-18] 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 and was significantly associated with a high risk of failure in the multivariate analysis, controlling for clinical characteristics.[19] With longer follow-up, presence of the small cell/lymphohistiocytic pattern maintained its prognostic significance on multivariate analysis.[20]
    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 histologic variants, had a significantly increased risk of failure.[18]
    Refer to the Tumor Biology (Genomics of anaplastic large cell lymphoma) section of this summary for more information about the tumor biology and genomic alterations.

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]

Table 2. Major Histopathological Categories of Non-Hodgkin Lymphoma in Children and Adolescentsa

WHO ClassificationImmunophenotype Clinical Presentation Chromosome Abnormalities Genes Affected
Burkitt lymphomaMature B cellIntra-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
Burkitt-like lymphoma with 11q aberration (provisional)Mature B cellNodal11q alteration, no MYC rearrangement
Large B-cell lymphoma with IRF4 rearrangementMature B cellNodal (typically head and neck)Cryptic IRF1 rearrangement with IGH locus IRF4
Diffuse large B-cell lymphoma Mature B cell Nodal, abdominal, bone, primary CNS (when associated with immunodeficiency), mediastinalNo consistent cytogenetic abnormality identified
Primary mediastinal (thymic) large B-cell lymphomaMature B cell, often CD30+Mediastinal, but may also have other nodal or extranodal disease (i.e., abdominal, often kidney)9p and 2p gainsCIITA, TNFAIP3, SOCS1, PTPN11, STAT6
ALK-positive large B-cell lymphomaGeneralized lymphadenopathy, bone marrow in 25%t(2;5)(p23;q35); less common variant translocations involving ALKALK, NPM
T-lymphoblastic leukemia/lymphomaT lymphoblasts (TdT, CD2, CD3, CD7, CD4, CD8)Mediastinal mass, bone marrow
B-lymphoblastic leukemia/lymphomaB lymphoblasts (CD19, CD79a, CD22, CD10, TdT)Skin, soft tissue, bone, lymph nodes, bone marrow
Pediatric-type follicular lymphomaMature B cellNodal (typically head and neck)TNFRSF14, MAP2K1
Pediatric nodal marginal zone lymphomaMature B cellNodal (typically head and neck)

CNS = central nervous system; TdT = terminal deoxynucleotidyl transferase; WHO = World Health Organization; + = positive.

aAdapted from Percy et al.[1]

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 most recent WHO classification has designated pediatric-type follicular lymphoma and pediatric nodal marginal zone lymphoma as distinct entities from the counterparts observed in adults.[2]

Refer to the following PDQ summaries for more information about the treatment of NHL in adult patients:

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 November 12, 2021.
  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. [PMC free article: PMC4874220] [PubMed: 26980727]
  3. 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.
  4. 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. [PubMed: 16173961]
  5. 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. [PMC free article: PMC3269965] [PubMed: 22215753]
  6. 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. [PMC free article: PMC1852229] [PubMed: 17132719]
  7. 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. [PubMed: 15486066]
  8. 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. [PubMed: 18371107]
  9. 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. [PMC free article: PMC3544113] [PubMed: 23149845]
  10. 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. [PubMed: 16862570]
  11. 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. [PMC free article: PMC2988438] [PubMed: 19020548]
  12. 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. [PMC free article: PMC2921871] [PubMed: 19895612]
  13. 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. [PMC free article: PMC7720281] [PubMed: 32492302]
  14. 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. [PubMed: 21487109]
  15. 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. [PubMed: 32239695]
  16. 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. [PubMed: 11090048]
  17. 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. [PubMed: 19139435]
  18. 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. [PMC free article: PMC4682366] [PubMed: 25156886]
  19. 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. [PubMed: 22084369]
  20. 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. [PMC free article: PMC7598675] [PubMed: 32987765]

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 NHL in more than 2,500 patients. Overall, CNS involvement was diagnosed in 6% of patients. CNS involvement (percentage of patients) according to NHL subtype was as follows:[10]

  • Burkitt lymphoma/leukemia: 8.8%.
  • Precursor B-cell lymphoblastic lymphoma: 5.4%.
  • T-cell lymphoblastic lymphoma: 3.7%.
  • 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. [PubMed: 2915234]
  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. [PMC free article: PMC4461808] [PubMed: 25940716]
  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. [PubMed: 17242397]
  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. [PubMed: 17701585]
  5. Cheson BD, Pfistner B, Juweid ME, et al.: Revised response criteria for malignant lymphoma. J Clin Oncol 25 (5): 579-86, 2007. [PubMed: 17242396]
  6. Cheson BD: The International Harmonization Project for response criteria in lymphoma clinical trials. Hematol Oncol Clin North Am 21 (5): 841-54, 2007. [PubMed: 17908623]
  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. [PubMed: 22357895]
  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. [PubMed: 22957898]
  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. [PMC free article: PMC4979083] [PubMed: 25113753]
  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. [PubMed: 17761975]

Treatment Option Overview for Childhood NHL

Many of the improvements in childhood cancer survival have been made by employing combinations of known and/or new agents aimed at improving the best available, accepted therapy. Clinical trials in pediatrics are designed to compare potentially better therapy with therapy that is currently accepted as standard. 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 be considered for entry into 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:

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.[3-6]
  • 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 histologic 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/leukemia) 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.[9-14] 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 the 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 GroupTreatment Options
Mature B-cell NHL:
Burkitt lymphoma/leukemiaNewly diagnosedSurgery (for stage I and II only)
Chemotherapy with or without rituximab
Recurrent or refractory Chemotherapy with or without rituximab
Allogeneic or autologous SCT
Bispecific antibody
CAR T-cell therapy
Diffuse large B-cell lymphomaNewly diagnosedSurgery (for stage I and II only)
Chemotherapy with or without rituximab
Recurrent or refractory Chemotherapy with or without rituximab
Allogeneic or autologous SCT
Bispecific antibody
CAR T-cell therapy
Primary mediastinal B-cell lymphoma Chemotherapy and rituximab
Lymphoblastic lymphomaNewly diagnosed Chemotherapy
Cranial radiation therapy for overt CNS disease only
Recurrent or refractory Nelarabine or nelarabine-containing chemotherapy regimens
Chemotherapy
Bortezomib with chemotherapy
Allogeneic SCT
Anaplastic large cell lymphomaNewly diagnosedSurgery followed by chemotherapy (for stage I)
Chemotherapy
Recurrent or refractory Chemotherapy, brentuximab, and/or ALK inhibitors (e.g., crizotinib or alectinib)
Allogeneic or autologous SCT
Lymphoproliferative disease associated with immunodeficiency:
Lymphoproliferative disease associated with primary immunodeficiency Chemotherapy with or without rituximab
Allogeneic SCT
NHL associated with DNA repair defect syndromes Chemotherapy
HIV-associated NHL Chemotherapy with or without rituximab
PTLDSurgery and reduction of immunosuppressive therapy, if possible
Rituximab alone
Standard or slightly modified chemotherapy with or without rituximab (for B-cell PTLD)
Low-dose chemotherapy with or without rituximab (for EBV-positive B-cell PTLD)
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
Radiation therapy
Peripheral T-cell lymphoma Chemotherapy
Radiation therapy
Allogeneic or autologous SCT
Cutaneous T-cell lymphoma No standard treatments have been established

CAR = chimeric antigen receptor; CNS = central nervous system; EBV = Epstein-Barr virus; MALT = mucosa-associated lymphoid tissue; PTLD = posttransplant lymphoproliferative disease; SCT = stem cell transplantation.

