RATIONALE: Less intensive therapy may attain in the same results as intensive therapy in children with non-Hodgkin's lymphoma.

PURPOSE: Randomized phase III trial to study the effectiveness of less intensive therapy for children who have non-Hodgkin's lymphoma.

OBJECTIVES:

• Confirm the previously found excellent survival for low-risk patients (Group A) with B-cell lymphoma/leukemia treated with the LMB 89 regimen.
• Verify that good event-free survival is retained in intermediate-risk patients (Group B) when the dose of cyclophosphamide (CTX) or the number of CTX-containing regimens is reduced.
• Verify that good event-free survival is retained in high-risk patients (Group C) despite reduction in doses during consolidation therapy and a reduced number of maintenance courses, and, for patients with CNS involvement, additional intravenous and intrathecal methotrexate in place of cranial irradiation.
• Monitor survival and event-free survival of all patients registered prior to the first chemotherapy course.
• Compare the survival and event-free survival of Group C patients with CNS involvement against results from those treated on the LMB 89 study.
• Compare event-free survival and survival of patients with large cell and Burkitt's and Burkitt's-like lymphoma.
• Monitor the long-term toxicity in patients treated on this study, including fertility, cardiotoxicity, and secondary malignancy.
• Characterize further the biology of childhood small non-cleaved cell lymphoma with respect to drug resistance (i.e., topoisomerase II and MDR activity), viral association (i.e., Epstein-Barr virus, human immunodeficiency virus, human herpesvirus 6), and specific breakpoint translocations (i.e., IgH and C-myc) per companion study CCG-B944.
• Characterize further the biology of childhood mature B-cell lymphoma per UKCCSG studies.

OUTLINE: This is a randomized study. Patients are stratified according to participating group (UKCCSG vs SFOP vs CCG), histology (large cell vs small non-cleaved cell), risk group (Group A vs Group B vs Group C). Stage III Group B patients are further stratified according to Murphy stage (stages I/II vs III vs III/IV) and by LDH (less than twice normal vs twice normal or higher). Group C patients are further stratified based on presence of CNS disease (yes vs no).

Patients with resected stage I and resected abdominal-only stage II disease are treated on the Group A Regimen. Patients with unresected stage I/II, stage III, or CNS-negative stage IV disease with fewer than 25% blasts in bone marrow are treated on the Group B Regimen. Patients with 25% or more blasts in bone marrow or with CNS involvement (i.e., L3 blasts in CSF, cranial nerve palsy, clinical spinal cord compression, isolated intracerebral mass, or parameningeal cranial or spinal extension) are treated on the Group C Regimen.

The following acronyms are used:

• ARA-C Cytarabine, NSC-63878
• CF Leucovorin calcium, NSC-3590
• COP CTX/VCR/PRED (or PRDL)
• COPAD CTX/VCR/PRED (or PRDL)/DOX
• COPADM CTX/VCR/PRED (or PRDL)/DOX/MTX
• CTX Cyclophosphamide, NSC-26271
• CYM ARA- C/MTX
• CYVE ARA-C/VP-16
• DOX Doxorubicin, NSC-123127
• G-CSF Granulocyte Colony-Stimulating Factor (Amgen), NSC-614629
• HC Hydrocortisone, NSC-10483
• HD High Dose
• MTX Methotrexate, NSC-740
• PRDL Prednisolone, NSC-9900
• PRED Prednisone, NSC-10023
• TIT Triple Intrathecal Chemotherapy (IT MTX/IT HC/IT ARA-C)
• VCR Vincristine, NSC-67574
• VP-16 Etoposide, NSC-141540

Group A Regimen (Low-Risk Patients)

• Induction: Patients receive COPAD: VCR IV on days 1 and 6, oral PRED (or IV) twice daily on days 1-5, then tapered over 3 days, CTX IV over 15 minutes every 12 hours on days 1-3, and DOX IV over 6 hours on day 1 starting after the first CTX dose. G-CSF SC is administered until hematopoietic recovery beginning on day 7. Patients receive a second course beginning on day 21.

Group B Regimen (Intermediate-Risk Patients)

• Induction 1: Patients receive CTX IV over 15 minutes on day 1, VCR IV on day 1, and oral PRED on days 1-7, and MTX IT and HC IT on day 1. Patients with responding disease proceed with COPADM. Patients with no response proceed to treatment on arm I of the Group C Regimen.
• COPADM 1: Patients receive VCR IV on day 8, oral PRED twice daily on days 8-12, then tapered over 3 days, MTX IV over 3 hours on day 8, oral CF every 6 hours for 12 doses beginning 24 hours after start of MTX, CTX IV over 15 minutes every 12 hours on days 9-11, and DOX IV over 6 hours on day 9 beginning after the first CTX dose. G-CSF is administered as in the Group A Regimen. MTX IT and HC IT are given on days 9 and 13.
• Group B patients are randomized to 1 of 4 treatments following recovery and disease assessment:

