TITLE:Less Intensive Therapy for Children With Non-Hodgkin's Lymphoma

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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FAB LMB 96 -- Treatment of Mature B-CELL Lymphoma/Leukemia: A SFOP LMB 96/CCG 5961/UKCCSG NHL 9600 Cooperative Study

Conditions
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Leukemia, Lymphoma

Intervention / Treatment
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* Biological: filgrastim
* Drug: cyclophosphamide
* Drug: cytarabine
* Drug: doxorubicin hydrochloride
* Drug: etoposide
* Drug: methotrexate
* Drug: prednisolone
* Drug: prednisone
* Drug: therapeutic hydrocortisone
* Drug: vincristine sulfate


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Maximum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group A<br>All resected stage I and Abdominal stage II only. All Group A patients will be treated with two cycles of COPAD and will be followed in a confirmatory study of the current result of nearly 100% cure rate. | Biological: filgrastim<br> <br> * Other names: NSC-614629;Drug: cyclophosphamide<br> <br> * Other names: NSC-26271;Drug: doxorubicin hydrochloride<br> <br> * Other names: NSC-123127;Drug: prednisone<br> <br> * Other names: NSC-10023;Drug: vincristine sulfate<br> <br> * Other names: NSC-675574;|
| Active Comparator: Group B<br>Non resected stage I & II, stage III & st IV (CNS - ve, BM < 25%). Patients with bulky disease are at risk from metabolic complications secondary to tumor lysis syndrome. Vigorous measures should be taken to minimise the risk of this. Prior to any chemotherapy being administered intravenous hydration fluids should be given run at a rate of 3000 mls/m2/day. Alkalinisation may be necessary Pay close attention to fluid balance and continue hydration fluids after the administration of COP for as long as the risk of tumour lysis persists. | Biological: filgrastim<br> <br> * Other names: NSC-614629;Drug: cyclophosphamide<br> <br> * Other names: NSC-26271;Drug: doxorubicin hydrochloride<br> <br> * Other names: NSC-123127;Drug: methotrexate<br> <br> * Other names: NSC-740;Drug: prednisolone<br> <br> * Other names: NSC-10023;Drug: prednisone<br> <br> * Other names: NSC-10023;Drug: therapeutic hydrocortisone<br> <br> * Other names: NSC-10483;Drug: vincristine sulfate<br> <br> * Other names: NSC-675574;|
| Active Comparator: Group C<br>Bone marrow > 25% but CNS negative Patients with bulky disease are at risk from metabolic complications secondary to tumor lysis syndrome. Vigorous measures should be taken to minimize the risk of this. Intravenous hydration fluids should be given prior to chemotherapy. Alkalinisation may be necessary. Monitor fluid balance and continue hydration fluids after the administration of COP for as long as the risk of tumor lysis persists | Biological: filgrastim<br> <br> * Other names: NSC-614629;Drug: cyclophosphamide<br> <br> * Other names: NSC-26271;Drug: cytarabine<br> <br> * Other names: NSC-63878;Drug: doxorubicin hydrochloride<br> <br> * Other names: NSC-123127;Drug: etoposide<br> <br> * Other names: NSC-141540;Drug: methotrexate<br> <br> * Other names: NSC-740;Drug: prednisolone<br> <br> * Other names: NSC-10023;Drug: therapeutic hydrocortisone<br> <br> * Other names: NSC-10483;Drug: vincristine sulfate<br> <br> * Other names: NSC-675574;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event Free Survival | Minimum time to death from any cause, relapse, or progressive disease, measured from the beginning of chemotherapy. Failure to respond to initial COP therapy, and biopsy positive residual disease at the third evaluation are not considered failures in this definition. However, death, relapse or disease progression following protocol mandated therapy intensification after these occurrences will be considered failures. In addition, biopsy positive residual disease at the completion of intensification is considered an event. |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Conditional Survival | Time to death from any cause, measured from the time of randomization in Groups B and C. |  | 
| Failure Free Survival | Minimum time to death from any cause, progressive disease before the third evaluation, no CR at the third evaluation, relapse after the third evaluation, measured from the beginning of chemotherapy. Failure to respond to COP therapy in Groups B and C is not considered a treatment failure, but biopsy positive residual disease after the third evaluation are considered failures in this definition. |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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childhood Burkitt lymphoma, untreated childhood acute lymphoblastic leukemia, L3 childhood acute lymphoblastic leukemia, stage I childhood small noncleaved cell lymphoma, stage I childhood large cell lymphoma, stage II childhood small noncleaved cell lymphoma, stage II childhood large cell lymphoma, stage III childhood small noncleaved cell lymphoma, stage III childhood large cell lymphoma, stage IV childhood small noncleaved cell lymphoma, stage IV childhood large cell lymphoma