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PDQ Cancer Information Summaries [Internet].

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Childhood Non-Hodgkin Lymphoma Treatment (PDQ®)

Health Professional Version

.

Published online: August 6, 2019.

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 45% to 87% in children younger than 15 years and from 48% to 82% for adolescents aged 15 to 19 years.[1] 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, the vast majority of NHL cases occurring in childhood and adolescence fall into three categories:

  1. Aggressive mature B-cell NHL (Burkitt and Burkitt-like 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.[2,3]

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

  • 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.[4]
  • Race: The incidence of NHL is higher in whites than in African Americans, and Burkitt lymphoma/leukemia is more common in non-Hispanic whites (3.2 cases/million person-years) than in Hispanic whites (2.0 cases/million person-years).[5]
  • Age: Although there is no sharp age peak, childhood NHL occurs most commonly in the second decade of life, and occurs infrequently in children younger than 3 years.[2] NHL in infants is very rare (1% in Berlin-Frankfurt-Münster [BFM] trials from 1986 to 2002).[6] The incidence of NHL is increasing overall because of a slight increase in the incidence for those aged 15 to 19 years; however, the incidence of NHL in children younger than 15 years has remained constant over the past several decades.[2]
  • 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.[2,7] A review of Surveillance, Epidemiology, and End Results (SEER) 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).[2] 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.[2]

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.[2]

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 seen in the immunodeficient population.[2] Almost all Burkitt lymphoma/leukemia is associated with EBV in endemic Africa; however, approximately 15% of cases in Europe and the United States will have EBV detectable in the tumor tissue.[8]
  • Immunodeficiency: Immunodeficiency, both congenital and acquired (HIV or posttransplant immunodeficiency), increases the risk of NHL.[2,3] U.S. transplant and cancer registries show that posttransplant lymphoproliferative disease (PTLD) accounts for about 3% of all pediatric NHL diagnoses; and that 65% of PTLDs are diffuse large B-cell lymphoma histology, and 9% are Burkitt histology.[9]
  • 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.[10]
  • 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 of whom (0.3%) were later diagnosed with NHL as a subsequent neoplasm before age 19 years.[11] In this small cohort, outcomes were similar to those for patients with de novo NHL who were treated with standard therapy.[11]

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.[3] For example, 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.[12,13] 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 exam.
  • 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.
  • 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.[14]

Prognostic factors for childhood NHL include the following:

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.[15-17]

  • 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) of 30%.[18,19]
  • 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.[20]

International pediatric NHL response criteria have been proposed but require prospective evaluation. The clinical utility of these new criteria are under investigation.[21]

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

  • Burkitt lymphoma/leukemia: One study suggests an inferior outcome for patients with Burkitt lymphoma/leukemia who had detectable MRD after induction chemotherapy.[22] 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 blood or bone marrow at diagnosis.[23,24]
  • T-cell lymphoblastic lymphoma: In a small study, one of ten patients had measurable MRD at the end of induction, and this was the only patient who relapsed.[25]
  • 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.[26][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 (a 5-year survival rate of approximately 90%), regardless of histology.[18,20,27-30] Apart from this finding, the outcome by clinical stage, if the correct therapy is given, does not differ significantly.

A surrogate for tumor burden (i.e., elevated levels of LDH) has been shown to be prognostic in many studies.[18,28,31,32]

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 suggests MDD is predictive of outcome,[33,34] while another study does not.[23]
  • T-cell lymphoblastic lymphoma: A Children's Oncology Group (COG) study demonstrated a 2-year EFS of 91% for patients who had an MDD level by flow cytometry lower than 1%, compared with 68% if the MDD level exceeded 1%, and 52% if the MDD was 5% and higher.[35] This has been confirmed by others.[36]
  • Anaplastic large cell lymphoma: In a retrospective subset analysis of children with anaplastic large cell lymphoma, MDD detected by RT-PCR for the NPM-ALK gene transcript could be found in 57% of patients at diagnosis and correlated with clinical stage.[37] The presence of MDD was associated with a 46% cumulative incidence of relapse, compared with a 15% cumulative incidence of relapse in patients with no bone marrow involvement.[37] Patients with MDD who achieved MRD-negative status before their second course of therapy had an intermediate EFS (69%) compared with MDD-negative patients (82%) and patients with both MDD and MRD-positive status (19%).[37]
    The presence of MDD is significantly associated with uncommon histologic subtypes containing small cell and/or lymphohistiocytic components.[37]

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.[19,20,38] Although these intensive therapies produce improved outcomes, patients who present with CNS disease continue to have the worst outcomes.[19,20,38,39] Patients with mature B-cell lymphoma/leukemia with CNS disease at presentation have a 3-year EFS of around 70%, while those with bone marrow involvement alone have a 3-year EFS of 90%.[19,28,32] The combination of CNS involvement and bone marrow disease appears to impact outcome the most.[19]
  • Mediastinum: Mediastinal involvement in children and adolescents with nonlymphoblastic NHL results in an inferior outcome.[14,18,28,32] In children and young adults with primary mediastinal B-cell lymphoma, series have reported a 3-year EFS of 50% to 70%.[28,31,32,40] However, studies using the dose-adjusted (DA)–EPOCH protocol (etoposide, prednisone, vincristine, and doxorubicin) with rituximab have reported an EFS higher than 80%.[41,42]
  • 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.[43] In a subsequent study analysis from EICNHL utilizing biologic risk factors, the clinical risk features were not found to be significant.[44] In the CCG-5941 (NCT00002590) study for anaplastic large cell lymphoma patients, these clinical risk factors could not be confirmed; only bone marrow involvement predicted inferior progression-free survival (PFS).[45][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.[46,47]
  • Testicle: Testicular involvement does not affect prognosis.[20,27,48]
  • Head and Neck: For 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.[13]
  • Skin: The prognostic implication of skin involvement is limited to anaplastic large cell lymphoma and depends on whether the disease is localized to skin. ALK-negative, skin-limited anaplastic large cell lymphoma appears 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.[44,45]

Age

NHL in infants is rare (1% in BFM trials from 1986 to 2002).[6] In this retrospective review, the outcome for infants was inferior compared with the outcome for older patients with NHL.[6]

Adolescents have been reported to have outcomes inferior to those of younger children.[12,14,49,50] 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, compared with younger children with these diagnoses.[14,50] On the other hand, for patients with Burkitt and Burkitt-like lymphoma/leukemia who were treated on the FAB/LMB-96 (COG-C5961) clinical trial, adolescent age (≥15 years) was not an independent risk factor for inferior outcome.[32]

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.[51] 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 a PFS of 28% (low risk), 68% (intermediate risk), and 93% (all remaining patients) (P < .0001).[44]

References

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  32. 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]
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  34. Pillon M, Mussolin L, Carraro E, et al.: Detection of prognostic factors in children and adolescents with Burkitt and Diffuse Large B-Cell Lymphoma treated with the AIEOP LNH-97 protocol. Br J Haematol 175 (3): 467-475, 2016. [PubMed: 27392319]
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  38. 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]
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  42. 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]
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  45. 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]
  46. 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]
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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.[1-3] The World Health Organization (WHO) classifies NHL according to the following features:[3]