Medical Emergencies

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

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) scans or echocardiograms.[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 physiologic 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 cytologic 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.[19-24] 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 on the basis of imaging requires caution because false-positive results are common.[25-28] 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 on the basis of 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. [PubMed: 8606720]
  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. [PubMed: 9345074]
  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. [PubMed: 16421426]
  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. [PMC free article: PMC2843413] [PubMed: 19194463]
  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. [PubMed: 11389005]
  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. [PMC free article: PMC1852225] [PubMed: 17138821]
  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. [PMC free article: PMC2288716] [PubMed: 18258798]
  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. [PubMed: 8501488]
  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. [PubMed: 19738127]
  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. [PubMed: 16445832]
  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. [PubMed: 21709186]
  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. [PMC free article: PMC3730818] [PubMed: 23598171]
  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. [PubMed: 22614995]
  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. [PubMed: 32730187]
  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. [PubMed: 4087108]
  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. [PubMed: 9044140]
  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. [PubMed: 7652680]
  18. Prakash UB, Abel MD, Hubmayr RD: Mediastinal mass and tracheal obstruction during general anesthesia. Mayo Clin Proc 63 (10): 1004-11, 1988. [PubMed: 3172849]
  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. [PubMed: 11157020]
  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. [PubMed: 11342423]
  21. Cairo MS, Bishop M: Tumour lysis syndrome: new therapeutic strategies and classification. Br J Haematol 127 (1): 3-11, 2004. [PubMed: 15384972]
  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. [PubMed: 20331465]
  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. [PMC free article: PMC3835461] [PubMed: 24032600]
  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. [PubMed: 18509186]
  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. [PubMed: 16772881]
  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. [PubMed: 22691506]
  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. [PubMed: 24248697]
  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. [PMC free article: PMC4351138] [PubMed: 25382494]
  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. [PubMed: 17786707]
  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. [PMC free article: PMC4568999] [PubMed: 23574119]

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.

(Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)

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. [PMC free article: PMC4136455] [PubMed: 24853691]
  2. American Academy of Pediatrics: Standards for pediatric cancer centers. Pediatrics 134 (2): 410-4, 2014. Also available online. Last accessed February 1, 2022.

Aggressive Mature B-cell NHL

Burkitt Lymphoma/Leukemia

Incidence

In the United States, Burkitt lymphoma/leukemia accounts for about 40% of childhood non-Hodgkin lymphoma (NHL) cases and exhibits a consistent, aggressive clinical behavior.[1,2] The overall incidence of Burkitt lymphoma/leukemia in the United States is 2.5 cases per 1 million person-years and is higher among boys than girls (3.9 vs. 1.1).[2,3] (Refer to Table 1 for more information about the incidence of Burkitt lymphoma by age and sex distribution.)

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/leukemia

The malignant cells of Burkitt lymphoma/leukemia 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/leukemias express CD10.[1]

Burkitt lymphoma/leukemia 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.[5-7] The presence of one of the variant translocations t(2;8) or t(8;22) does not appear to affect response or outcome.[8,9]

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 hypermutation; translocations resulting from aberrant variable, diversity, and joining (VDJ) gene segment recombinations are rare.[10] 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 mutations that have been identified in Burkitt lymphoma in pediatric and adult cases are listed below. The clinical significance of these mutations for pediatric Burkitt lymphoma remains to be elucidated.

  • Activating mutations in the transcription factor TCF3 and inactivating mutations in its negative regulator ID3 are observed in approximately 70% of Burkitt lymphoma cases.[10-14]
  • Mutations in TP53 are observed in one-third to one-half of cases.[11,13]
  • Mutations in CCND3 are commonly observed in sporadic Burkitt lymphoma (approximately 40% of cases) but are rare in endemic Burkitt lymphoma.[11,13]
  • Mutually exclusive mutations in SMARCA4 and ARID1A,[10] components of the SWItch/Sucrose Non-Fermentable (SWI/SNF) complex, are observed in more than one-half of pediatric Burkitt lymphoma cases.[9]
  • Mutations in MYC itself are observed in approximately one-half of Burkitt lymphoma cases and appear to enhance tumorigenesis, in part, by increasing MYC stability.[10,11,15]

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 mutations for endemic and sporadic cases and for EBV-positive and EBV-negative cases; however, EBV-positive cases showed significantly lower mutation rates for selected genes/pathways, including SMARCA4, CCND3, TP53, and apoptosis.[9]

Cytogenetic evidence of MYC rearrangement is the gold standard for diagnosis of Burkitt lymphoma/leukemia. 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/leukemia 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/leukemia and has no clinical implications.[16]

Genomics of Burkitt-like lymphoma with 11q aberration

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.[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 Burkitt lymphoma with 11q aberration 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 mutational landscape of Burkitt-like lymphoma with 11q aberration is distinct from that of Burkitt lymphoma; mutations commonly observed in Burkitt lymphoma (e.g., ID3, TCF3, and CCND3) are uncommon in Burkitt-like lymphoma with 11q aberration.[18] Conversely, mutations in GNA13 appear to be common (up to 50%) in patients with Burkitt-like lymphoma with 11q aberration and are less common in patients with Burkitt lymphoma.

Prognostic factors

Refer to the Prognosis and Prognostic Factors for Childhood NHL section of this summary for information about prognostic factors for Burkitt lymphoma/leukemia.

Standard treatment options for Burkitt lymphoma/leukemia

The treatment of Burkitt lymphoma/leukemia 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/leukemia or diffuse large B-cell lymphoma). Pediatric Burkitt lymphoma/leukemia and diffuse large B-cell lymphoma are clinically very aggressive, and patients are treated with very intensive regimens.[21-26]

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. (Refer to the Tumor lysis syndrome section in the Treatment Option Overview for Childhood NHL section of this summary for more information.)

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 Burkitt leukemia should be treated with protocols designed for Burkitt lymphoma.[21,23,26]

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

StratumDisease Manifestation
COG-C5961 (FAB/LMB-96);[22,23,27] COG-ANHL1131 (Inter-B-NHL Ritux 2010) [26]ACompletely resected stage I and abdominal stage II
BaMultiple 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
CMature B-cell ALL (>25% blasts in marrow) and/or CNS disease
BFM Group [28]R1Completely resected stage I and abdominal stage II
R2Nonresected stage I or II and stage III with LDH <500 IU/L
R3Stage III with LDH 500–999 IU/L
Stage IV, B-ALL (>25% blasts), no CNS disease, and LDH <1,000 IU/L
R4Stage III, IV, B-cell ALL with LDH >1,000 IU/L
Any CNS disease

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.

aBased 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 study ANHL1131 (NCT01516567).[22]

The following studies have contributed to the development of current treatment regimens for pediatric patients with Burkitt lymphoma/leukemia 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: 2A]
    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, with poor responders (i.e., <20% resolution of disease) having 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]).[21-23,28]

Evidence (rituximab):

  1. In a phase II study performed by the BFM group, single-agent rituximab showed activity in pediatric patients with Burkitt lymphoma/leukemia.[29][Level of evidence: 2Div]
  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]; [24][Level of evidence: 3iiiA]
    • 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 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]
    • 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, 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).

