Combination Chemotherapy in Treating Patients With Lymphoma

A Randomized Prospective Study of Early Intensification Versus Alternating Triple Therapy for Patients With Poor Prognosis Lymphoma

RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Combining chemotherapy with peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more cancer cells. PURPOSE: Randomized phase III trial to compare the effectiveness of two regimens of combination chemotherapy in treating patients who have intermediate-grade or immunoblastic lymphoma.

OBJECTIVES: Compare the efficacy of early intensification vs alternating triple chemotherapy in patients with intermediate-grade or immunoblastic lymphoma with poor prognostic features. Compare, in a prospective manner, the cost/benefit ratio of these regimens in these patients. Determine the value of monitoring minimal residual disease detection via in vitro culture methods and polymerase chain reaction analysis of peripheral stem cell apheresis products and by longitudinal monitoring of blood and bone marrow samples in these patients treated with these regimens. OUTLINE: This is a randomized study. Patients are stratified according to tumor score (3 or 4 vs 5 or 6). During the first course of induction, patients receive IDSHAP comprising idarubicin (IDA) and cisplatin IV continuously on days 1-4, cytarabine (ARA-C) IV over 2 hours on day 5, and methylprednisolone (MePRDL) IV over 15 minutes on days 1-5. During the second course of induction, patients receive MBIDCOS comprising vincristine, bleomycin, and cyclophosphamide IV over 15 minutes on day 1, IDA IV continuously and MePRDL IV over 15 minutes on days 1-3, methotrexate (MTX) IV over 2 hours on day 10, and oral leucovorin calcium every 6 hours on days 11 and 12. Each course lasts 3 weeks in the absence of disease progression or unacceptable toxicity. Patients with stable or responding disease after induction are randomized to 1 of 2 treatment arms. Arm I Patients receive the following 3 courses of early intensification. First course: Patients receive ifosfamide (IFF) IV continuously and etoposide (VP-16) IV over 2 hours every 12 hours on days 1-3. Filgrastim (G-CSF) is administered subcutaneously (SC) beginning on day 5 and continuing until blood counts recover and then autologous peripheral blood stem cells (PBSC) are harvested, selected for CD34 positive cells, and purged in vitro. If more than 5% of the WBC contains lymphoma cells after induction, then 2 courses of IFF and VP-16 are administered before PBSC harvest. Second course: Patients receive IFF IV continuously on days 1-3, mitoxantrone (DHAD) IV on day 1, and G-CSF SC as in the first course. Third course: Patients receive carmustine IV over 1 hour on day -6, ARA-C and VP-16 IV every 12 hours on days -5 to -2, and melphalan IV on day -1. PBSC are reinfused on day 0. G-CSF is administered SC beginning on day 0 and continuing until blood counts recover. Each course lasts 3 weeks in the absence of disease progression or unacceptable toxicity. Arm II Patients receive IDSHAP during courses 2 and 5, MBIDCOS during courses 3 and 6, and IFF and VP-16 IV over 1 hour on days 1-3 and DHAD IV over 15 minutes on day 1 during courses 1, 4, and 7. Each course lasts 4 weeks in the absence of disease progression or unacceptable toxicity. Patients with residual disease after completion of arm I or II treatment undergo radiotherapy to areas of bulk disease if feasible. Patients on both arms with meningeal involvement receive ARA-C intrathecally (IT) alternated with MTX every other day until 1 week after clearing of CNS disease and then 2 IT injections during every course of chemotherapy thereafter. Patients with divergent histology who achieve complete response after completion of arm I or II treatment receive interferon alfa 3 times a week for 1 year. Patients are followed at 1 month, every 3 months for 1 year, every 6 months for 1 year, and then annually for 2 years. PROJECTED ACCRUAL: A maximum of 136 patients will be accrued for this study within 4 years.