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

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

  1. Mature B-cell NHL: Burkitt and Burkitt-like lymphoma/leukemia, diffuse large B-cell lymphoma, and primary mediastinal B-cell lymphoma.
    Compared with treatments for adults, aggressive Burkitt regimens in pediatrics have been used to treat both Burkitt lymphoma/leukemia and large B-cell histologies, resulting in no difference in outcome based on histology.[4-8] The exception is primary mediastinal B-cell lymphoma, which has had an inferior outcome with these regimens.[4-7,9,10]
    For pediatric Burkitt lymphoma/leukemia patients, secondary cytogenetic abnormalities, other than MYC rearrangement, are associated with an inferior outcome,[11,12] and cytogenetic abnormalities involving gain of 7q or deletion of 13q appeared to have an inferior outcome on the FAB/LMB-96 chemotherapy protocol.[12,13] For pediatric patients with diffuse large B-cell lymphoma and chromosomal rearrangement at MYC (8q24), outcome appeared to be worse.[12]
    A subset of pediatric diffuse large B-cell lymphoma cases were found to have a translocation that juxtaposes the IRF4 oncogene next to one of the immunoglobulin loci and has been associated with favorable prognosis compared with diffuse large B-cell lymphoma cases lacking this finding.[14]
  2. Lymphoblastic lymphoma: Primarily precursor T-cell lymphoma and, less frequently, precursor B-cell lymphoma.
    For pediatric patients with T-cell lymphoblastic lymphoma, the Berlin-Frankfurt-Münster group reported that loss of heterozygosity (LOH) at chromosome 6q was observed in 12% of patients (25 of 217) and was associated with unfavorable prognosis (probability of event-free survival [pEFS], 27% vs. 86%, P < .0001).[15,16] NOTCH1 mutations were seen in 60% of patients (70 of 116) and were associated with favorable prognosis (pEFS, 84% vs. 66%; P = .021). NOTCH1 mutations were rarely seen in patients with LOH at 6q.[15]
  3. Anaplastic large cell lymphoma: 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.[17-19] In a 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.[20]
    In the COG-ANHL0131 (NCT00059839) study, despite a different chemotherapy backbone, the small cell variant of anaplastic large cell lymphoma, as well as other histologic variants, had a significantly increased risk of failure.[19]

Refer to the following sections of this summary for more information about the tumor biology associated with each type of NHL:

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.[1,3]

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 locusIRF4
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; LOH = loss of heterozygosity; 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 occur rarely 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.[3]

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. Bethesda, Md: National Cancer Institute, SEER Program, 1999. NIH Pub.No. 99-4649, pp 35-50. Also available online. Last accessed April 12, 2019.
  2. Sandlund JT, Downing JR, Crist WM: Non-Hodgkin's lymphoma in childhood. N Engl J Med 334 (19): 1238-48, 1996. [PubMed: 8606720]
  3. 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]
  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. Reiter A, Schrappe M, Tiemann M, et al.: Improved treatment results in childhood B-cell neoplasms with tailored intensification of therapy: A report of the Berlin-Frankfurt-Münster Group Trial NHL-BFM 90. Blood 94 (10): 3294-306, 1999. [PubMed: 10552938]
  10. Gerrard M, Waxman IM, Sposto R, et al.: Outcome and pathologic classification of children and adolescents with mediastinal large B-cell lymphoma treated with FAB/LMB96 mature B-NHL therapy. Blood 121 (2): 278-85, 2013. [PMC free article: PMC3544113] [PubMed: 23149845]
  11. Onciu M, Schlette E, Zhou Y, et al.: Secondary chromosomal abnormalities predict outcome in pediatric and adult high-stage Burkitt lymphoma. Cancer 107 (5): 1084-92, 2006. [PubMed: 16862570]
  12. Poirel HA, Cairo MS, Heerema NA, et al.: Specific cytogenetic abnormalities are associated with a significantly inferior outcome in children and adolescents with mature B-cell non-Hodgkin's lymphoma: results of the FAB/LMB 96 international study. Leukemia 23 (2): 323-31, 2009. [PMC free article: PMC2988438] [PubMed: 19020548]
  13. Nelson M, Perkins SL, Dave BJ, et al.: An increased frequency of 13q deletions detected by fluorescence in situ hybridization and its impact on survival in children and adolescents with Burkitt lymphoma: results from the Children's Oncology Group study CCG-5961. Br J Haematol 148 (4): 600-10, 2010. [PMC free article: PMC2921871] [PubMed: 19895612]
  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. Bonn BR, Rohde M, Zimmermann M, et al.: Incidence and prognostic relevance of genetic variations in T-cell lymphoblastic lymphoma in childhood and adolescence. Blood 121 (16): 3153-60, 2013. [PubMed: 23396305]
  16. Burkhardt B, Moericke A, Klapper W, et al.: Pediatric precursor T lymphoblastic leukemia and lymphoblastic lymphoma: Differences in the common regions with loss of heterozygosity at chromosome 6q and their prognostic impact. Leuk Lymphoma 49 (3): 451-61, 2008. [PubMed: 18297521]
  17. Stein H, Foss HD, Dürkop H, et al.: CD30(+) anaplastic large cell lymphoma: a review of its histopathologic, genetic, and clinical features. Blood 96 (12): 3681-95, 2000. [PubMed: 11090048]
  18. Brugières L, Le Deley MC, Rosolen A, et al.: Impact of the methotrexate administration dose on the need for intrathecal treatment in children and adolescents with anaplastic large-cell lymphoma: results of a randomized trial of the EICNHL Group. J Clin Oncol 27 (6): 897-903, 2009. [PubMed: 19139435]
  19. Alexander S, Kraveka JM, Weitzman S, et al.: Advanced stage anaplastic large cell lymphoma in children and adolescents: results of ANHL0131, a randomized phase III trial of APO versus a modified regimen with vinblastine: a report from the children's oncology group. Pediatr Blood Cancer 61 (12): 2236-42, 2014. [PMC free article: PMC4682366] [PubMed: 25156886]
  20. Lamant L, McCarthy K, d'Amore E, et al.: Prognostic impact of morphologic and phenotypic features of childhood ALK-positive anaplastic large-cell lymphoma: results of the ALCL99 study. J Clin Oncol 29 (35): 4669-76, 2011. [PubMed: 22084369]

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. Radionuclide bone scans may be considered for patients in whom bone involvement is suspected.

The role of functional imaging in pediatric NHL is controversial. 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 Harmonization Project for PET (now called the International Working Group) 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]
  • It has been 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 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 outcome for lymphoblastic lymphoma was superior with longer acute lymphoblastic leukemia–like therapy, while nonlymphoblastic NHL (Burkitt lymphoma/leukemia) had superior outcome with short, intensive, pulsed therapy; the large cell lymphoma outcome was similar with either approach.[8]

Outcomes for recurrent NHL in children and adolescents remain very poor, with the exception of anaplastic large cell lymphoma.[9-13] 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 and Burkitt-like lymphoma/leukemiaNewly diagnosedSurgery (for stage I and II only)
Chemotherapy with or without rituximab
RecurrentChemotherapy with or without rituximab
Allogeneic or autologous SCT
Diffuse large B-cell lymphomaNewly diagnosedSurgery (for stage I and II only)
Chemotherapy with or without rituximab
RecurrentChemotherapy with or without rituximab
Allogeneic or autologous SCT
Primary mediastinal B-cell lymphomaChemotherapy and rituximab
Lymphoblastic lymphomaNewly diagnosedChemotherapy
Cranial radiation therapy for overt CNS disease only
RecurrentNelarabine or nelarabine-containing chemotherapy regimens
Chemotherapy
Allogeneic SCT
Anaplastic large cell lymphomaNewly diagnosedSurgery followed by chemotherapy (for stage I)
Chemotherapy
RecurrentChemotherapy, brentuximab, and/or crizotinib
Allogeneic or autologous SCT
Lymphoproliferative disease associated with immunodeficiency:
Lymphoproliferative disease associated with primary immunodeficiencyChemotherapy with or without rituximab
Allogeneic SCT
NHL associated with DNA repair defect syndromesChemotherapy
HIV-associated NHLChemotherapy 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 lymphomaSurgery only
Chemotherapy with or without rituximab
Marginal zone lymphomaSurgery only
Radiation therapy
Rituximab with or without chemotherapy
Antibiotic therapy, for MALT lymphoma
Primary CNS lymphomaChemotherapy
Peripheral T-cell lymphomaChemotherapy
Radiation therapy
Allogeneic or autologous SCT
Cutaneous T-cell lymphomaNo standard treatments have been established

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 or Burkitt-like 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.[14]

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.[15,16] 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.[17]

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. Most procedures, including CT and echocardiography, can be performed with the patient on his or her side or prone. 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 obtained 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 a number of 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.[18-23] 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.[24-26] Data also demonstrate that PET scanning can produce false-negative results.[27] 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.[28] 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.[29]

Special Considerations for the Treatment of Children With Cancer

Cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975.[30] 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 surgical 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.)