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

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

Trial StratumDisease Manifestations Treatment
COG-C5961 (FAB/LMB-96) [22,27] COG-ANHL1131 (Inter-B-NHL Ritux 2010) [26]ACompletely resected stage I and abdominal stage II Two cycles of chemotherapy [27]
BMultiple extra-abdominal sites Prephase + four cycles of chemotherapy (reduced-intensity arm) [22]
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]
CMature 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 IITwo cycles of chemotherapy
R2 Nonresected stage I/II and stage III with LDH <500 IU/LPrephase + four cycles of chemotherapy (4-hour methotrexate infusion)

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.

Treatment options for recurrent or refractory Burkitt lymphoma/leukemia

There is no standard treatment option for patients with recurrent or progressive disease. For patients with recurrent or refractory aggressive mature B-cell NHL, reported survival ranges between 10% to 50%; in the largest series, survival was reported to be about 20%.[23,31,32]; [33][Level of evidence: 3iiiA] Three large retrospective multivariable analyses identified the following prognostic factors:

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

  1. R-ICE regimen (rituximab plus ifosfamide, carboplatin, and etoposide [ICE]).[36]
  2. CYVE regimen (high-dose cytarabine and etoposide) for relapsed group A and group B disease.[34]
  3. Allogeneic or autologous SCT.[37-39]
  4. Bispecific antibody (anti-CD20, anti-CD3).[40]
  5. Chimeric antigen receptor (CAR) T-cell therapy.[41]
  6. R-VICI regimen (rituximab, vincristine, idarubicin, ifosfamide, carboplatin, and dexamethasone).[33][Level of evidence: 3iiiA]

Chemoresistance makes remission difficult to achieve.

Evidence (treatment of recurrent or refractory Burkitt lymphoma/leukemia):

  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:[42]
    • The most favorable outcomes occurred in patients who received rituximab and an autologous SCT.
    • 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 transplantation.
  2. In a COG study of 20 patients with relapsed/refractory B-cell NHL (Burkitt lymphoma/leukemia [n = 14] and diffuse large B-cell lymphoma) who were treated with R-ICE, the following was observed:[36][Level of evidence: 3iiA]
    • 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.[43]
    • 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.[34]
    • 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/leukemia 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:[33][Level of evidence: 3iiiA]
    • Of the 75 patients, 29 (41%) had Burkitt leukemia.
    • 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 SCT.
    • Reinduction with intensive continuous chemotherapy with R-VICI therapy before SCT improved survival (4-year OS rate, 67%).
    • Initial disease risk category was prognostic: Low risk (R1/R2) had improved survival (4-year OS rate, 50%) compared with high risk (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 SCT was prognostic (4-year OS rate, 63%).

If remission can be achieved, high-dose therapy plus SCT remains the best option for survival. Patients not in remission at the time of transplant fare significantly worse.[34,37,42,44-46] 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.[37,45,46] 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).[37,42,43,45,47] The benefit of autologous versus allogeneic SCT remains unclear.[32,37,47,48]; [44][Level of evidence: 2A]; [49][Level of evidence: 3iiiDii]

(Refer to the PDQ summary on Childhood Hematopoietic Cell Transplantation for more information about transplantation).

Evidence (SCT therapy):

  1. An analysis of data from the Center for International Blood and Marrow Transplant Research demonstrated the following:[37]
    • 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/leukemia who survived to undergo a transplant.
    • Some graft-versus-lymphoma effect has been implied by the lower relapse rate in the allogeneic SCT patients; however, that was balanced by the higher treatment-related mortality.
  2. A small, single-center, prospective study used autologous transplantation followed by reduced-intensity allogeneic SCT to treat patients with relapsed NHL.[38]
    • The study reported an EFS rate of 60%.

Treatment options under clinical evaluation for Burkitt leukemia/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, refer to the ClinicalTrials.gov website.

The following is an example of a national and/or institutional clinical trial that is 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 using a next-generation sequencing targeted assay of more than 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
    Tumor tissue from progressive or recurrent disease must be available for molecular characterization. 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.
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 most recent WHO classification. (Refer to the Primary Mediastinal B-cell Lymphoma section of this summary for more information.)

Incidence

Diffuse large B-cell lymphoma is an aggressive mature B-cell neoplasm that represents 10% to 20% of pediatric NHL cases.[2,50] Diffuse large B-cell lymphoma occurs more frequently during the second decade of life than during the first decade.[2,51] (Refer to Table 1 for more information on the incidence of diffuse large B-cell lymphoma by age and sex distribution.)

Clinical presentation

Pediatric diffuse large B-cell lymphoma may present in a manner clinically similar to that of Burkitt lymphoma/leukemia, although more often it is localized, and less often it involves the bone marrow or CNS.[50,51] (Refer to the Clinical presentation section in the Burkitt Lymphoma/Leukemia section of this summary for more information.)

Tumor biology

Genomics of diffuse large B-cell lymphoma

The World Health Organization (WHO) classification system categorizes diffuse large B-cell lymphoma on the basis of molecular characteristics into the germinal center B-cell subtype and the activated B-cell subtype, with the remaining types being classified as diffuse large B-cell lymphoma, not otherwise specified (NOS).[52]

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.[8,53-55] The age at which the favorable germinal center subtype changes to the less favorable nongerminal center subtype was shown to be a continuous variable.[56]
  • 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.[53]
  • 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/leukemia.[57,58]
  • 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 with approximately one-half of the nonrearranged cases showing MYC gain or amplification.[58,59]
  • In a report that 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 mutations). 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).[55]

Large B-cell lymphoma with IRF4 rearrangement (LBCL-IRF4) was added as a provisional entity in the 2017 revision of the WHO classification of lymphoid neoplasms.[60]

  • 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.[61] 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, and commonly present with nodal involvement of the head and neck (particularly the Waldeyer ring) and less commonly in the gastrointestinal tract.[20,55,62,63]
  • LBCL-IRF4 shows strong IRF4/MUM1 expression, and in a study of 17 cases, the most frequently mutated 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.[20,55,62]

High-grade B-cell lymphoma, NOS is defined as a clinically aggressive B-cell lymphoma that lacks MYC plus BCL2 and/or BCL6 rearrangements and that does not meet criteria for diffuse large B-cell lymphoma, NOS or Burkitt lymphoma.[64]

  • High-grade B-cell lymphoma, NOS is a biologically heterogeneous disease. In a study of eight pediatric high-grade B-cell lymphoma, NOS cases, four had mutational profiles similar to that of Burkitt lymphoma (e.g., MYC rearrangements and mutations in CCND3, ID3, and DDX3X).[55] The remaining cases lacked MYC rearrangements and had mutational profiles closer to GCB-DLBCL (e.g., TNFRSF14, CARD11 and EZH2 mutations), and lacked MYC translocations.

Prognostic factors

Refer to the Prognosis and Prognostic Factors for Childhood NHL section of this summary for information about prognostic factors for diffuse large B-cell lymphoma.

