Standard Treatment Options
Treatment Options Under Clinical Evaluation
Current Clinical Trials

Patients with disseminated mature B-lineage non-Hodgkin lymphoma (NHL) (Burkitt or Burkitt-like lymphoma and diffuse large B-cell lymphoma [DLBCL]) 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, Burkitt-like, or DLBCL) with current therapy in pediatric trials.[1-3]

For the Berlin-Frankfurt-Munster (BFM) group, disseminated mature B-lineage NHL defined by R2 is unresected disease or stage III disease with lactate deyhdrogenase (LDH) levels lower than 500 u/L; R3 is stage III disease and LDH concentrations between 500 u/L and 1,000 u/L or leukemic disease (>25% blasts in marrow) with LDH levels lower than 1,000 u/L; R4 is stage III/IV disease or leukemic disease with LDH levels higher than 1,000 u/L and/or central nervous system (CNS) involvement.[1] All patients receive a cytoreductive prophase. R2 group patients receive four cycles of intensive chemotherapy; R3 patients receive five cycles of intensive chemotherapy; and R4 patients receive six cycles of intensive chemotherapy. In the BFM-90 ¹ study, it was demonstrated that increasing the dose and duration of infusion (24 hours) of methotrexate resulted in an improved outcome.[4] In the BFM-95 trial, it was shown that reducing the infusion time of methotrexate from 24 hours to 4 hours resulted in inferior outcome for R3 and R4 group patients.[1] Event-free survival (EFS) with best therapy in 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 central nervous system (CNS) disease at presentation (70% 3-year EFS).[4] In the FAB/LMB-96 ² study, group B consists of all patients (stage I–IV) with unresected disease but excludes those with leukemic (>25% marrow involvement) and/or CNS involvement, while group C patients have leukemic and/or marrow involvement.[2,3] 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.[2] The 3-year EFS was 98%, 90%, and 86% for stage I/II, stage III, and stage IV (CNS-negative) patients, respectively, while patients with primary mediastinal B-cell lymphoma had a 3-year EFS of 70%.[2] In group C patients, reduction of therapy 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 BFM and FAB/LMB studies demonstrated that omission of craniospinal irradiation, even in patients presenting with CNS disease, does not affect outcome (FAB/LMB96 ², NHL-BFM 90 ¹).[1-4]

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] Poor prognostic factors for B-cell NHL include: high levels of LDH,[1,2,4] primary mediastinal disease,[1,2] CNS disease at presentation,[1,3] suboptimal response to cytoreductive prophase,[3] and age older than 15 years, which appears to be attributable primarily to patients with DLBCL.[1,5] Data suggest that secondary cytogenetic abnormalities, other than c-myc rearrangement, are associated with an inferior outcome.[6] The prognostic role of minimal residual disease (MRD) in the treatment of Burkitt leukemia remains unclear. Results from a single study suggest inferior outcome for patients with detectable MRD.[7] Testicular disease at diagnosis does not seem to confer poor prognosis.[8]

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 Treatment Option Overview ³ 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.[9]

Rituximab is a mouse/human chimeric monoclonal antibody targeting the CD20 antigen. Among the lymphomas that occur in children, DLBCL and Burkitt lymphoma both express high levels of CD20.[10] 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 DLBCL (CAN-NCIC-LY9 ⁴).[11,12] In an adult study, rituximab has also been safely combined with an intensive chemotherapy regimen used to treat patients with Burkitt lymphoma.[13] At present, there are no data that rituximab improves outcome when added to current regimens used to treat pediatric NHL patients. A Children’s Oncology Group (COG) pilot study (COG-ANHL01P1 ⁵) is evaluating rituximab in combination with the intensive chemotherapy regimen based on the French LMB-89 protocol.

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

• FAB/LMB-96 ² : cyclophosphamide, vincristine, prednisone, methotrexate (IT), high-dose methotrexate, doxorubicin, cytarabine, etoposide. Reduced intensity arm for group B, and full intensity for group C.[2,3]
• NHL-BFM 95: dexamethasone, cyclophosphamide, methotrexate, cytarabine, prednisolone (IT), ifosfamide, etoposide, vindesine, doxorubicin.[1]

• COG-ANHL01P1 ⁵ : addition of rituximab to FAB/LMB-96–based therapy for stage III/IV (group B) and group C patients.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage III childhood large cell lymphoma ⁶, stage III childhood small noncleaved cell lymphoma ⁷, stage IV childhood large cell lymphoma ⁸ and stage IV childhood small noncleaved cell lymphoma ⁹. 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 ¹⁰.

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. 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]
   
   
5. Burkhardt B, Zimmermann M, Oschlies I, et al.: The impact of age and gender on biology, clinical features and treatment outcome of non-Hodgkin lymphoma in childhood and adolescence. Br J Haematol 131 (1): 39-49, 2005.  [PUBMED Abstract]
   
   
6. 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 Abstract]
   
   
7. 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.  [PUBMED Abstract]
   
   
8. Dalle JH, Mechinaud F, Michon J, et al.: Testicular disease in childhood B-cell non-Hodgkin's lymphoma: the French Society of Pediatric Oncology experience. J Clin Oncol 19 (9): 2397-403, 2001.  [PUBMED Abstract]
   
   
9. Cairo MS, Bishop M: Tumour lysis syndrome: new therapeutic strategies and classification. Br J Haematol 127 (1): 3-11, 2004.  [PUBMED Abstract]
   
   
10. 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]
    
    
11. 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]
    
    
12. 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]
    
    
13. 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]