Guidelines for pediatric cancer centers and their role in the treatment of children with cancer have been outlined by the American Academy of Pediatrics.[31] 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 in these trials is offered to most patients/families. Clinical trials for children and adolescents with cancer are generally designed to compare therapy that is accepted as the best currently available therapy (standard therapy) with potentially better 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. 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. 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]
  15. 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]
  16. 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]
  17. Prakash UB, Abel MD, Hubmayr RD: Mediastinal mass and tracheal obstruction during general anesthesia. Mayo Clin Proc 63 (10): 1004-11, 1988. [PubMed: 3172849]
  18. 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]
  19. 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]
  20. Cairo MS, Bishop M: Tumour lysis syndrome: new therapeutic strategies and classification. Br J Haematol 127 (1): 3-11, 2004. [PubMed: 15384972]
  21. 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]
  22. 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]
  23. 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]
  24. 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]
  25. 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]
  26. 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]
  27. 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]
  28. 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]
  29. 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]
  30. 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]
  31. Corrigan JJ, Feig SA; American Academy of Pediatrics: Guidelines for pediatric cancer centers. Pediatrics 113 (6): 1833-5, 2004. [PubMed: 15173520]

Aggressive Mature B-cell NHL

Burkitt and Burkitt-like Lymphoma/Leukemia

Incidence

In the United States, Burkitt and Burkitt-like lymphoma/leukemia account for about 40% of childhood non-Hodgkin lymphoma (NHL) and exhibit a consistent, aggressive clinical behavior.[1-3] 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).[2,4] (Refer to Table 1 for more information about the incidence of Burkitt lymphoma by age and sex distribution.)

Tumor biology

The malignant cells show a mature B-cell phenotype and are negative for the enzyme terminal deoxynucleotidyl transferase. These malignant cells usually express surface immunoglobulin, most bearing a clonal surface immunoglobulin M 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 and Burkitt-like lymphomas/leukemias express CALLA (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 immunoglobulin locus regulatory elements, resulting in the inappropriate expression of MYC, a gene involved in cellular proliferation.[3,5,6] The presence of one of the variant translocations t(2;8) or t(8;22) does not appear to affect response or outcome.[7]

While MYC translocations are present in all Burkitt lymphoma, cooperating genomic alterations appear to be required for lymphoma development. 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.[8-11]
  • Mutations in TP53 are observed in one-third to one-half of cases.[8,10]
  • Mutations in cyclin D3 (CCND3) are commonly observed in sporadic Burkitt lymphoma (approximately 40% of cases) but are rare in endemic Burkitt lymphoma.[8,10]
  • Mutations in MYC itself are observed in approximately one-half of Burkitt lymphoma cases and appear to increase MYC stability.[8,12]

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, apoptosis, CCND3, and TP53.[13]

The distinction between Burkitt and Burkitt-like lymphoma/leukemia is controversial. Burkitt lymphoma/leukemia consists of uniform, small, noncleaved cells, whereas the diagnosis of Burkitt-like lymphoma/leukemia is highly disputed among pathologists because of features that are consistent with diffuse large B-cell lymphoma.[14]

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.[15]

Studies have demonstrated that the vast majority of Burkitt-like or atypical Burkitt lymphoma/leukemia cases have a gene expression signature similar to Burkitt lymphoma/leukemia.[16,17] Additionally, as many as 30% of pediatric diffuse large B-cell lymphoma cases will have a gene signature similar to Burkitt lymphoma/leukemia.[16,18]

Burkitt-like lymphoma with 11q aberration was added as a provisional entity in the 2017 revised WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues.[14] 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.[19,20] Most patients present in the adolescent and young adult age range with localized nodal disease, and outcomes appear favorable in the small number of cases identified. Cases show a very high proliferative index and can show a focal starry sky pattern. 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.[19] 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.

Clinical presentation

The most common primary sites of disease are the abdomen and the lymphatic tissue of Waldeyer ring.[3,4] 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.

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 and Burkitt-like lymphoma/leukemia

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

Unlike mature B-lineage NHL seen in adults, there is no difference in outcome based on histology (Burkitt or Burkitt-like lymphoma/leukemia or diffuse large B-cell lymphoma). Pediatric Burkitt and Burkitt-like lymphoma/leukemia and diffuse large B-cell lymphoma are clinically very aggressive and are treated with very intensive regimens.[21-25]

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]

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

StratumDisease Manifestation
FAB/LMB International Study [22,23,26]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 [27]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 = Lymphomes Malins B; 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 (NCT01595048).[22]

The following studies have contributed to the development of current treatment regimens for pediatric Burkitt and Burkitt-like 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 (completely resected disease) with two cycles of multiagent chemotherapy (GER-GPOH-NHL-BFM-90 and GER-GPOH-NHL-BFM-95).[21,27] For unresected stage I or stage II disease (R2), patients received a cytoreductive phase followed by five cycles of chemotherapy.[21,27]
      • In the NHL-BFM-90 study, it was shown that reducing the dose of methotrexate did not affect the results for low-stage disease.[27]
      • In the NHL-BFM-95 study, it was demonstrated that prolonging the duration of methotrexate infusion did not improve outcome for patients with low-stage disease.[21]
      • Event-free survival (EFS) with best therapy in NHL-BFM-95 was more than 95% for R1 and R2 group patients.[21]
    2. Advanced/disseminated disease (R3 and R4 groups): In the NHL-BFM-95 study, reducing the infusion time of methotrexate from 24 hours to 4 hours for R3 and R4 group patients resulted in less mucositis, but inferior outcome.[21]
      • EFS with best therapy in NHL-BFM-95 was 93% for R3 and R4 group patients.[21]
      • Inferior outcome was observed for patients with CNS disease at presentation (70% 3-year EFS).[27]
  2. French Society of Pediatric Oncology Lymphomes Malins B (LMB) and French-American British (FAB) studies
    1. Localized disease (group A): Patients with completely resected stage I and abdominal stage II (group A) disease who received two cycles of multiagent chemotherapy, without intrathecal chemotherapy or rituximab had an excellent outcome (COG-C5961 [FAB/LMB-96]).[26][Level of evidence: 2A]
      • The 3-year EFS was 98% for stage I or stage II.[22]
    2. Advanced disease (group B): For unresected stage I through IV disease (without CNS or leukemic disease), the above-mentioned FAB/LMB-96 study demonstrated that reducing the duration of therapy to four cycles of chemotherapy after a cytoreduction phase and reducing the cumulative doses of cyclophosphamide and doxorubicin did not affect outcome.[22]
      • The 3-year EFS was 90% for stage III 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 of 86% compared with 96% in those with lower LDH levels.
    3. Disseminated disease (group C): For patients with leukemic or CNS involvement in the FAB study, reduction in the cumulative dose of therapy and the number of maintenance cycles resulted in inferior outcome.[23]
      • Patients with leukemic disease only, and no CNS disease, had a 3-year EFS of 90%, while patients with CNS disease at presentation had a 70% 3-year EFS.
      • Patients who were CNS positive but marrow negative did better, with an EFS of 82%, while those with combined marrow and CNS disease at diagnosis had an EFS 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 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]).[21-23,27]