Treatment options for diffuse large B-cell lymphoma

As with Burkitt lymphoma/leukemia, 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/leukemia. Refer to the Standard treatment options for Burkitt lymphoma/leukemia section of this summary for information about the treatment of diffuse large B-cell lymphoma.

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/leukemia. Refer to the Treatment options for recurrent or refractory Burkitt lymphoma/leukemia section of this summary for more information.

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, refer to the ClinicalTrials.gov website.

The following is an example of a national and/or institutional clinical trial that is 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 using a next-generation sequencing targeted assay of more than 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
    Tumor tissue from progressive or recurrent disease must be available for molecular characterization. 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.
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.[51,65-67]

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 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.[68]

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 most recent World Health Organization (WHO) classification.[69] 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.[69]
  • Hodgkin lymphoma: Primary mediastinal B-cell lymphoma may be difficult to clinically and morphologically distinguish from Hodgkin lymphoma, especially with small mediastinal biopsies because of extensive sclerosis and necrosis.

Primary mediastinal B-cell lymphoma has distinctive gene expression and mutation profiles compared with diffuse large B-cell lymphoma; however, its gene expression and mutation profiles have features similar to those seen in Hodgkin lymphoma.[70-72] 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, and the genomic alterations lead to increased expression of these checkpoint proteins.[72-76]

    -

    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, and they lead to loss of MHC class II expression.[72,76,77]

    -

    Approximately 50% of primary mediastinal B-cell lymphoma cases show mutations or focal copy number losses in B2M, the gene that encodes beta-2-microglobulin (the invariant chain of the MHC class I), which leads to reduced expression of MHC class I.[72,76]

  • Genomic alterations involving JAK-STAT pathway genes are observed in most cases of primary mediastinal B-cell lymphoma.[78]
    -

    STAT6 is mutated in approximately 40% of primary mediastinal B-cell lymphoma cases.[72,76]

    -

    The chromosome 9p region that shows gains and amplification in primary mediastinal B-cell lymphoma encodes JAK2, which activates the STAT pathway.[66,67]

    -

    SOCS1, a negative regulator of JAK-STAT signaling, is inactivated in approximately 50% to 60% of primary mediastinal B-cell lymphoma cases by either mutation or gene deletion.[72,76,79,80]

    -

    The IL4R gene shows activating mutations in approximately 20% to 30% of primary mediastinal B-cell lymphoma cases, and IL4R activation leads to increased JAK-STAT pathway activity.[72,76,78]

  • 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.[66,67,72,76] Genes encoding negative regulators of NF-kB signaling (e.g., TNFAIP3 and NFKBIE) show inactivating mutations in primary mediastinal B-cell lymphoma.[72,76]
  • Other genes that are mutated in primary mediastinal B-cell lymphoma include ZNF217, XPO1, and EZH2.[72,76]

Prognostic factors

Refer to the Prognosis and Prognostic Factors for Childhood NHL section of this summary for information on prognostic factors for primary mediastinal B-cell lymphoma.

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).

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.[81][Level of evidence: 2A] 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.[82]

Evidence (DA-EPOCH-R):

  1. A single-arm study in young adults utilized the DA-EPOCH-R regimen (usually six cycles) with filgrastim and no radiation therapy.[82][Level of evidence: 2A]
    • 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 went through 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 single-arm modification of DA-EPOCH-R (usually six cycles with filgrastim and no radiation therapy) was completed by the BFM group, in which the cumulative doxorubicin dose was kept at 360 mg/m2 and intrathecal chemotherapy was added.[83]
    • The study showed a 2-year OS rate of 92% among the 15 consecutive pediatric patients treated.
  3. A multicenter, retrospective study of 38 pediatric patients (aged <21 years) and 118 adult patients treated with DA-EPOCH-R observed the following:[84]
    • 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.

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.[85]

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, refer to the ClinicalTrials.gov website.

The following is an example of a national and/or institutional clinical trial that is 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 using a next-generation sequencing targeted assay of more than 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
    Tumor tissue from progressive or recurrent disease must be available for molecular characterization. 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.

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  53. Oschlies I, Klapper W, Zimmermann M, et al.: Diffuse large B-cell lymphoma in pediatric patients belongs predominantly to the germinal-center type B-cell lymphomas: a clinicopathologic analysis of cases included in the German BFM (Berlin-Frankfurt-Munster) Multicenter Trial. Blood 107 (10): 4047-52, 2006. [PubMed: 16424389]
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  57. Klapper W, Szczepanowski M, Burkhardt B, et al.: Molecular profiling of pediatric mature B-cell lymphoma treated in population-based prospective clinical trials. Blood 112 (4): 1374-81, 2008. [PubMed: 18509088]
  58. Deffenbacher KE, Iqbal J, Sanger W, et al.: Molecular distinctions between pediatric and adult mature B-cell non-Hodgkin lymphomas identified through genomic profiling. Blood 119 (16): 3757-66, 2012. [PMC free article: PMC3335381] [PubMed: 22374697]
  59. 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. [PMC free article: PMC2988438] [PubMed: 19020548]
  60. 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.
  61. 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. [PMC free article: PMC6941672] [PubMed: 31012208]
  62. 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. [PubMed: 21487109]
  63. 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. [PMC free article: PMC3566339] [PubMed: 23108024]
  64. 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.
  65. 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. [PubMed: 12721255]
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  67. 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. [PMC free article: PMC3031694] [PubMed: 20971819]
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  69. 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.
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  73. 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. [PMC free article: PMC2995356] [PubMed: 20628145]
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Lymphoblastic Lymphoma

Incidence

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

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, and the 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/leukemia.

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.

Tumor Biology

Genomics of lymphoblastic lymphoma

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

As opposed to pediatric T-cell acute lymphoblastic leukemia (T-ALL), chromosomal abnormalities and the molecular biology 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 mutations and FBXW7 mutations (which also induce NOTCH pathway signaling) are common in T-ALL;[6] NOTCH1 and FBXW7 mutations are also observed in approximately 60% to 65% and 15% to 25% of T-cell lymphoblastic lymphoma cases, respectively.[7-10]
  • 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.[6,10]
  • Loss of heterozygosity at chromosome 6q is observed in approximately 15% of T-ALL cases.[10]
  • PTEN mutations are observed in approximately 15% of T-ALL cases and in a comparable percentage of T-lymphoblastic lymphoma cases.[6,9,10]
  • Mutations in KMT2D are observed in approximately 10% of T-lymphoblastic lymphoma cases.[10] Other genes associated with epigenetics that are mutated in T-ALL include PHF6 and KMT2C.

For the genomic alterations described above, NOTCH1 and FBXW7 mutations may confer a more favorable prognosis for patients with T-cell lymphoblastic lymphoma, while loss of heterozygosity at chromosome 6q, PTEN mutations, and KMT2D mutations may be associated with an inferior prognosis.[7-11] For example, one study noted that the presence of a KMT2D and/or PTEN mutation was associated with a high risk of relapse in patients with wild-type NOTCH1/FBXW7, but these mutations were not associated with an increased risk of relapse in patients with mutations in NOTCH1 or FBXW7.[10] 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. A report describing copy number alterations for pediatric B-lymphoblastic lymphoma cases 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

Refer to the Prognosis and Prognostic Factors for Childhood NHL section of this summary for information about prognostic factors for lymphoblastic lymphoma.

