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.[1-4]

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% marrow disease) 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.[2] R2 disease receives five cycles of intensive chemotherapy and has a disease-free survival (DFS) of more than 90%. The R3 group receives six cycles of intensive chemotherapy and has about 85% DFS. The R4 group receives seven cycles of intensive chemotherapy with approximately 80% DFS. For the French Society of Pediatric Oncology (FAB/LMB), group B consists of all patients 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.[1] In an international randomized trial (FAB/LMB96), the outcome of group B patients who had a greater than 20% response to prophase reduction was not affected by a reduction of the total dose of cyclophosphamide by 50% and elimination of one cycle of maintenance.[3] In group C patients, reduction of therapy resulted in inferior outcome.[4] This study also demonstrated that patients with leukemic disease only, and no CNS disease, had a 3-year event free survival (EFS) of 90%.[4] 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%.[4] As opposed to mature B-lineage NHL seen in adults, there is no difference in outcome based on histology with current therapy in pediatric trials.[1-4] This improvement has developed through the use of short, intensive, pulsed chemotherapy with aggressive CNS-directed chemotherapy without cranial radiation. The use of high-dose methotrexate (>5 g/m²), cytarabine, and etoposide have appeared to be helpful.[1-4] Even patients with CNS involvement can achieve a DFS of approximately 75% with current intensive therapy.[1,2,4] Intrathecal (IT) methotrexate should be used in all patients, but prophylactic cranial radiation is not necessary.[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.[1-4] Poor prognostic factors for B-cell NHL include high levels of LDH,[1,3,5] primary mediastinal disease,[2,3] and age older than 15 years, which appears to be attributable primarily to patients with DLBCL.[2,6] Data suggest that secondary cytogenetic abnormalities, other than c-myc rearrangement, are associated with an inferior outcome.[7] 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.[8] Testicular disease at diagnosis does not seem to confer poor prognosis.[9] Results from the pediatric international FAB/LMB study and BFM groups demonstrate that CNS disease at diagnosis is the strongest predictor of relapse for pediatric NHL, with the exception being lymphoblastic lymphoma.[4,10] Treating children with B-cell NHL with short, intensive, pulsed multiagent chemotherapy has markedly improved results, particularly in patients with extensive disease. All patients should be considered for entry into a clinical trial.

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 section of this summary for more information.) For reduction of the complications of tumor lysis syndrome, current treatment regimens use a prephase of reduced intensity to cytoreduce patients;[1-4] 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.[11]

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.[12] Data from adult clinical trials have demonstrated that rituximab is active against DLBCL.[13,14] Rituximab has been safely combined with standard doxorubicin, cyclophosphamide, vincristine, and prednisone (CHOP) chemotherapy; in a randomized trial of adults with DLBCL comparing CHOP with CHOP plus rituximab, the rituximab arm demonstrated a superior outcome.[15] In an adult study, rituximab has also been safely combined with an intensive chemotherapy regimen used to treat patients with Burkitt lymphoma.[16] A Children’s Oncology Group (COG) pilot study (COG-ANHL01P1) 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: cyclophosphamide, vincristine, prednisone, methotrexate (IT), high-dose methotrexate, doxorubicin, cytarabine, etoposide. Reduced intensity arm for group B, and full intensity for group C.[3,4]



• NHL-BFM 95: dexamethasone, cyclophosphamide, methotrexate, cytarabine, prednisolone (IT), ifosfamide, etoposide, vindesine, doxorubicin.[2]

• COG-ANHL01P1 : addition of rituximab to FAB/LMB-96–based therapy.

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, 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. Patte C, Auperin A, Michon J, et al.: The Société Française d'Oncologie Pédiatrique LMB89 protocol: highly effective multiagent chemotherapy tailored to the tumor burden and initial response in 561 unselected children with B-cell lymphomas and L3 leukemia. Blood 97 (11): 3370-9, 2001.  [PUBMED Abstract]
   
   
2. 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]
   
   
3. 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]
   
   
4. 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]
   
   
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. 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]
   
   
7. 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]
   
   
8. 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]
   
   
9. 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]
   
   
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 Abstract]
    
    
11. Cairo MS, Bishop M: Tumour lysis syndrome: new therapeutic strategies and classification. Br J Haematol 127 (1): 3-11, 2004.  [PUBMED Abstract]
    
    
12. 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]
    
    
13. Coiffier B, Haioun C, Ketterer N, et al.: Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: a multicenter phase II study. Blood 92 (6): 1927-32, 1998.  [PUBMED Abstract]
    
    
14. Vose JM, Link BK, Grossbard ML, et al.: Long-term update of a phase II study of rituximab in combination with CHOP chemotherapy in patients with previously untreated, aggressive non-Hodgkin's lymphoma. Leuk Lymphoma 46 (11): 1569-73, 2005.  [PUBMED Abstract]
    
    
15. 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]
    
    
16. 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]
    
    

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