Rituximab is a mouse/human chimeric monoclonal antibody targeting the CD20 antigen. Burkitt lymphoma/leukemia and diffuse large B-cell lymphoma both express high levels of CD20.[5]

Evidence (rituximab):

  1. Rituximab has been safely combined with standard doxorubicin, cyclophosphamide, vincristine, and prednisone (CHOP) chemotherapy and has been shown to improve outcome in a randomized trial of adults with diffuse large B-cell lymphoma (CAN-NCIC-LY9).[28] (Refer to the Standard Treatment Options for Aggressive, Noncontiguous Stage II/III/IV Adult NHL section in the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information.)
  2. In children, a single-agent phase II study of rituximab performed by the BFM group showed activity in Burkitt lymphoma/leukemia.[29][Level of evidence: 2Div]
  3. 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, despite a trend toward higher peak levels of rituximab in younger patients.
  4. An international randomized phase III trial that evaluated the benefit of adding rituximab to standard therapy was closed early.[31]
    • Superior results were observed in the rituximab arm, with 94% EFS for this high-risk group of patients (stage III with elevated LDH and stage IV).

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

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

Trial StratumDisease Manifestations Treatment
POG-8314/POG-8719/POG 9219 [32]Grossly resected stage I and II (completely resected abdominal stage II disease) Three cycles of outpatient chemotherapy (no radiation or maintenance therapy)
COG-C5961 (FAB/LMB-96) [22,23,26] COG-ANHL1131 (Inter-B-NHL Ritux 2010) [31]ACompletely resected stage I and abdominal stage II Two cycles of chemotherapy
BMultiple extra-abdominal sites Prephase + four cycles of chemotherapy (reduced-intensity arm)
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
CMature B-cell ALL (>25% blasts in marrow) and/or stage IV CNS disease Prephase + six cycles of chemotherapy (full-intensity arm) + six doses of rituximab
GER-GPOH-NHL-BFM-95 [21,27]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 = Lymphomes Malins B; NHL = non-Hodgkin lymphoma; POG = Pediatric Oncology Group.

Treatment options for recurrent Burkitt and Burkitt-like lymphoma/leukemia

There is no standard treatment option for patients with recurrent or progressive disease. For recurrent or refractory B-lineage NHL, survival is generally 10% to 30%.[23,33-37] A review of patients treated on the LMB-89, LMB-96 (NCT00002757), and LMB-2001 trials identified 67 of 1,322 patients who relapsed. A multivariate analysis demonstrated that the following factors were associated with better survival:[37]

  • One site of disease at relapse.
  • Diffuse large B-cell lymphoma histology.
  • Initial good-risk disease (i.e., group A or group B with normal LDH).
  • Duration of complete remission of more than 6 months.

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

  1. R-ICE (ifosfamide, carboplatin, and etoposide plus rituximab).[38]
  2. CYVE (high-dose cytarabine and etoposide) for relapsed group A and group B disease.[37]
  3. Allogeneic or autologous stem cell transplantation (SCT).[39,40]
  4. Bispecific antibody (anti-CD20, anti-CD3).[41]

Chemoresistance makes remission difficult to achieve.

Evidence (treatment of recurrent Burkitt and Burkitt-like 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 showed the most favorable outcomes for those 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.[42]
  2. The COG conducted a study of 20 patients (14 of whom had Burkitt lymphoma/leukemia) using R-ICE to treat relapsed/refractory B-cell NHL (Burkitt lymphoma/leukemia and diffuse large B-cell lymphoma).[38][Level of evidence: 3iiA]
    • Study results showed a complete remission/partial remission rate of 60%.
  3. The Japanese Pediatric Leukemia/Lymphoma Study Group performed a phase II study using R-ICE in 28 patients.[43]
    • The investigators observed a 70% complete and partial response rate.
  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 ifosfamide, carboplatin, and etoposide (ICE) with or without rituximab.[37]
    • 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.

If remission can be achieved, high-dose therapy plus SCT remains the best option for survival. However, the benefit of autologous versus allogeneic SCT is unclear.[35,39,44,45]; [46][Level of evidence: 2A]; [47][Level of evidence: 3iiiDii]

Patients not in remission at the time of transplant fare significantly worse.[37,39,46] The very poor outcome of patients whose disease is refractory to salvage chemotherapy suggests that a transplant option should not be pursued in these patients.[48]

(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:[39]
    • No difference using either autologous or allogeneic donor stem cell sources, with 2-year EFS of 50% for diffuse large B-cell lymphoma and 30% for Burkitt lymphoma/leukemia patients who survived to have 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 relapsed NHL.[40]
    • The study reported an EFS of 60%.

Treatment options under clinical evaluation for Burkitt/Burkitt-like 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.[2,3,49] Diffuse large B-cell lymphoma occurs more frequently during the second decade of life than during the first decade.[2,50] (Refer to Table 1 for more information on the incidence of diffuse large B-cell lymphoma by age and sex distribution.)

Tumor biology

The World Health Organization (WHO) classification system does not recommend subclassification of diffuse large B-cell lymphoma on the basis of morphologic variants (e.g., immunoblastic, centroblastic).[51]

Diffuse large B-cell lymphoma in children and adolescents differs biologically from diffuse large B-cell lymphoma in adults in the following ways:

  • The vast majority of pediatric diffuse large B-cell lymphoma cases have a germinal center B-cell phenotype, as assessed by immunohistochemical analysis of selected proteins found in normal germinal center B cells, such as the BCL6 gene product and CD10.[7,52,53] The age at which the favorable germinal center subtype changes to the less favorable nongerminal center subtype was shown to be a continuous variable.[54]
  • Pediatric diffuse large B-cell lymphoma rarely demonstrates the t(14;18) translocation involving the immunoglobulin heavy-chain gene and the BCL2 gene that is seen in adults.[52]
  • 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.[16,18]
  • 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.[18,55]
  • A subset of pediatric diffuse large B-cell lymphoma cases was found to have a translocation that juxtaposes the IRF4 oncogene next to one of the immunoglobulin loci. Diffuse large B-cell lymphoma cases with an IRF4 translocation were significantly more frequent in children than in adults (15% vs. 2%), were germinal center–derived B-cell lymphomas, and were associated with favorable prognosis compared with diffuse large B-cell lymphoma cases lacking this abnormality.[56] Large B-cell lymphoma with IRF4 rearrangement was added as a distinct entity in the 2016 revision of the WHO classification of lymphoid neoplasms.
    [57]

Clinical presentation

Pediatric diffuse large B-cell lymphoma may present in a manner clinically similar to that of Burkitt or Burkitt-like lymphoma/leukemia, although more often it is localized, and less often it involves the bone marrow or CNS.[49,50,58] (Refer to the Clinical presentation section in the Burkitt and Burkitt-like Lymphoma/Leukemia section of this summary for more information.)

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

Treatment options for recurrent diffuse large B-cell lymphoma

The treatment of recurrent diffuse large B-cell lymphoma is the same as the treatment of recurrent Burkitt and Burkitt-like lymphoma/leukemia. Refer to the Treatment options for recurrent Burkitt and Burkitt-like 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.[50,59-61]

Tumor biology

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.[62] 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 are similar to the ones seen in diffuse large B-cell lymphoma, such as CD19, CD20, CD22, CD79a, and PAX-5. Primary mediastinal B-cell lymphoma often lacks cell surface immunoglobulin expression but may display cytoplasmic immunoglobulins. CD30 expression is commonly present.[62]
  • 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 a distinctive gene expression profile compared with diffuse large B-cell lymphoma; however, its gene expression profile has features similar to those seen in Hodgkin lymphoma.[63,64] 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.