Standard Treatment Options for Lymphoblastic Lymphoma

Current data do not suggest superiority for the following treatment options.

Standard treatment options for lymphoblastic lymphoma include the following:

  1. GER-GPOH-NHL-BFM-95: Prednisone, dexamethasone, vincristine, daunorubicin, doxorubicin, L-asparaginase, cyclophosphamide, cytarabine, methotrexate, mercaptopurine, thioguanine, and CNS radiation therapy for CNS-positive patients only. Treatment duration for T-cell and B-cell precursor lymphoblastic lymphoma is 24 months.[12 ,13]
  2. COG-A5971 (NCT00004228): Prednisone, dexamethasone, vincristine, daunorubicin, doxorubicin, L-asparaginase, cyclophosphamide, cytarabine, methotrexate, mercaptopurine, and thioguanine.[14,15]
    1. Stage I or II (arm A0; localized disease): Modified Children's Cancer Group (CCG) BFM regimen (prednisone, dexamethasone, vincristine, daunorubicin, doxorubicin, L-asparaginase, cyclophosphamide, cytarabine, methotrexate, mercaptopurine, thioguanine, and reduced number of intrathecal treatments during maintenance).
    2. Stage III or IV (2 × 2 randomization):

      First randomization

      • Arm A1 (disseminated disease, no CNS disease): Modified CCG BFM regimen without intensification. No high-dose methotrexate administered during the interim maintenance phase, but intrathecal therapy is 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 maintenance.

      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 arms A1, B1, A2, and B2.

Patients with low-stage (stage I or stage II) lymphoblastic lymphoma have long-term disease-free survival (DFS) rates of about 60% with short, pulsed chemotherapy followed by 6 months of maintenance, with an overall survival (OS) rate higher than 90%.[16,17] However, with the use of an ALL approach and induction, consolidation, and maintenance therapy for a total of 24 months, DFS rates higher than 90% have been reported for children with low-stage lymphoblastic lymphoma.[12-14]

Patients with high-stage (stage III or stage IV) lymphoblastic lymphoma have long-term survival rates higher than 80%.[12,13,15] Mediastinal radiation 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 is usually employed. (Refer to the Mediastinal masses section of the Treatment Option Overview for Childhood NHL section of this summary for more information.)

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

  1. In the GER-GPOH-NHL-BFM-90 study, the 5-year DFS was 90%, and there was no difference in outcome between stage III and stage IV patients.[12] Patients with precursor B-cell lymphoblastic lymphoma appeared to have similar results using the same therapy.[2]
  2. In the GER-GPOH-NHL-BFM-95 study, the prophylactic cranial radiation was omitted, and the intensity of induction therapy was decreased slightly.[13]
    • There were no significant increases in CNS relapses, suggesting cranial radiation may be reserved for patients with CNS disease at diagnosis.
    • Of interest, the probability of 5-year event-free survival (EFS) was worse in NHL-BFM-95 (82%) than in NHL-BFM-90 (90%). It was proposed that the major difference in EFS between NHL-BFM-90 and NHL-BFM-95 resulted from the increased number of subsequent neoplasms observed in NHL-BFM-95. NHL-BFM-95 also had a reduction of asparaginase and doxorubicin in induction, which may have affected outcome, although this difference was not statistically significant.
  3. A trial (A5971 [NCT00004228]) of stage III and stage IV lymphoblastic lymphoma patients evaluated two strategies for CNS prophylaxis, without the use of CNS irradiation. Patients were randomly assigned to receive high-dose methotrexate in interim maintenance (BFM-95) or intrathecal chemotherapy throughout maintenance (CCG-BFM).[15][Level of evidence: 1iiA]
    • The overall incidence of CNS relapse was 1.2%, and there was no difference between the treatment arms for CNS relapse, DFS, or OS.
    • The benefit of intensifying induction therapy with continuous infusion daunomycin earlier in induction/delayed intensification phases and the addition of cyclophosphamide was also studied in a randomized fashion. Intensification of therapy did not improve DFS or OS, but increased grade III and grade IV toxicities.

The Pediatric Oncology Group conducted a trial to test the effectiveness of the addition of high-dose methotrexate in the treatment of patients with T-cell ALL and T-cell lymphoblastic lymphoma. In the lymphoma patients, high-dose methotrexate did not demonstrate benefit. In the small cohort (n = 66) of lymphoma patients who did not receive high-dose methotrexate, the 5-year EFS was 88%.[18][Level of evidence: 1iiA] Of note, all of these patients received prophylactic cranial radiation therapy, which has been demonstrated not to be required in T-cell lymphoblastic lymphoma patients.[13,15] In this study, the benefit of adding the cardioprotectant dexrazoxane was tested in a randomized fashion. The addition of dexrazoxane did not affect the outcome and showed cardioprotective benefit on the basis of echocardiographic and laboratory assessments.[19][Level of evidence: 2A]

In addition to the NHL-BFM-95 trial, 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 do not support this finding.[15,21,22]

Treatment Options for Recurrent or Refractory Lymphoblastic Lymphoma

For patients with recurrent or refractory lymphoblastic lymphoma, reports of survival range from 10% to 40%.[21,23]; [24][Level of evidence: 2A]; [25,26][Level of evidence: 3iiiA] As in patients with Burkitt lymphoma/leukemia, 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).[27-29]
  2. ICE regimen (ifosfamide, carboplatin, and etoposide).[30]
  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).[31]
  4. Allogeneic stem cell transplantation (SCT).[32,33]

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%.[27]
  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.[28]
    • A complete response rate of 36% was observed.
  3. Two small series have treated patients with recurrent or refractory T-cell leukemia/lymphoma using nelarabine, cyclophosphamide, and etoposide.[29,34]
    1. One study treated 27 patients.[29]
      • 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 other study treated seven patients.[34]
      • The partial/complete response rate was 100%.
      • Of the two lymphoma patients, both achieved partial responses but later progressed.
  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.[31]
    • 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 SCT.[26]
  6. A Center for International Blood and Marrow Transplant Research analysis demonstrated that EFS was significantly worse when an autologous (4%) versus allogeneic (40%) donor stem cell source was used, with all failures resulting from progressive disease.[32]

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, refer to the ClinicalTrials.gov website.

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

  • NCT03384654 (An Open-label, Multicenter, Phase II Study Evaluating the Efficacy and Safety of Daratumumab in Pediatric and Young Adult Subjects Aged ≥1 and ≤30 Years With Relapsed/Refractory Precursor B-cell or T-cell Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma): Patients receive daratumumab (anti-CD38) with vincristine, prednisone, doxorubicin, and peg-asparaginase (cycle 1) and with cyclophosphamide, cytarabine, 6-mercaptopurine, and methotrexate (cycle 2).
  • 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 using a next-generation sequencing targeted assay of more than 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
    Tumor tissue from progressive or recurrent disease must be available for molecular characterization. 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.