stage I grade 3 follicular lymphoma, stage I adult diffuse small cleaved cell lymphoma, stage I adult diffuse mixed cell lymphoma, stage I adult diffuse large cell lymphoma, stage I adult immunoblastic large cell lymphoma, stage III grade 3 follicular lymphoma, stage III adult diffuse small cleaved cell lymphoma, stage III adult diffuse mixed cell lymphoma, stage III adult diffuse large cell lymphoma, stage III adult immunoblastic large cell lymphoma, stage IV grade 3 follicular lymphoma, stage IV adult diffuse small cleaved cell lymphoma, stage IV adult diffuse mixed cell lymphoma, stage IV adult diffuse large cell lymphoma, stage IV adult immunoblastic large cell lymphoma, contiguous stage II grade 3 follicular lymphoma, contiguous stage II adult diffuse small cleaved cell lymphoma, contiguous stage II adult diffuse mixed cell lymphoma, contiguous stage II adult immunoblastic large cell lymphoma, contiguous stage II adult diffuse large cell lymphoma, noncontiguous stage II grade 3 follicular lymphoma, noncontiguous stage II adult diffuse small cleaved cell lymphoma, noncontiguous stage II adult diffuse mixed cell lymphoma, noncontiguous stage II adult immunoblastic large cell lymphoma, noncontiguous stage II adult diffuse large cell lymphoma

3 courses of early intensification: First course: Ifosfamide (IFF) IV continuously and Etoposide (VP-16) IV over 2 hours every 12 hours on days 1-3. Filgrastim (G-CSF) administered subcutaneously (SC) beginning on day 5 and continuing until blood counts recover then autologous peripheral blood stem cells (PBSC) are harvested, selected for CD34 positive cells, and purged in vitro. If more than 5% of the WBC contains lymphoma cells after induction, then 2 courses of IFF and VP-16 are administered before PBSC harvest. Second course: IFF IV continuously on days 1-3, mitoxantrone (DHAD) IV on day 1, and G-CSF SC as in first course. Third course: Carmustine IV over 1 hour on day -6, ARA-C and VP-16 IV every 12 hours on days -5 to -2, and melphalan IV on day -1. PBSC are reinfused on day 0. G-CSF is administered SC beginning on day 0 and continuing until blood counts recover. Each course lasts 3 weeks in the absence of disease progression or unacceptable toxicity.

IDSHAP during 4 week courses 2 and 5, MBIDCOS during courses 3 and 6, and IFF and VP-16 IV over 1 hour on days 1-3 and DHAD IV over 15 minutes on day 1 during courses 1, 4, and 7.

Arm 1: Administered subcutaneously (SC) beginning on day 5 and continuing until blood counts recover through Course 1 then 2 courses administered before PBSC harvest and same regimen with Course 2, then daily with Day 0 of infusion.

DISEASE CHARACTERISTICS: Diagnosis of previously untreated intermediate-grade or immunoblastic lymphoma Tumor score of 3 or greater, defined by the presence of 3 or more of the following criteria : Ann Arbor stage III or IV disease B symptoms (fever, sweats, and weight loss greater than 10%) At least 1 tumor mass greater than 7 cm or mediastinal mass visible on plain chest x-ray Beta-2 microglobulin at least 3.0 Lactic dehydrogenase at least 1.1 times the upper limit of normal T- and B-cell lymphomas allowed if intermediate grade or immunoblastic Divergent histologies, including bone marrow involvement, allowed CNS involvement allowed NOTE: A new classification scheme for adult non-Hodgkin's lymphoma has been adopted by PDQ. The terminology of "indolent" or "aggressive" lymphoma will replace the former terminology of "low", "intermediate", or "high" grade lymphoma. However, this protocol uses the former terminology. PATIENT CHARACTERISTICS: Age: 15 to 59 Performance status: Not specified Life expectancy: Not specified Hematopoietic: Not specified Hepatic: Bilirubin less than 2.0 mg/dL (unless elevation due to lymphoma) Renal: Creatinine no greater than 1.5 mg/dL (unless elevation due to lymphoma) Cardiovascular: LVEF greater than 50% by echocardiogram if over age 45 No congestive heart failure, angina, history of myocardial infarction, or arrhythmia unless cleared by principal investigator after cardiology consultation Pulmonary: No history of chronic obstructive or restrictive lung disease Pulmonary consultation required for smokers or patients with questionable lung function Other: HIV negative Not pregnant or nursing Fertile patients must use effective contraception No prior malignancy with poor prognosis (less than 90% probability of surviving for 5 years) No geographic, economic, emotional, or social condition that would preclude study PRIOR CONCURRENT THERAPY: Biologic therapy No prior biologic therapy Chemotherapy No prior chemotherapy Endocrine therapy No prior endocrine therapy Radiotherapy No prior radiotherapy Surgery Not specified