  • Structural rearrangements and copy number gains at chromosome 9p24 are common in primary mediastinal B-cell lymphoma. This region encodes the immune checkpoint genes PD-L1 (PDL1) and PD-L2 (PDCD1LG2), and the genomic alterations lead to increased expression of these checkpoint proteins.[65-67]
  • 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 lead to loss of MHC class II expression. Loss of MHC class II expression provides another mechanism of immune escape for primary mediastinal B-cell lymphoma.[68]
  • Genomic alterations involving JAK-STAT pathway genes are observed in most cases of primary mediastinal B-cell lymphoma.[69]
    • The chromosome 9p region that shows gains and amplification in primary mediastinal B-cell lymphoma encodes Janus kinase 2 (JAK2), which activates the signal transducer and activator of transcription (STAT) pathway.[60,61]
    • SOCS1, a negative regulator of JAK-STAT signaling, is inactivated in approximately 50% of primary mediastinal B-cell lymphoma by either mutation or gene deletion.[70,71]
    • The interleukin-4 receptor gene (IL4R) shows activating mutations in approximately 20% of primary mediastinal B-cell lymphoma cases, and IL4R activation leads to increased JAK-STAT pathway activity.[69]
  • Copy number gains and amplifications at 2p16.1, a region that encodes BCL11A and REL, also occur in primary mediastinal B-cell lymphoma.
    [60,61]

Clinical presentation

As the name would suggest, 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.[72]

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 of 66%, compared with 85% for adolescents with nonmediastinal diffuse large B-cell lymphoma.[73][Level of evidence: 2A] Similarly, in the NHL-BFM-95 trial, patients with primary mediastinal B-cell lymphoma had an EFS of 50% at 3 years.[21] However, a study of young adults treated with DA-EPOCH-R showed excellent disease-free survival rates.[74]

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.[74][Level of evidence: 2A]
    • The 5-year EFS was 93%, and overall survival (OS) 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.[75]
    • The study showed a 2-year OS 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:[76]
    • Pediatric patients had a 3-year EFS of 81% and a 3-year OS of 91%. These results were not significantly different from the results observed in adults.

Treatment options for refractory or relapsed 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.[77]

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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Lymphoblastic Lymphoma

Incidence

Lymphoblastic lymphoma comprises approximately 20% of childhood non-Hodgkin lymphoma (NHL).[1-3] (Refer to Table 1 for more information about the incidence of lymphoblastic lymphoma by age and sex distribution.)

Tumor Biology

Lymphoblastic lymphomas are usually positive for terminal deoxynucleotidyl transferase, with more than 75% having a T-cell immunophenotype and the remainder having a precursor B-cell phenotype.[3,4]

As opposed to pediatric acute lymphoblastic leukemia, chromosomal abnormalities and the molecular biology of pediatric lymphoblastic lymphoma are not well characterized. The Berlin-Frankfurt-Münster group reported that loss of heterozygosity at chromosome 6q was observed in 12% of patients and NOTCH1 mutations were seen in 60% of patients, but NOTCH1 mutations are rarely seen in patients with loss of heterozygosity at 6q.

[5,6]

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, bone, or subcutaneous tissue. Abdominal involvement is less than what is observed 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.[7] The debate centers on whether they truly represent the same disease.[8] It is not yet clear whether these arbitrary definitions are biologically distinct or relevant for treatment design.

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, 6-mercaptopurine, 6-thioguanine, and CNS radiation therapy for CNS-positive patients only. Treatment duration for T-cell and B-cell precursor lymphoblastic lymphoma is 24 months.[9 ,10]
  2. COG-A5971 (NCT00004228): Prednisone, dexamethasone, vincristine, daunorubicin, doxorubicin, L-asparaginase, cyclophosphamide, cytarabine, methotrexate, 6-mercaptopurine, and 6-thioguanine.[11,12]
    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, 6-mercaptopurine, 6-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%.[13,14] 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.[9-11]

Patients with high-stage (stage III or stage IV) lymphoblastic lymphoma have long-term survival rates higher than 80%.[9,10,12] 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.[9] 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.[10]
    • 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).[12][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%.[15][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.[10,12] 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.[16][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.[17] However, studies from the Children's Oncology Group (COG) and the Childhood Cancer Survivor Study Group do not support this finding.[12,18,19]

Treatment Options for Recurrent Lymphoblastic Lymphoma

For patients with recurrent or refractory lymphoblastic lymphoma, reports of survival range from 10% to 40%.[18,20]; [21][Level of evidence: 2A]; [22,23][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 progressive disease.

Treatment options for recurrent lymphoblastic lymphoma include the following:

  1. Nelarabine or nelarabine-containing chemotherapy regimens (nelarabine, cyclophosphamide, and etoposide).[24-26]
  2. ICE (ifosfamide, carboplatin, and etoposide).[27]
  3. Allogeneic stem cell transplantation (SCT).[28]

Evidence (treatment of recurrent lymphoblastic lymphoma):

  1. A COG phase II study of nelarabine (compound 506U78) as a single agent demonstrated a response rate of 40%.[24]
  2. A phase IV multicenter study of patients with relapsed T-cell leukemia/lymphoma (n = 28, 11 lymphoma) were treated with single-agent nelarabine.[25]
    • A complete response rate of 36% was observed.
  3. Two small series have treated patients with relapsed T-cell leukemia/lymphoma using nelarabine, cyclophosphamide, and etoposide.[26,29]
    1. One study treated 27 patients.[26]
      • 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.[29]
      • The partial/complete response rate was 100%.
      • Of the two lymphoma patients, both achieved partial responses but later progressed.
  4. 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.[23]
  5. 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.[28]

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:

  • NCI-2014-00712; AALL1231 (NCT02112916) (Combination Chemotherapy With or Without Bortezomib in Treating Younger Patients With Newly Diagnosed T-Cell ALL or Stage II–IV T-Cell Lymphoblastic Lymphoma): This phase III trial is utilizing a modified augmented BFM regimen for patients aged 1 to 30 years. Patients are classified into one of three risk groups (standard, intermediate, or very high) on the basis of the amount of minimal detected disease at diagnosis, radiographic response, and minimal residual disease status at day 29. The objectives of the trial include the following:
    -

    To compare EFS in patients who are randomly assigned to receive or not to receive bortezomib on a modified augmented BFM backbone. For those randomly assigned to receive bortezomib, it is administered during the induction phase (four doses) and again during the delayed intensification phase (four doses).

    -

    To determine the safety and feasibility of modifying standard COG therapy for T-cell ALL by using dexamethasone instead of prednisone during the induction and maintenance phases and additional doses of PEG-asparaginase during the induction and delayed intensification phases.

    -

    To determine whether prophylactic cranial radiation can be omitted in patients with T-cell lymphoblastic lymphoma without CNS3 disease at diagnosis.

