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Childhood Non-Hodgkin Lymphoma Treatment (PDQ®)

  • Last Modified: 04/03/2014

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High-Stage Childhood B-cell NHL Treatment

Standard Treatment Options
Treatment Options Under Clinical Evaluation
Current Clinical Trials

Patients with high-stage (stage III or stage IV) mature B-lineage non-Hodgkin lymphoma (NHL) (Burkitt or Burkitt-like lymphoma and diffuse large B-cell lymphoma) have an 80% to 90% long-term survival.[1-3] Unlike mature B-lineage NHL seen in adults, there is no difference in outcome based on histology (Burkitt or Burkitt-like lymphoma or diffuse large B-cell lymphoma) with current therapy in pediatric trials.[1-3]

Involvement of the bone marrow may lead to confusion as to 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.[1,3]

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 subsection in the Treatment Option Overview section of this summary for more information.) For reduction of the complications of tumor lysis syndrome, current treatment regimens use a prophase of reduced intensity to cytoreduce patients;[1-3] however, this does not obviate the use of hyperhydration and allopurinol or rasburicase (urate oxidase). Hyperuricemia and tumor lysis syndrome, particularly when associated with ureteral obstruction, frequently result in life-threatening complications. Gastrointestinal bleeding, obstruction, and (rarely) perforation may occur. Patients with NHL should be managed only in institutions having pediatric tertiary care facilities.[4]

In the NHL-BFM-95 trial, it was shown that when the dose of methotrexate was reduced for R1 and R2 patients, outcome was not inferior; however, 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.[1] Event-free survival (EFS) with best therapy in NHL-BFM-95 was more than 95% for R1 and R2 group patients and was 93% for R3 and R4 group patients. Inferior outcome was observed for patients with primary mediastinal B-cell lymphoma (50% 3-year EFS) and CNS disease at presentation (70% 3-year EFS).[5] In the COG-C5961 (FAB/LMB-96) study, the outcome of group B patients, who had a greater than 20% response to cytoreductive prophase, was not affected by a reduction of the total dose of cyclophosphamide by 50% and elimination of one cycle of maintenance therapy.[2] The 3-year EFS was 98% for stage I/II, 90% for stage III, and 86% for stage IV (CNS-negative) patients, while patients with primary mediastinal B-cell lymphoma had a 3-year EFS of 70%.[2] In group C patients, reduction in cumulative dose of therapy and number of maintenance cycles resulted in inferior outcome.[3] 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.[3] This study identified response to prophase reduction as the most significant prognostic factor, with poor responders (i.e., <20% resolution of disease) having an EFS of 30%.[3] Both the Berlin-Frankfurt-Munster (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]).[1-3,5]

Rituximab is a mouse/human chimeric monoclonal antibody targeting the CD20 antigen. Among the lymphomas that occur in children, diffuse large B-cell lymphoma and Burkitt lymphoma both express high levels of CD20.[6] 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).[7,8] In an adult study, rituximab has also been safely combined with an intensive chemotherapy regimen used to treat patients with Burkitt lymphoma.[9] In children, a single-agent phase II study of rituximab performed by the BFM group showed activity in Burkitt leukemia and lymphoma.[10][Level of evidence: 2Div] 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; compared with chemotherapy-only protocols, toxicity was similar, despite a trend toward higher peak rituximab levels in younger patients.[11]; [12][Level of evidence: 3iiiA] The addition of rituximab to standard chemotherapy is now being tested in a randomized trial.

Standard Treatment Options

 [Note: Current data do not suggest superiority for either of the following standard treatment options.]

