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

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

    The incidence of NHL is higher in whites than in African Americans, and Burkitt lymphoma is more frequent in non-Hispanic whites (3.2 cases/million person-years) than in Hispanic whites (2.0 cases/million person-years).[7]

    Relatively little is known of the epidemiology of childhood NHL. However, immunodeficiency, both congenital and acquired (human immunodeficiency virus infection [HIV] or posttransplant immunodeficiency), increases the risk of NHL. Epstein-Barr virus (EBV) is associated with most cases of NHL seen in the immunodeficient population.[3] Although 85% or more of Burkitt lymphoma is associated with the EBV in endemic Africa, approximately 15% of cases in Europe or the United States will have EBV detectable in the tumor tissue.[8]

    NHL presenting as a secondary malignancy is rare in pediatrics. A retrospective review of the German Childhood Cancer Registry identified 11 (0.3%) of 2,968 newly diagnosed children older than 20 years with NHL as having a secondary malignancy.[9] In this small cohort, outcome was similar to patients with de novo NHL when treated with standard therapy.[9]

    Prognostic Factors for Childhood NHL

    With current treatments, more than 80% of children and adolescents with NHL will survive at least 5 years, though outcome is variable depending on a number of factors, including clinical stage and histology.[10]

    Prognostic factors for childhood NHL include the following:

    • Age: NHL in infants is rare (1% in Berlin-Frankfurt-Munster [BFM] trials from 1986 to 2002).[5] In this retrospective review, the outcome for infants was inferior compared with the outcome for older patients with NHL.[5]

      Adolescents have been reported to have inferior outcome compared with younger children.[10,11,12,13] A review of survival for various subtypes of NHL in children and adolescents between 1986 and 2007 has been reported by the BFM group.[13] Event-free survival (EFS) was 79% for adolescents and 85% for children. This adverse affect of age appears to be most pronounced for adolescents with T-cell lymphoblastic lymphoma and diffuse large B-cell lymphoma compared with children with these diagnoses.[13] The poorer outcome of patients older than 15 years appears to be attributable primarily to patients with diffuse large B-cell lymphoma.[10] On the other hand, for patients with Burkitt and Burkitt-like lymphoma on the FAB LMB 96 (COG-C5961) clinical trial, adolescent age (≥ 15 years) was not an independent risk factor for inferior outcome, with 3-year EFS of 89% ± 1.0% for children younger than 15 years and 84% ± 3.4% for patients aged 15 years and older.[14]

    • Site of disease: 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.[15,16,17,18,19,20] Patients with NHL arising in bone have an excellent prognosis, regardless of histology.[21,22] Testicular involvement does not affect prognosis.[16,17,23] As opposed to adults, mediastinal involvement in children and adolescents with nonlymphoblastic NHL results in an inferior outcome.[10,14,15,18] For patients with primary mediastinal B-cell lymphoma, 3-year EFS is 50% to 70%,[14,15,18,24] and for patients with central nervous system (CNS) disease at presentation, the 3-year EFS is 70%.[14,18,25]

      In 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.[26] An immune response against the ALK protein (i.e., anti-ALK antibody titer) appears to correlate with lower clinical stage and absence of these clinical risk features (mediastinal and visceral organ involvement) and predicts relapse risk but not overall survival.[27] However, in the CCG-5941 study for anaplastic large cell lymphoma patients, only bone marrow involvement predicted inferior progression-free survival.[28][Level of evidence: 2A] Patients with leukemic involvement (>25% blasts in marrow) or CNS involvement at diagnosis require intensive therapy.[17,25,29] Although these intensive therapies have improved the outcome for patients with high-stage (stage III or IV) or advanced-stage disease, patients who present with CNS disease have the worst outcome.[17,25,29,30] The combination of CNS involvement and marrow disease appears to impact outcome the most for Burkitt lymphoma/leukemia.[25] 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.[25]