Arm I:

• Induction 2 (begins no sooner than 16 days after start of COPADM 1): Patients receive COPADM 2 according to the same schedule as in COPADM 1 in Induction 1 except CTX is increased. G-CSF is administered as in the Group A Regimen. Patients receive MTX IT and HC IT on days 2 and 6.
• Consolidation: Patients receive CYM: MTX IV over 3 hours on day 1, oral CF every 6 hours for a maximum of 12 doses beginning 24 hours after the start of MTX, and ARA-C IV over 24 hours on days 2-6. Patients receive TIT: MTX IT on day 2, HC IT on days 2 and 7, and ARA-C IT on day 7.
• Response is assessed upon recovery with resection of residual masses. If histology is negative patients proceed to a second course of CYM. If histology is positive patients proceed to CYVE on arm I of the Group C Regimen.
• Maintenance: Patients receive COPADM 3 as in COPADM 1 in Induction 1, except CTX IV is administered over 30 minutes on days 2 and 3, and MTX IT and HC IT are administered on day 2.

Arm II:

• Induction 2: Patients receive COPADM 2 as in arm I of the Group B Regimen. G-CSF is administered as in the Group A Regimen. MTX IT and HC IT are administered as in Induction 1.
• Consolidation: Patients receive CYM, TIT, and response assessment as in arm I of the Group B Regimen.
• Maintenance: Patients receive no maintenance therapy.

Arm III:

• Induction 2: Patients receive COPADM 2 as in COPADM 1 in Induction 1. G-CSF is administered as in the Group A Regimen. Patients receive MTX IT and HC IT as in Induction 1.
• Consolidation: Patients receive CYM, TIT, and response assessment as in arm I of the Group B Regimen.
• Maintenance: Patients receive COPADM 3 as in arm I of the Group B Regimen. Patients receive MTX IT and HC IT on day 2.

Arm IV:

• Induction 2: Patients receive COPADM 2 as in COPADM 1 in Induction 1. G-CSF is administered as in the Group A Regimen. Patients receive MTX IT and HC IT as in Induction 1.
• Consolidation: Patients receive CYM, TIT, and response assessment as in arm I of the Group B Regimen.
• Maintenance: Patients receive no maintenance therapy.

Group C Regimen (High-Risk Patients)

• Induction: Patients receive COP as in Induction 1 of the Group B Regimen, TIT on days 1, 3, and 5, and oral CF every 12 hours on days 2 and 4. Tumor response is evaluated on day 7 and treatment decisions are made as in Induction 1 of the Group B Regimen. Patients receive COPADM 1 as in COPADM 1 in Induction 1 of the Group B Regimen except HD MTX IV is given over 4 hours on day 1. G-CSF is administered as in the Group A Regimen. TIT is given on days 2, 4, and 6. Patients receive COPADM 2 as in COPADM 2 in arm I of the Group B Regimen, Induction 2 except HD MTX IV is given over 4 hours on day 1. G-CSF is administered as in the Group A Regimen. Patients receive TIT on days 2, 4, and 6.
• Patients are randomized to 1 of 2 treatment arms upon recovery and disease assessment:

Arm I:

• Consolidation: Patients receive CYVE: ARA-C IV on days 1-5, and VP-16 IV over 2 hours on days 2-5. G-CSF is administered as in the Group A Regimen. For patients with CNS disease: MTX IT and HC IT on day 1, 6 hours prior to initiation of ARA-C, HD MTX IV over 4 hours, about day 18, oral CF every 6 hours for a maximum of 12 doses, beginning 24 hours after starting MTX, and TIT prior to beginning CF.
• Response is assessed upon recovery with resection of residual masses. Patients with a complete response receive a second course of CYVE (no HD MTX/CF), beginning 1 week after HD MTX.

• Maintenance (28 days between courses):

  • Course 1: Patients receive COPADM as in arm I Maintenance in the Group B Regimen, except HD MTX is administered as in Group C Induction, and TIT is given on day 2 replacing MTX IT and HC.
  • Course 2: Patients receive CYVE: ARA-C IV every 12 hours on days 1-5, and VP-16 IV over 90 minutes on days 1-3.
  • Course 3: Patients receive COPAD as in Group B Induction 1, except CTX IV is administered over 30 minutes on days 1 and 2.
  • Course 4: Patients receive treatment identical to Course 2.

Arm II:

• Consolidation: Patients receive Mini-CYVE: ARA-C IV on days 1-5, and VP-16 IV over 1 hour on days 2-5. G-CSF is administered as in the Group A Regimen. For patients with CNS disease: MTX IT and HC IT as in arm I in the Group C Regimen, and HD MTX, CF, and TIT as in arm I in the Group C Regimen.
• Response is assessed upon recovery with resection of residual masses. Patients with a complete response receive a second course of CYVE (no HD MTX and CF) beginning 1 week after HD MTX.
• Maintenance: Patients receive COPADM and TIT as in arm I of the Group C Regimen in Course 1 for 1 course only.