  • COG-AALL0932 (Risk-Adapted Chemotherapy in Younger Patients With Newly Diagnosed Standard-Risk ALL or Localized B-lineage Lymphoblastic Lymphoma): In this study, all patients with stage I and stage II B-cell lymphoblastic lymphoma are treated with average-risk ALL therapy.
    All lymphoma patients will receive a three-drug induction (dexamethasone, vincristine, and intravenous [IV] PEG-L-asparaginase) with intrathecal chemotherapy.
    The objective for enrolled lymphoma patients is to collect biological data on B-cell lymphoblastic lymphoma and evaluate the effect of dose de-escalation on OS.
  • 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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  4. Neth O, Seidemann K, Jansen P, et al.: Precursor B-cell lymphoblastic lymphoma in childhood and adolescence: clinical features, treatment, and results in trials NHL-BFM 86 and 90. Med Pediatr Oncol 35 (1): 20-7, 2000. [PubMed: 10881003]
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  9. Reiter A, Schrappe M, Ludwig WD, et al.: Intensive ALL-type therapy without local radiotherapy provides a 90% event-free survival for children with T-cell lymphoblastic lymphoma: a BFM group report. Blood 95 (2): 416-21, 2000. [PubMed: 10627444]
  10. 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]
  11. Termuhlen AM, Smith LM, Perkins SL, et al.: Outcome of newly diagnosed children and adolescents with localized lymphoblastic lymphoma treated on Children's Oncology Group trial A5971: a report from the Children's Oncology Group. Pediatr Blood Cancer 59 (7): 1229-33, 2012. [PubMed: 22488718]
  12. Termuhlen AM, Smith LM, Perkins SL, et al.: Disseminated lymphoblastic lymphoma in children and adolescents: results of the COG A5971 trial: a report from the Children's Oncology Group. Br J Haematol 162 (6): 792-801, 2013. [PubMed: 23889312]
  13. 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]
  14. 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]
  15. Asselin BL, Devidas M, Wang C, et al.: Effectiveness of high-dose methotrexate in T-cell lymphoblastic leukemia and advanced-stage lymphoblastic lymphoma: a randomized study by the Children's Oncology Group (POG 9404). Blood 118 (4): 874-83, 2011. [PMC free article: PMC3292437] [PubMed: 21474675]
  16. Asselin BL, Devidas M, Chen L, et al.: Cardioprotection and Safety of Dexrazoxane in Patients Treated for Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia or Advanced-Stage Lymphoblastic Non-Hodgkin Lymphoma: A Report of the Children's Oncology Group Randomized Trial Pediatric Oncology Group 9404. J Clin Oncol 34 (8): 854-62, 2016. [PMC free article: PMC4872007] [PubMed: 26700126]
  17. Leung W, Sandlund JT, Hudson MM, et al.: Second malignancy after treatment of childhood non-Hodgkin lymphoma. Cancer 92 (7): 1959-66, 2001. [PubMed: 11745271]
  18. 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]
  19. 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]
  20. 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]
  21. 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]
  22. 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]
  23. 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]
  24. 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]
  25. 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]
  26. 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]
  27. 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]
  28. 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]
  29. 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.)

Tumor Biology

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.[2]

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.[3] 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 only of ALK is associated with the variant ALK translocations, as shown in Table 6.[4]

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

Gene FusionPartner Chromosome Location Frequency of Gene Fusion
NPM-ALK5q36.1~80%
TPM3-ALK1p23 ~15%
ALO17-ALK17q25.3 Rare
ATIC-ALK2q35 Rare
CLTC-ALK17q23 Rare
MSN-ALKXp11.1 Rare
MYH9-ALK22q13.1 Rare
TFG-ALK3q12.2 Rare
TPM4-ALK19p13 Rare
TRAF1-ALK9q33.2 Rare

aAdapted from Tsuyama et al.[4]

In adults, ALK-positive anaplastic large cell lymphoma is viewed differently from other peripheral T-cell lymphomas because prognosis tends to be superior.[5] Also, adult ALK-negative anaplastic large cell lymphoma patients have an inferior outcome compared with patients who have ALK-positive disease.[6] 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.[7-9]

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).[8] 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.

[9]

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.[10]

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.[11 ,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 of approximately 60% to 75%.[13-18]

It is unclear which treatment strategy is best for 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: 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 low-stage lymphoma used three cycles of doxorubicin, cyclophosphamide, vincristine, and prednisone (CHOP).[19]
    • A 5-year event-free survival (EFS) of 88% for patients with large cell lymphoma (anaplastic large cell lymphoma and diffuse large B-cell lymphoma) was reported.
  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]
    • The minority of stage I patients (6 of 36) 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, FRE-IGR-ALCL99 randomly assigned patients to limited vinblastine or prolonged (1 year) vinblastine exposure. Patients who received the vinblastine-plus-chemotherapy regimen had a better EFS 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 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. COG-ANHL0131 (NCT00059839) showed that the addition of vinblastine to the doxorubicin, prednisone, and vincristine (APO) regimen increased toxicity, but did not improve the survival.[9]
  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 LNH-92, 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 LNH-92, with more intensive induction and consolidation with maintenance for 1 year total duration of therapy. Similar outcomes and similar significant increase in hematologic toxicity were observed.[17][Level of evidence: 2A]

CNS involvement in 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 was 50% (95% confidence interval [CI], 25%–75%) and OS 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 Anaplastic Large Cell Lymphoma

Unlike mature B-cell or lymphoblastic lymphoma, the prognosis for recurrent or refractory anaplastic large cell lymphoma is 40% to 60%.[25-27]

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

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

  1. ICE (ifosfamide, carboplatin, and etoposide).[28]
  2. Vinblastine.[29]
  3. Brentuximab.[30]; [31][Level of evidence: 2Div]
  4. Crizotinib.[32]
  5. Allogeneic or autologous stem cell transplantation (SCT).[33,34]

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.[35]

Chemotherapy, followed by autologous SCT or allogeneic SCT if remission can be achieved, has been employed in this setting.[26,27,33,34,36]

Evidence (chemotherapy and targeted therapy):

  1. Vinblastine is active as a single agent in recurrent/refractory anaplastic large cell lymphoma.
    In one study, patients with recurrent anaplastic large cell lymphoma were treated with vinblastine alone, and the following was observed:[29][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. 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.[37]
    • 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.[32,38][Level of evidence: 2Div]
    • Although complete responses are common, the duration of therapy remains unclear.[39][Level of evidence: 3iiiDiii]
    • The most common adverse event was neutropenia.[38]
  3. Brentuximab vedotin has been evaluated in adults with anaplastic large cell lymphoma.
    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.
    • Complete remission rates of approximately 55% to 60% and partial remission rates of 29% were observed.[30]
    • For the 38 patients who achieved a complete remission (28 ALK-negative patients, 10 ALK-positive patients), 5-year progression-free survival (PFS) was 79%, and OS was 57%. PFS was similar for ALK-positive and ALK-negative patients.[40]
    • 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.[40]
  4. Brentuximab vedotin has been evaluated in children with recurrent or refractory anaplastic large cell lymphoma.
    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.[31][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, and the OS rate at 24 months was 93.3%.

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. Several additional studies suggest that allogeneic SCT may result in better outcome for refractory/relapsed anaplastic large cell lymphoma.[33,36,41]

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.