Current Clinical Trials

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

References

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  21. Abromowitch M, Sposto R, Perkins S, et al.: Shortened intensified multi-agent chemotherapy and non-cross resistant maintenance therapy for advanced lymphoblastic lymphoma in children and adolescents: report from the Children's Oncology Group. Br J Haematol 143 (2): 261-7, 2008. [PMC free article: PMC3057023] [PubMed: 18759768]
  22. 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. [PMC free article: PMC2288716] [PubMed: 18258798]
  23. Attarbaschi A, Dworzak M, Steiner M, et al.: Outcome of children with primary resistant or relapsed non-Hodgkin lymphoma and mature B-cell leukemia after intensive first-line treatment: a population-based analysis of the Austrian Cooperative Study Group. Pediatr Blood Cancer 44 (1): 70-6, 2005. [PubMed: 15368550]
  24. Michaux K, Bergeron C, Gandemer V, et al.: Relapsed or Refractory Lymphoblastic Lymphoma in Children: Results and Analysis of 23 Patients in the EORTC 58951 and the LMT96 Protocols. Pediatr Blood Cancer 63 (7): 1214-21, 2016. [PubMed: 27037853]
  25. Mitsui T, Mori T, Fujita N, et al.: Retrospective analysis of relapsed or primary refractory childhood lymphoblastic lymphoma in Japan. Pediatr Blood Cancer 52 (5): 591-5, 2009. [PubMed: 19156862]
  26. Burkhardt B, Reiter A, Landmann E, et al.: Poor outcome for children and adolescents with progressive disease or relapse of lymphoblastic lymphoma: a report from the berlin-frankfurt-muenster group. J Clin Oncol 27 (20): 3363-9, 2009. [PubMed: 19433688]
  27. Berg SL, Blaney SM, Devidas M, et al.: Phase II study of nelarabine (compound 506U78) in children and young adults with refractory T-cell malignancies: a report from the Children's Oncology Group. J Clin Oncol 23 (15): 3376-82, 2005. [PubMed: 15908649]
  28. Zwaan CM, Kowalczyk J, Schmitt C, et al.: Safety and efficacy of nelarabine in children and young adults with relapsed or refractory T-lineage acute lymphoblastic leukaemia or T-lineage lymphoblastic lymphoma: results of a phase 4 study. Br J Haematol 179 (2): 284-293, 2017. [PubMed: 28771663]
  29. Kuhlen M, Bleckmann K, Möricke A, et al.: Neurotoxic side effects in children with refractory or relapsed T-cell malignancies treated with nelarabine based therapy. Br J Haematol 179 (2): 272-283, 2017. [PubMed: 28771662]
  30. Kung FH, Harris MB, Krischer JP: Ifosfamide/carboplatin/etoposide (ICE), an effective salvaging therapy for recurrent malignant non-Hodgkin lymphoma of childhood: a Pediatric Oncology Group phase II study. Med Pediatr Oncol 32 (3): 225-6, 1999. [PubMed: 10064193]
  31. Horton TM, Whitlock JA, Lu X, et al.: Bortezomib reinduction chemotherapy in high-risk ALL in first relapse: a report from the Children's Oncology Group. Br J Haematol 186 (2): 274-285, 2019. [PMC free article: PMC6606340] [PubMed: 30957229]
  32. Gross TG, Hale GA, He W, et al.: Hematopoietic stem cell transplantation for refractory or recurrent non-Hodgkin lymphoma in children and adolescents. Biol Blood Marrow Transplant 16 (2): 223-30, 2010. [PMC free article: PMC2911354] [PubMed: 19800015]
  33. 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. [PMC free article: PMC6759733] [PubMed: 31511228]
  34. 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. [PubMed: 20528871]

Anaplastic Large Cell Lymphoma

Incidence

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

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 anaplastic large cell lymphoma patients 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 the predominant immunophenotype of anaplastic large cell lymphoma is mature T cell, 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]

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 fusion protein NPM-ALK; the other 15% of cases are composed of variant ALK translocations.[6] 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 protein, whereas cytoplasmic staining of ALK is only associated with the variant ALK translocations, as shown in Table 6.[7]

Table 6. Variant ALK Translocation and Associated Partner Chromosome Location and Frequencya

Gene FusionPartner Chromosome Location Frequency of Gene Fusion
NPM-ALK 5q36.1Approximately 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

aAdapted from Tsuyama et al.[7]

In adults, ALK-positive anaplastic large cell lymphoma is viewed differently from other peripheral T-cell lymphomas because prognosis tends to be superior.[8] Also, adult patients with ALK-negative anaplastic large cell lymphoma have an inferior outcome compared with patients who have ALK-positive disease.[9] 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.[10-12]

In a European series of 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 was significantly associated with a high risk of failure in the multivariate analysis, controlling for clinical characteristics (hazard ratio, 2.0; P = .002).[11] The prognostic implication of the small cell variant of anaplastic large cell lymphoma was also shown in the COG-ANHL0131 (NCT00059839) study, despite a different chemotherapy backbone.[12]

Prognostic Factors

Refer to the Prognosis and Prognostic Factors for Childhood NHL section of this summary for information on prognostic factors for anaplastic large cell lymphoma.

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%.[13-18]

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.[19]
  2. GER-GPOH-NHL-BFM-90: Prephase plus three cycles of chemotherapy (only for completely resected disease).[14]
  3. APO regimen: Doxorubicin, prednisone, and vincristine.[15] 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.[20] 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).[19]
    • 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.[21][Level of evidence: 2A]
    • 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 (81%) and overall survival (OS) (97%) rates for patients without complete resection 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]).[14,22,23]; [20][Level of evidence: 1iiA] 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.[22][Level of evidence: 1iiC] However, methotrexate 3 g/m2 over 3 hours had less toxicity than methotrexate 1 g/m2 over 24 hours.[22]; [20][Level of evidence: 1iiDi]
    • 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.[23][Level of evidence: 1iiDi] 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.[12]
  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.[15]
  6. The Italian Association of Pediatric Hematology/Oncology group used a leukemia-like regimen for 24 months in the LNH-92 trial, with results similar to those of other regimens, although the duration of first remission was prolonged by the longer therapy.[16]
  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.[17][Level of evidence: 2A]

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% confidence interval [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.[24]

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 is 40% to 60%.[25-28]

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).[29]
  2. Vinblastine.[30]
  3. Brentuximab.[31]; [32][Level of evidence: 2Div]
  4. Crizotinib [33] and other ALK inhibitors (e.g., alectinib).[34]
  5. Allogeneic or autologous stem cell transplantation (SCT).[35-37]

Although remissions can be achieved with single-agent therapy (e.g., vinblastine, brentuximab, or crizotinib), CNS progressions after therapy have been observed in patients with recurrent anaplastic large cell lymphoma. In one series, four of five patients who developed CNS progressions achieved complete remissions with either radiation therapy or high-dose methotrexate.[38]

Chemotherapy, followed by autologous SCT or allogeneic SCT, if remission can be achieved, has been employed in this setting.[26,27,35,36,39]