    • Chromosomal abnormalities: Though data for cytogenetics is less robust than for childhood leukemia, some chromosomal abnormalities have been reported to have prognostic value.
      • For pediatric Burkitt lymphoma patients, secondary cytogenetic abnormalities, other than c-myc rearrangement, are associated with an inferior outcome,[31,32] and cytogenetic abnormalities involving gain of 7q or deletion of 13q appear to have an inferior outcome on current chemotherapy protocols.[32,33]
      • For pediatric patients with diffuse large B-cell lymphoma and chromosomal rearrangement at MYC (8q24), outcome appears to be lower.[32]
      • The BFM group reported that in pediatric patients with T-cell lymphoblastic lymphoma, loss of heterozygosity at chromosome 6q was observed in 12% (25 of 217) of patients and was associated with unfavorable prognosis (probability of EFS [pEFS], 27% vs. 86%, P <.0001).[34,35]NOTCH1 mutations were seen in 60% (70 of 116) of patients and were associated with favorable prognosis (pEFS, 84% vs. 66%; P = .021). NOTCH1 mutations were rarely seen in patients with loss of heterozygosity in 6q16.[34]
    • Tumor burden: A surrogate for tumor burden (i.e., elevated levels of lactate dehydrogenase) has been shown to be prognostic in many studies.[14,15,18,24]

      More recently, detection of minimal disease at diagnosis or minimal residual disease (MRD) appears to be prognostic in most subtypes of childhood NHL. In a retrospective subset analysis, there was evidence that submicroscopic bone marrow and peripheral blood involvement, detected by reverse transcription-polymerase chain reaction (RT-PCR) from NPM-ALK, was found in approximately 50% of patients and correlated with clinical stage;[36] marrow involvement detected by PCR was associated with a 50% cumulative incidence of relapse. The prognostic role of MRD in the treatment of Burkitt leukemia remains unclear.[37,38,39]

    • Response to therapy: One of the most important predictive factors for Burkitt lymphoma/leukemia is response to the initial prophase treatment; poor responders (i.e., <20% resolution of disease) had an EFS of 30%.[15] Results from two studies suggest inferior outcome for patients with Burkitt leukemia that had detectable MRD after induction chemotherapy.[37,38]


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    13. Burkhardt B, Oschlies I, Klapper W, et al.: Non-Hodgkin's lymphoma in adolescents: experiences in 378 adolescent NHL patients treated according to pediatric NHL-BFM protocols. Leukemia 25 (1): 153-60, 2011.
    14. 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.
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    17. 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.
    18. 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.
    19. 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.
    20. 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.
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    23. Dalle JH, Mechinaud F, Michon J, et al.: Testicular disease in childhood B-cell non-Hodgkin's lymphoma: the French Society of Pediatric Oncology experience. J Clin Oncol 19 (9): 2397-403, 2001.
    24. 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.
    25. 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.
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    28. 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.
    29. 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.
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    33. 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.
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    37. Mussolin L, Pillon M, Conter V, et al.: Prognostic role of minimal residual disease in mature B-cell acute lymphoblastic leukemia of childhood. J Clin Oncol 25 (33): 5254-61, 2007.
    38. Mussolin L, Pillon M, d'Amore ES, et al.: Minimal disseminated disease in high-risk Burkitt's lymphoma identifies patients with different prognosis. J Clin Oncol 29 (13): 1779-84, 2011.
    39. Shiramizu B, Goldman S, Kusao I, et al.: Minimal disease assessment in the treatment of children and adolescents with intermediate-risk (Stage III/IV) B-cell non-Hodgkin lymphoma: a children's oncology group report. Br J Haematol 153 (6): 758-63, 2011.

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

    WebMD Public Information from the National Cancer Institute

    Last Updated: May 28, 2015
    This information is not intended to replace the advice of a doctor. Healthwise disclaims any liability for the decisions you make based on this information.
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