Table 5. Standard Treatment Options for High-Stage B-cell NHL
 Stratum Disease Manifestations Treatment 
ALL = acute lymphoblastic leukemia; BFM = Berlin-Frankfurt-Munster; CNS = central nervous system; LDH = lactate dehydrogenase; NHL= non-Hodgkin lymphoma.
FAB/LMB-96 International Study COG-C5961 (FAB/LMB-96) [2,3]BMultiple extra-abdominal sitesPrephase + four cycles of chemotherapy (reduced intensity arm) [2]
Nonresected stage I and II, III, IV
Marrow <25% blasts
No CNS disease
CMature B-cell ALL (>25% blasts in marrow) and/or CNS diseasePrephase + eight cycles of chemotherapy (full intensity arm) [3]
BFM Group [1,5]R2Nonresected stage I/II and stage III with LDH <500 IU/LPrephase + four cycles of chemotherapy (4 h methotrexate infusion) [1]
R3Stage III with LDH 500–999 IU/LPrephase + five cycles of chemotherapy (24 h methotrexate infusion) [1]
Stage IV, B-cell ALL (>25% blasts) and LDH <1,000 IU/L
No CNS disease
R4Stage III, IV, B-cell ALL with LDH >1,000 IU/LPrephase + six cycles of chemotherapy (24 h methotrexate infusion) [1]
Any CNS disease

Treatment Options Under Clinical Evaluation

The following is an example of a national or international clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.

  • COG-ANHL1131 (Combination Chemotherapy With or Without Rituximab in Treating Younger Patients With Stage III–IV Non-Hodgkin Lymphoma or B-Cell Acute Leukemia): This randomized study of patients with high-risk disease (defined as Group B with high lactate dehydrogenase and Group C) examines the addition of rituximab to the standard FAB LMB 96 (COG-C5961) chemotherapy regimen. Additionally, the dose-adjusted EPOCH-R regimen (etoposide, prednisone, vincristine, doxorubicin, and rituximab) will be tested in a single-arm, phase II trial for pediatric patients with primary mediastinal B-cell lymphoma.
Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage III childhood large cell lymphoma, stage III childhood small noncleaved cell lymphoma, stage IV childhood large cell lymphoma and stage IV childhood small noncleaved cell lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References
  1. 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 Abstract]

  2. 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.  [PUBMED Abstract]

  3. 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.  [PUBMED Abstract]

  4. Cairo MS, Bishop M: Tumour lysis syndrome: new therapeutic strategies and classification. Br J Haematol 127 (1): 3-11, 2004.  [PUBMED Abstract]

  5. 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 Abstract]

  6. Perkins SL, Lones MA, Davenport V, et al.: B-Cell non-Hodgkin's lymphoma in children and adolescents: surface antigen expression and clinical implications for future targeted bioimmune therapy: a children's cancer group report. Clin Adv Hematol Oncol 1 (5): 314-7, 2003.  [PUBMED Abstract]

  7. Coiffier B, Lepage E, Briere J, et al.: CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346 (4): 235-42, 2002.  [PUBMED Abstract]

  8. Pfreundschuh M, Trümper L, Osterborg A, et al.: CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 7 (5): 379-91, 2006.  [PUBMED Abstract]

  9. Thomas DA, Faderl S, O'Brien S, et al.: Chemoimmunotherapy with hyper-CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia. Cancer 106 (7): 1569-80, 2006.  [PUBMED Abstract]

  10. Meinhardt A, Burkhardt B, Zimmermann M, et al.: Phase II window study on rituximab in newly diagnosed pediatric mature B-cell non-Hodgkin's lymphoma and Burkitt leukemia. J Clin Oncol 28 (19): 3115-21, 2010.  [PUBMED Abstract]

  11. Barth MJ, Goldman S, Smith L, et al.: Rituximab pharmacokinetics in children and adolescents with de novo intermediate and advanced mature B-cell lymphoma/leukaemia: a Children's Oncology Group report. Br J Haematol 162 (5): 678-83, 2013.  [PUBMED Abstract]

  12. Goldman S, Smith L, Anderson JR, et al.: Rituximab and FAB/LMB 96 chemotherapy in children with Stage III/IV B-cell non-Hodgkin lymphoma: a Children's Oncology Group report. Leukemia 27 (5): 1174-7, 2013.  [PUBMED Abstract]