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:[30][Level of evidence: 3iiiA]
      • 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.[40]
      • 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.[33,41][Level of evidence: 2Div]
      • Although complete responses are common, the duration of therapy remains unclear.[42][Level of evidence: 3iiiDiii]
      • The most common adverse event was neutropenia.[41]
    2. Alectinib is a second-generation ALK inhibitor that showed superiority over crizotinib in phase III studies for patients with ALK-mutant non-small cell lung cancer.[43]
      • 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.[34]
  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 were administered 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.[31]
      • Complete remission rates of approximately 55% to 60% and partial remission rates of 29% were observed.[31]
      • For the 38 patients who achieved a complete remission (28 ALK-negative patients, 10 ALK-positive patients), the 5-year progression-free survival (PFS) rate was 79%, and the OS rate was 57%. PFS was similar for ALK-positive and ALK-negative patients.[44]
      • Sixteen patients (11 ALK-negative patients, 5 ALK-positive patients) remained in remission without the start of new therapy other than consolidative SCT 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 SCT, and one received no therapy other than brentuximab vedotin.[44]
  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.[32][Level of evidence: 2Div]
      • 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 SCT):

  1. A retrospective study of relapsed or refractory anaplastic large cell lymphoma in patients who received BFM-type first-line therapy, reinduction chemotherapy, followed by autologous SCT reported the following:[27][Level of evidence: 2A]
    • A 5-year EFS rate of 59% and an OS rate of 77%. However, outcome of patients with bone marrow or CNS involvement, relapse during first-line therapy, or CD3-positive anaplastic large cell lymphoma was poor. These patients may benefit from allogeneic transplantation.
  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 SCT. Relapsed patients with CD3-positive disease received less-intense multiagent chemotherapy and allogeneic SCT (recommended therapy) or autologous SCT if no donors were available. Relapsed patients with CD3-negative disease (<1 year from diagnosis) received less-aggressive chemotherapy and autologous SCT. Relapsed patients with CD3-negative disease (>1 year from diagnosis) received single-agent vinblastine for 2 years.[28] 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 SCT achieved the best results (i.e., long-term EFS rate, 65%).
    • Patients who received autologous SCT 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 SCT may result in better outcome for refractory/relapsed anaplastic large cell lymphoma.[35,37,39,45]

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, refer to the ClinicalTrials.gov website.

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

  • COG-ANHL12P1 (NCT01979536) (A Randomized Phase II study of Brentuximab Vedotin and Crizotinib in Patients with Newly Diagnosed Anaplastic Large Cell Lymphoma): This is a feasibility study for safety and toxicity. Patients are randomly assigned to receive crizotinib or brentuximab vedotin in combination with the FRE-IGR-ALCL99 regimen of dexamethasone, cyclophosphamide, ifosfamide, etoposide, doxorubicin, IV methotrexate (3 g/m2 arm), cytarabine, prednisolone, and vinblastine.
  • 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 using a next-generation sequencing targeted assay of more than 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
    Tumor tissue from progressive or recurrent disease must be available for molecular characterization. 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,[46,47] and two patients with ALK-positive anaplastic large cell lymphoma treated with the checkpoint inhibitor nivolumab achieved complete responses.[48,49] 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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  33. 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. [PMC free article: PMC3730818] [PubMed: 23598171]
  34. Fukano R, Mori T, Sekimizu M, et al.: Alectinib for relapsed or refractory anaplastic lymphoma kinase-positive anaplastic large cell lymphoma: An open-label phase II trial. Cancer Sci 111 (12): 4540-4547, 2020. [PMC free article: PMC7734006] [PubMed: 33010107]
  35. Gross TG, Hale GA, He W, et al.: Hematopoietic stem cell transplantation for refractory or recurrent non-Hodgkin lymphoma in children and adolescents. Biol Blood Marrow Transplant 16 (2): 223-30, 2010. [PMC free article: PMC2911354] [PubMed: 19800015]
  36. Strullu M, Thomas C, Le Deley MC, et al.: Hematopoietic stem cell transplantation in relapsed ALK+ anaplastic large cell lymphoma in children and adolescents: a study on behalf of the SFCE and SFGM-TC. Bone Marrow Transplant 50 (6): 795-801, 2015. [PubMed: 25822227]
  37. 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. [PMC free article: PMC6759733] [PubMed: 31511228]
  38. Ruf S, Hebart H, Hjalgrim LL, et al.: CNS progression during vinblastine or targeted therapies for high-risk relapsed ALK-positive anaplastic large cell lymphoma: A case series. Pediatr Blood Cancer 65 (6): e27003, 2018. [PubMed: 29512859]
  39. 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. [PubMed: 16611309]
  40. Gambacorti-Passerini C, Messa C, Pogliani EM: Crizotinib in anaplastic large-cell lymphoma. N Engl J Med 364 (8): 775-6, 2011. [PubMed: 21345110]
  41. 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. [PMC free article: PMC5617123] [PubMed: 28787259]
  42. 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. [PubMed: 26736010]
  43. 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. [PubMed: 28586279]
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  47. 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. [PubMed: 31383967]
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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 after transplantation (solid organ transplant or allogeneic hematopoietic stem cell transplantation [HSCT]). Epstein-Barr virus (EBV) is associated with most of these tumors, but some tumors are not associated with any infectious agent.

Clinical Presentation

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

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 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 stem cell transplantation (SCT).

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: 3iiiA] Recurrences in these patients are common and may not represent the same clonal disease.[6] Immunologic correction through allogeneic SCT 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 the majority of 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 5-year to 10-year survival rates 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, 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/leukemia, 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, and 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/leukemia 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.[22-24]
  4. For EBV-positive B-cell PTLD, low-dose chemotherapy with or without rituximab.[19]; [25][Level of evidence: 3iiDiii]

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: 3iiiA]
    • Approximately 70% of the patients who received rituximab survived.
    • Survival was also associated with reduction of immunosuppression, but older age, extranodal disease, and acute GVHD were predictors of poor outcome.

(Refer to the Posttransplantation Lymphoproliferative Disorder [PTLD] section in the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information.)

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: 2A] 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: 3iiDiii] Patients with T-cell or Hodgkin-like PTLD are usually treated with standard lymphoma-specific chemotherapy regimens.[28-31]

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 SCT.

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 transplantation.[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 who had either progressed during rituximab treatment, not fully responded to rituximab treatment, or had a recurrence 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, refer to 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.

References

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  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. [PubMed: 21923652]
  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. [PMC free article: PMC4088002] [PubMed: 16688815]
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  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. [PubMed: 8607435]
  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. [PubMed: 11719381]
  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. [PubMed: 22935659]
  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. [PubMed: 28926410]
  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. [PubMed: 7743481]
  18. Collins MH, Montone KT, Leahey AM, et al.: Autopsy pathology of pediatric posttransplant lymphoproliferative disorder. Pediatrics 107 (6): E89, 2001. [PubMed: 11389287]
  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. [PMC free article: PMC3484187] [PubMed: 22883417]
  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. [PMC free article: PMC5693631] [PubMed: 28759103]
  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. [PubMed: 23771985]
  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. [PubMed: 11196263]
  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. [PubMed: 21446044]
  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. [PubMed: 19459198]
  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. [PubMed: 16170157]
  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. [PubMed: 10562971]
  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. [PubMed: 31062898]
  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. [PMC free article: PMC3419753] [PubMed: 17051534]
  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. [PubMed: 17318876]
  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. [PubMed: 15009846]
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  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. [PMC free article: PMC3012598] [PubMed: 20826724]
  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. [PMC free article: PMC6994129] [PubMed: 31689242]