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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  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. Duyster J, Bai RY, Morris SW: Translocations involving anaplastic lymphoma kinase (ALK). Oncogene 20 (40): 5623-37, 2001. [PubMed: 11607814]
  4. Tsuyama N, Sakamoto K, Sakata S, et al.: Anaplastic large cell lymphoma: pathology, genetics, and clinical aspects. J Clin Exp Hematop 57 (3): 120-142, 2017. [PMC free article: PMC6144189] [PubMed: 29279550]
  5. Savage KJ, Harris NL, Vose JM, et al.: ALK- anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project. Blood 111 (12): 5496-504, 2008. [PubMed: 18385450]
  6. Vose J, Armitage J, Weisenburger D, et al.: International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol 26 (25): 4124-30, 2008. [PubMed: 18626005]
  7. 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]
  8. 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]
  9. 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]
  10. Sevilla DW, Choi JK, Gong JZ: Mediastinal adenopathy, lung infiltrates, and hemophagocytosis: unusual manifestation of pediatric anaplastic large cell lymphoma: report of two cases. Am J Clin Pathol 127 (3): 458-64, 2007. [PubMed: 17276937]
  11. Onciu M, Behm FG, Raimondi SC, et al.: ALK-positive anaplastic large cell lymphoma with leukemic peripheral blood involvement is a clinicopathologic entity with an unfavorable prognosis. Report of three cases and review of the literature. Am J Clin Pathol 120 (4): 617-25, 2003. [PubMed: 14560573]
  12. Grewal JS, Smith LB, Winegarden JD, et al.: Highly aggressive ALK-positive anaplastic large cell lymphoma with a leukemic phase and multi-organ involvement: a report of three cases and a review of the literature. Ann Hematol 86 (7): 499-508, 2007. [PubMed: 17396261]
  13. Brugières L, Deley MC, Pacquement H, et al.: CD30(+) anaplastic large-cell lymphoma in children: analysis of 82 patients enrolled in two consecutive studies of the French Society of Pediatric Oncology. Blood 92 (10): 3591-8, 1998. [PubMed: 9808552]
  14. 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]
  15. Laver JH, Kraveka JM, Hutchison RE, et al.: Advanced-stage large-cell lymphoma in children and adolescents: results of a randomized trial incorporating intermediate-dose methotrexate and high-dose cytarabine in the maintenance phase of the APO regimen: a Pediatric Oncology Group phase III trial. J Clin Oncol 23 (3): 541-7, 2005. [PubMed: 15659500]
  16. Rosolen A, Pillon M, Garaventa A, et al.: Anaplastic large cell lymphoma treated with a leukemia-like therapy: report of the Italian Association of Pediatric Hematology and Oncology (AIEOP) LNH-92 protocol. Cancer 104 (10): 2133-40, 2005. [PubMed: 16211546]
  17. 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]
  18. Pillon M, Gregucci F, Lombardi A, et al.: Results of AIEOP LNH-97 protocol for the treatment of anaplastic large cell lymphoma of childhood. Pediatr Blood Cancer 59 (5): 828-33, 2012. [PubMed: 22389307]
  19. 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]
  20. 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]
  21. Attarbaschi A, Mann G, Rosolen A, et al.: Limited stage I disease is not necessarily indicative of an excellent prognosis in childhood anaplastic large cell lymphoma. Blood 117 (21): 5616-9, 2011. [PubMed: 21444917]
  22. Wrobel G, Mauguen A, Rosolen A, et al.: Safety assessment of intensive induction therapy in childhood anaplastic large cell lymphoma: report of the ALCL99 randomised trial. Pediatr Blood Cancer 56 (7): 1071-7, 2011. [PubMed: 21280197]
  23. Le Deley MC, Rosolen A, Williams DM, et al.: Vinblastine in children and adolescents with high-risk anaplastic large-cell lymphoma: results of the randomized ALCL99-vinblastine trial. J Clin Oncol 28 (25): 3987-93, 2010. [PubMed: 20679620]
  24. 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]
  25. 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]
  26. 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]
  27. 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]
  28. 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]
  29. 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]
  30. 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]
  31. Locatelli F, Mauz-Koerholz C, Neville K, et al.: Brentuximab vedotin for paediatric relapsed or refractory Hodgkin's lymphoma and anaplastic large-cell lymphoma: a multicentre, open-label, phase 1/2 study. Lancet Haematol 5 (10): e450-e461, 2018. [PubMed: 30290902]
  32. 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]
  33. 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]
  34. 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]
  35. 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]
  36. 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]
  37. Gambacorti-Passerini C, Messa C, Pogliani EM: Crizotinib in anaplastic large-cell lymphoma. N Engl J Med 364 (8): 775-6, 2011. [PubMed: 21345110]
  38. 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]
  39. 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]
  40. Pro B, Advani R, Brice P, et al.: Five-year results of brentuximab vedotin in patients with relapsed or refractory systemic anaplastic large cell lymphoma. Blood 130 (25): 2709-2717, 2017. [PMC free article: PMC5746164] [PubMed: 28974506]
  41. Fukano R, Mori T, Kobayashi R, et al.: Haematopoietic stem cell transplantation for relapsed or refractory anaplastic large cell lymphoma: a study of children and adolescents in Japan. Br J Haematol 168 (4): 557-63, 2015. [PubMed: 25312752]

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 transplantation 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%), and 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 is 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, but careful attention to prophylaxis against, 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 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 the monomorphic subtype are similar to those observed in NHL, with diffuse large B-cell lymphoma being the most common histology, followed by Burkitt lymphoma/leukemia, and with myeloma, plasmacytoma, and Hodgkin-like PTLD occurring rarely. 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, which has a poor prognosis; however, the use of rituximab and low-dose chemotherapy may improve the outcome.[18,19] U.S. transplant and cancer registries show that PTLD accounts for about 3% of all pediatric NHL diagnoses; and that 65% of PTLDs are diffuse large B-cell lymphoma histology, and 9% are 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 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 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. In a study of 144 children and adults who developed post-HSCT PTLD, it was reported that approximately 70% of 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.[21][Level of evidence: 3iiiA] Rituximab as a single agent to treat PTLD after organ transplant has demonstrated efficacy in adult patients, but data are lacking in pediatric patients. (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 EBV-positive, CD20-positive B-lineage PTLD.[19,27] An event-free survival of 67% was demonstrated in a Children's Oncology Group study using rituximab plus cyclophosphamide and prednisone in children with PTLD after solid organ transplantation in whom immune suppression was reduced.[19][Level of evidence: 2A] Other studies suggest that modified conventional lymphoma therapy is effective for 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-cells have been effective in treating PTLD after blood or bone marrow transplant.[32,33] Although this approach has been demonstrated to be feasible in patients with PTLD after solid organ transplant, it has not been demonstrated to be as effective or practical.[34]

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

  • ANHL1522 (NCT02900976) (Rituximab and Latent Membrane Protein [LMP]–Specific T Cells in Treating Pediatric Solid Organ Recipients With EBV-Positive Cluster of Differentiation (CD) 20–Positive PTLD): This is a limited-institution study for newly diagnosed patients (aged <30 years) with a monomorphic or polymorphic PTLD who have undergone a solid organ transplant. All patients will receive three weekly doses of rituximab followed by a response assessment. Patients who have a complete response (CR) to rituximab will receive an additional three doses of rituximab. Patients who do not achieve a CR to three doses of rituximab will receive LMP-specific T cells. LMP-specific T cells will be supplied from a third-party LMP-specific T-cell bank.