Patients are followed every 3 months for 6 months, every 6 months for 2.5 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 900 patients will be accrued for this study within 5 years. Yearly accrual is expected to be 20 Group A patients, 115 Group B patients, and 45 Group C patients.

• Leukemia
• Lymphoma

• Biological: filgrastim
• Drug: CHOP regimen
• Drug: cyclophosphamide
• Drug: cytarabine
• Drug: doxorubicin hydrochloride
• Drug: etoposide
• Drug: leucovorin calcium
• Drug: methotrexate
• Drug: prednisolone
• Drug: prednisone
• Drug: therapeutic hydrocortisone
• Drug: vincristine sulfate

• Poirel HA, Cairo MS, Heerema NA, Swansbury J, Aupérin A, Launay E, Sanger WG, Talley P, Perkins SL, Raphaël M, McCarthy K, Sposto R, Gerrard M, Bernheim A, Patte C; FAB/LMB 96 International Study Committee. 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. 2009 Feb;23(2):323-31. Epub 2008 Nov 20.
• Gerrard M, Cairo MS, Weston C, Auperin A, Pinkerton R, Lambilliote A, Sposto R, McCarthy K, Lacombe MJ, Perkins SL, Patte C; FAB LMB96 International Study Committee. 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. 2008 Jun;141(6):840-7. Epub 2008 Mar 26.
• Miles RR, Raphael M, McCarthy K, Wotherspoon A, Lones MA, Terrier-Lacombe MJ, Patte C, Gerrard M, Auperin A, Sposto R, Davenport V, Cairo MS, Perkins SL; SFOP/LMB96/CCG5961/UKCCSG/NHL 9600 Study Group. Pediatric diffuse large B-cell lymphoma demonstrates a high proliferation index, frequent c-Myc protein expression, and a high incidence of germinal center subtype: Report of the French-American-British (FAB) international study group. Pediatr Blood Cancer. 2008 Sep;51(3):369-74.
• Cairo MS, Gerrard M, Sposto R, Auperin A, Pinkerton CR, Michon J, Weston C, Perkins SL, Raphael M, McCarthy K, Patte C. Results of a randomized international study of high risk central nervous system B-non-Hodgkin's lymphoma and B-acute lymphoblastic leukemia in children and adolescents. Blood. 2006 Nov 30; [Epub ahead of print]
• Patte C, Auperin A, Gerrard M, Michon J, Pinkerton R, Sposto R, Weston C, Raphael M, Perkins SL, McCarthy K, Cairo MS. Results of the randomized international FAB/LMB96 trial for intermediate risk B-cell non-Hodgkin's lymphoma in children and adolescents: it is possible to reduce treatment for the early responding patients. Blood. 2006 Nov 28; [Epub ahead of print]
• Lones MA, Cairo MS, Perkins SL. T-cell-rich large B-cell lymphoma in children and adolescents: a clinicopathologic report of six cases from the Children's Cancer Group Study CCG-5961. Cancer. 2000 May 15;88(10):2378-86.
• Lones MA, Raphael M, Perkins SL, Wotherspoon A, Auperin A, Terrier-Lacombe MJ, Sposto R, Weston C, Gerrard M, Patte C, Cairo MS, McCarthy K. Mature B-cell lymphoma in children and adolescents: International group pathologist consensus correlates with histology technical quality. J Pediatr Hematol Oncol. 2006 Sep;28(9):568-74.

DISEASE CHARACTERISTICS:

• One of the following diagnoses:

  • Newly diagnosed B-cell non-Hodgkin's lymphoma in Revised European-American Lymphoma (REAL) categories II 9, 10, and 11, i.e.:

    • Diffuse large cell
    • Burkitt's
    • High-grade B-cell, Burkitt's-like
  • L3 leukemia with greater than 5% blasts in bone marrow
• No anaplastic large cell Ki1-positive lymphomas
• Immunophenotype and Murphy stage required prior to randomization

PATIENT CHARACTERISTICS:

Age:

• Over 6 months to under 21 years

  • Maximum age 18 years in France and the United Kingdom

Other:

• No congenital immunodeficiency
• No prior organ transplantation
• No prior malignancy
• Not HIV positive
• Available for at least 36 months of follow-up

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• Not specified

Chemotherapy:

• No prior chemotherapy

Endocrine therapy:

• Steroids initiated no more than 72 hours prior to entry allowed

  • Bone marrow and cerebrospinal fluid examination required prior to steroids

Radiotherapy:

• Emergency radiotherapy initiated no more than 72 hours prior to entry allowed

Surgery:

• Not specified

• National Cancer Institute (NCI)
• Societe Francaise Oncologie Pediatrique
• Children's Cancer and Leukaemia Group