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 most recent 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 pathologic 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 stem cell transplantations. 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.[1] The genetic hallmark of adult follicular lymphoma is t(14;18)(q32;q21) involving BCL2; however, this translocation must be excluded to make the diagnosis of pediatric-type follicular lymphoma.[1,5-7]

Pediatric-type follicular lymphoma predominantly occurs in males, is associated with a high proliferation rate, and is more likely to be localized disease.[5,8,9] 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.[1,5,7,9,10] Limited-stage disease is observed with pediatric-type follicular lymphoma, with cervical lymph nodes and tonsils as common sites, but disease has also occurred in extranodal sites such as the testis, kidney, gastrointestinal tract, and parotid gland.[5-7,10-12]

Tumor biology

Genomics of pediatric-type follicular lymphoma

Pediatric-type follicular lymphoma appears to be molecularly distinct from follicular lymphoma that is more commonly observed in adults. The pediatric type lacks BCL2 and IRF4 rearrangements, resulting in IRF4/MUM1 expression. BCL6 and MYC rearrangements are also not present.[13] The TNFSFR14 mutations are common in pediatric-type follicular lymphoma, and they appear to occur with similar frequency in adult follicular lymphoma.[9,14] However, MAP2K1 mutations, 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 mutated in cases without MAP2K1 mutations, suggesting that the MAP kinase pathway is important in the pathogenesis of pediatric-type follicular lymphoma.[15,16] Mutations in IRF8 and abnormalities in chromosome 1p have also been observed in pediatric-type follicular lymphoma.[14,17,18]

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%.[5,7-10,12] Unlike in adult follicular lymphoma, the clinical course in pediatric patients is not dominated by relapses.[5,7,10,11]

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).[2,5,8,9] 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 (refer to the Follicular Lymphoma section in the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information).

For patients with BCL2-rearranged tumors, treatment similar to that of adult patients with follicular lymphoma is administered (refer to the Follicular Lymphoma section in the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information).

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.[19,20]

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.[20,21]

Most pediatric patients with marginal zone lymphomas require no more than local therapy involving curative surgery and/or radiation therapy.[19,22] 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:[23][Level of evidence: 3iiiA]
    • The overall 5-year EFS rate was 70%.
    • The OS rate was 98%.
    • 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 stem cell transplantation; 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 (refer to the Marginal Zone Lymphoma section in the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information).

Intralesional interferon-alpha for conjunctival MALT lymphoma has been studied in trials.[24]

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 lymphoma. 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.[25-28]

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.
  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.[29]

There are case reports describing the administration of repeated doses of intraventricular rituximab in patients with refractory primary CNS lymphoma, with excellent results reported.[30,31] 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.[32,33]

(Refer to the PDQ summary on Primary CNS Lymphoma Treatment for more information about treatment options for non–AIDS-related primary CNS lymphoma.)

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, 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.[34-38]

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).[39] The incidence varies by region; the incidence is between 3% and 10% in Asian countries and 1% in western countries.[40] The common primary tumor sites are the nasal cavity and paranasal sinuses.[41] 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 transplantation (HSCT) and 11.1% for patients who did not receive HSCT (P = .054).[42][Level of evidence: 3iii]

Although very rare, gamma-delta hepatosplenic T-cell lymphoma may be seen in children.[37] 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.[43]

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:[34]
    • 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.[35]
    • 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.[44]
    • 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.[37][Level of evidence: 3iiiDiii]
    • Patients with peripheral T-cell lymphoma–not otherwise specified (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.

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.[45]

Subcutaneous panniculitic T-cell lymphomas are very rare lymphomas with panniculitis-like infiltration of subcutaneous tissue by cytotoxic T-cells.[46-48] Subcutaneous panniculitic T-cell lymphoma 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 subcutaneous panniculitic T-cell lymphoma is associated with a more aggressive course and a worse prognosis than is the alpha-beta subtype of subcutaneous panniculitic T-cell lymphoma.[49] Morbidity and mortality are frequently related to the development of hemophagocytic syndrome, which was reported in one series in adults to occur in 17% of patients with alpha-beta subcutaneous panniculitic T-cell lymphoma and in 45% of patients with gamma-delta subcutaneous panniculitic T-cell lymphoma. The 5-year OS rate is 82% for patients with alpha-beta subcutaneous panniculitic T-cell lymphoma and 11% for patients with gamma-delta subcutaneous panniculitic T-cell lymphoma.[49] Subcutaneous panniculitic T-cell lymphoma is heterogeneous in the pediatric age group and does not necessarily follow the course that is observed in adults. In a series of 11 pediatric patients with subcutaneous panniculitis-like T-cell lymphoma, most presented with multifocal disease (often on the trunk) and systemic symptoms (fever), and there was a frequent association with hemophagocytic syndrome.[50]

The diagnosis of primary cutaneous anaplastic large cell lymphoma can be difficult to distinguish pathologically from more benign diseases such as lymphomatoid papulosis.[51] Primary cutaneous lymphomas are now thought to represent a spectrum of disorders, distinguished by clinical presentation.

Mycosis fungoides is rarely reported in children and adolescents,[52 -54] accounting for about 2% of all cases. Patients present with low-stage disease, and it appears that the hypopigmented, CD8-positive variant of mycosis fungoides is more common in children than in adults.[55]; [56][Level of evidence: 3iiiDii] In one study of 23 pediatric patients, the median age of onset was 9 years, and the median age of diagnosis was 11 years. Patients were primarily treated with topical corticosteroids and phototherapy; 59.1% of patients achieved a complete remission, and 40.9% of patients achieved a partial response. Only two patients remained asymptomatic for 5 years.[57][Level of evidence: 3iiiDiv] (Refer to the PDQ summary on Mycosis Fungoides [Including Sézary Syndrome] Treatment for information about the treatment of adult patients.)

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.[58]

The best treatment for patients who have T-cell lymphomas with primarily pannicular involvement is not known. Treatment options include high-dose steroids, bexarotene, denileukin diftitox, multiagent chemotherapy, and HSCT.[48,58-63]

An oral retinoid (bexarotene) has been reported to be active against subcutaneous panniculitis-like T-cell lymphomas in a series of 15 patients from three institutions.[60] 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.[50] In general, however, the optimal therapy for non–anaplastic large cell lymphoma cutaneous T-cell lymphoma in childhood is unclear.

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.[64] 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.[65,66]

Mycosis fungoides occurring in pediatric patients may respond to various therapies, including topical steroids, retinoids, radiation therapy, or phototherapy (e.g., narrow-band ultraviolet B treatment), but remission may not be durable.[55,67-69]

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Changes to This Summary (11/12/2021)

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.

This summary was reformatted.

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® - NCI's Comprehensive Cancer Database 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:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

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:

  • 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)
  • 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)
  • Nita Louise Seibel, MD (National Cancer Institute)
  • Malcolm A. Smith, MD, PhD (National Cancer Institute)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

PDQ® Pediatric Treatment Editorial Board. PDQ Childhood 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]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.

Copyright Notice
Bookshelf ID: NBK65738PMID: 26389181

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