References

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  2. Seidemann K, Tiemann M, Henze G, et al.: Therapy for non-Hodgkin lymphoma in children with primary immunodeficiency: analysis of 19 patients from the BFM trials. Med Pediatr Oncol 33 (6): 536-44, 1999. [PubMed: 10573576]
  3. Loren AW, Porter DL, Stadtmauer EA, et al.: Post-transplant lymphoproliferative disorder: a review. Bone Marrow Transplant 31 (3): 145-55, 2003. [PubMed: 12621474]
  4. Jaffe ES, van Krieken JH, Onciu M, et al.: Lymphoproliferative diseases associated with primary immune disorders. In: Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th rev. ed. Lyon, France: International Agency for Research on Cancer, 2017, pp 444-61.
  5. Attarbaschi A, Carraro E, Abla O, et al.: Non-Hodgkin lymphoma and pre-existing conditions: spectrum, clinical characteristics and outcome in 213 children and adolescents. Haematologica 101 (12): 1581-1591, 2016. [PMC free article: PMC5479624] [PubMed: 27515251]
  6. Hoffmann T, Heilmann C, Madsen HO, et al.: Matched unrelated allogeneic bone marrow transplantation for recurrent malignant lymphoma in a patient with X-linked lymphoproliferative disease (XLP). Bone Marrow Transplant 22 (6): 603-4, 1998. [PubMed: 9758353]
  7. Sandoval C, Swift M: Treatment of lymphoid malignancies in patients with ataxia-telangiectasia. Med Pediatr Oncol 31 (6): 491-7, 1998. [PubMed: 9835901]
  8. Dembowska-Baginska B, Perek D, Brozyna A, et al.: Non-Hodgkin lymphoma (NHL) in children with Nijmegen Breakage syndrome (NBS). Pediatr Blood Cancer 52 (2): 186-90, 2009. [PubMed: 18937313]
  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]
  11. Fedorova A, Mlyavaya T, Alexeichik A, et al.: Successful treatment of the HIV-associated Burkitt lymphoma in a three-year-old child. Pediatr Blood Cancer 47 (1): 92-3, 2006. [PubMed: 16047357]
  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. Lyon, France: 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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  33. Rooney CM, Smith CA, Ng CY, et al.: Infusion of cytotoxic T cells for the prevention and treatment of Epstein-Barr virus-induced lymphoma in allogeneic transplant recipients. Blood 92 (5): 1549-55, 1998. [PubMed: 9716582]
  34. Bollard CM, Gottschalk S, Torrano V, et al.: Sustained complete responses in patients with lymphoma receiving autologous cytotoxic T lymphocytes targeting Epstein-Barr virus latent membrane proteins. J Clin Oncol 32 (8): 798-808, 2014. [PMC free article: PMC3940538] [PubMed: 24344220]

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]

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

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 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.[1,3-5] Pediatric-type follicular lymphoma predominantly occurs in males, is associated with a high proliferation rate, and is more likely to be localized disease.[3,6,7] 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.[1,3,5,7,8] 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.[3-5,8-10]

Tumor biology

Pediatric-type follicular lymphoma appears to be molecularly distinct from follicular lymphoma that is more commonly observed in adults. The pediatric type lacks BCL2 rearrangements; BCL6 and MYC rearrangements are also not present. The TNFSFR14 mutations are common in pediatric-type follicular lymphoma, and they appear to occur with similar frequency in adult follicular lymphoma.[7,11] However, MAP2K1 mutations, which are uncommon in adults, are observed in as many as 43% of pediatric-type follicular lymphomas. 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.[12,13] Translocations of the immunoglobulin locus and IRF4, mutations in IRF8, and abnormalities in chromosome 1p have also been observed in pediatric-type follicular lymphoma.
[11,14,15]

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 outcome of pediatric-type follicular lymphoma is excellent, with an event-free survival (EFS) of about 95%.[3,5-8,10] Unlike in adult follicular lymphoma, the clinical course is not dominated by relapses.[3,5,8,9]

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 94% EFS and 100% overall survival (OS) rates with a 2-year median follow-up.[2,3,6,7] 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 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.[16,17]

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.[17,18]

Most pediatric marginal zone lymphomas require no more than local therapy involving curative surgery and/or radiation therapy.[16,19] Treatment of 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 overall 5-year EFS was 70%, and OS was 98%. Patients primarily fell into the following two WHO-defined groups:[20][Level of evidence: 3iiiA]
    • 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 was 94%, and the OS 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 was 64%, and the OS 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 described.[21]

Primary Central Nervous System (CNS) Lymphoma

Other types of NHL that may be 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, 70%–80%) may be superior to that of adults with primary CNS lymphoma.[22-25]

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

Treatment options for primary CNS lymphoma

Treatment options for primary CNS lymphoma include the following:

  1. Chemotherapy.

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.[26]

There is a case report of repeated doses of rituximab, both intravenous and intraventricular, being administered to a 14-year-old boy with refractory primary CNS lymphoma, with an excellent result.[27] 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.

(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.[28-32]

A Japanese study described extranodal NK/T-cell lymphoma–nasal type as the most common peripheral T-cell lymphoma subtype among Japanese children (10 of 21 peripheral T-cell lymphoma cases). In adults, extranodal NK/T-cell lymphoma–nasal type is generally Epstein-Barr virus (EBV) positive, and 60% of the cases observed in Japanese children were EBV positive.[33]

Although very rare, gamma-delta hepatosplenic T-cell lymphoma may be seen in children.[31] 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.[34]

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 stem cell transplantation (SCT).

There have been four retrospective analyses of treatment and outcome for pediatric patients with peripheral T-cell lymphoma. The studies have reported the following:

  • The United Kingdom Children's Cancer Study Group (UKCCSG) reported on 25 children diagnosed over a 20-year period with peripheral T-cell lymphoma, with an approximate 50% 5-year survival rate.[28] The UKCCSG also observed that the use of acute lymphoblastic leukemia–like therapy, instead of NHL therapy, produced a superior outcome.
  • The COG reported on 20 patients older than 8 years who were treated on Pediatric Oncology Group NHL trials.[29] 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.
  • A study of Japanese children with peripheral T-cell lymphoma (N = 21) reported a 5-year OS rate of 85.2%. Treatment for peripheral T-cell lymphoma included chemotherapy (n = 18), radiation therapy (n = 2), and autologous (n = 2) and allogeneic (n = 9) SCT.[33]
  • The Berlin-Frankfurt-Münster study group reported 38 cases of peripheral T-cell lymphoma acquired over a 26-year period.[31][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 T-cell or NK-cell phenotype.[35]

Subcutaneous panniculitic T-cell lymphomas are very rare lymphomas with panniculitis-like infiltration of subcutaneous tissue by cytotoxic T-cells.[36-38] 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 carries a worse prognosis than does the alpha-beta subtype of subcutaneous panniculitic T-cell lymphoma.[39] 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 alpha-beta subcutaneous panniculitic T-cell lymphoma and 11% for gamma-delta subcutaneous panniculitic T-cell lymphoma.[39] Subcutaneous panniculitic T-cell lymphoma is heterogeneous in the pediatric age group and does not necessarily follow the course 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.[40]

The diagnosis of primary cutaneous anaplastic large cell lymphoma can be difficult to distinguish pathologically from more benign diseases such as lymphomatoid papulosis.[41] 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,[42 -44] 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.[45]; [46][Level of evidence: 3iiiDii]

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 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.[47]

The best treatment for T-cell lymphomas with primarily pannicular involvement is not known. Treatment options include high-dose steroids, bexarotene, denileukin diftitox, multiagent chemotherapy, and hematopoietic SCT.[38,47-52]

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.[49] 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.[40] 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.[53] There are reports of surgery alone also being curative for ALK-positive cutaneous anaplastic large cell lymphoma, but extensive staging and vigilant follow-up is required.[54,55]

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.[45,56-58]

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  47. Johnston EE, LeBlanc RE, Kim J, et al.: Subcutaneous panniculitis-like T-cell lymphoma: Pediatric case series demonstrating heterogeneous presentation and option for watchful waiting. Pediatr Blood Cancer 62 (11): 2025-8, 2015. [PubMed: 26146844]
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Changes to This Summary (08/06/2019)

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.

Anaplastic Large Cell Lymphoma

Added text to state that although remissions can be achieved with single-agent therapy, central nervous system (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 (cited Ruf et al. as reference 35).

Lymphoproliferative Disease Associated With Immunodeficiency in Children

Added Twist et al. as reference 27.

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 who care for cancer 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.

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Bookshelf ID: NBK65738PMID: 26389181

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