Chemotherapy and Rituximab With or Without Total-Body Irradiation and Peripheral Stem Cell Transplant in Treating Patients With Lymphoma

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Monoclonal antibodies such as rituximab can locate cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells. Combining chemotherapy with monoclonal antibody therapy, total-body irradiation, and peripheral stem cell transplant may allow the doctor to give higher doses of chemotherapy drugs and kill more cancer cells. PURPOSE: This phase II trial is studying how well giving chemotherapy with rituximab followed by combination chemotherapy with or without rituximab, total-body irradiation, and peripheral stem cell transplant works in treating patients with lymphoma.

Detailed Description
-----------------
OUTLINE: Patients are stratified according to risk (low-intermediate vs high-intermediate or high). Patients receive induction chemotherapy comprising cyclophosphamide IV, doxorubicin IV over 15 minutes, and vincristine IV over 1-2 minutes on day 1; oral prednisone once daily on days 1-5; and filgrastim (G-CSF) subcutaneously (SC) once daily on days 7-11 or PEG-filgrastim once at least 24 hours after infusion. Patients also receive rituximab IV 2-3 days apart for a total of 2 doses during the week prior to the first course of chemotherapy and on day 1 of courses 2-4 of chemotherapy. Treatment repeats every 14 days for a total of 4 courses in the absence of disease progression or unacceptable toxicity. After the completion of induction chemotherapy, patients undergo CT scan and positron emission tomography (PET) scanning. If the PET scan is positive in one or more nodal sites, a repeat biopsy is performed. Patients with a negative PET scan OR a negative repeat biopsy (including no evidence of lymphoma on repeat bone marrow biopsy) are assigned to receive regimen A for consolidation therapy. Patients with a positive repeat biopsy are assigned to receive regimen B for consolidation therapy. Regimen A: Patients receive consolidation chemotherapy comprising etoposide IV over 1 hour on days 1-3, ifosfamide IV continuously over 24 hours on day 2, carboplatin IV on day 2, and G-CSF SC once daily on days 5-12 or PEG-filgrastim once at least 24 hours after infusion. Treatment repeats every 14 days for a total of 3 courses in the absence of disease progression or unacceptable toxicity. Regimen B: Patients receive consolidation chemotherapy as in regimen A for 3 courses. Patients also receive rituximab IV on days -3 to -1 of course 3 of chemotherapy. Patients undergo leukapheresis at the completion of course 3 (G-CSF continues from day 5 until the end of leukapheresis). After completion of leukapheresis, patients begin a regimen of high-dose chemoradiotherapy comprising either total body irradiation twice daily on days -10 to -7 and ifosfamide IV over 1 hour and etoposide IV continuously on days -6 to -2 or BEAM chemotherapy comprising carmustine, etoposide, cytarabine, and melphalan. Autologous peripheral blood stem cells (APBSC) are reinfused on day 0. Patients also receive G-CSF SC daily beginning on day 5 and continuing until blood counts recover. Beginning on day 42 post-APBSC, if blood counts have recovered, patients receive rituximab IV once weekly for 4 weeks. Rituximab is repeated beginning on day 180 in the absence of disease progression. Patients who receive consolidation therapy on regimen A are followed at 4-6 weeks after chemotherapy and patients who receive consolidation therapy on regimen B are followed at 90-120 days after transplantation. All patients are followed closely for 5 years and then annually thereafter. PROJECTED ACCRUAL: A total of 40-98 patients will be accrued for this study within 4 years.

Official Title
-----------------
Risk-Adapted Therapy for Patients With Untreated Age-Adjusted International Prognostic Index II or III Diffuse Large B Cell Lymphoma

Conditions
-----------------
Lymphoma

Intervention / Treatment
-----------------
* Biological: filgrastim
* Biological: rituximab
* Drug: carboplatin
* Drug: cyclophosphamide
* Drug: doxorubicin hydrochloride
* Drug: etoposide
* Drug: ifosfamide
* Drug: prednisone
* Drug: vincristine sulfate
* Procedure: peripheral blood stem cell transplantation
* Radiation: radiation therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
DISEASE CHARACTERISTICS: Histologically confirmed aggressive diffuse large B-cell lymphoma CD20-positive disease Age-adjusted International Prognostic Index II or III defined by the presence of at least 1 of the following: Karnofsky performance status 10-70% Lactate dehydrogenase greater than 200 U/L Stage III or IV disease Positron emission tomography avid measurable disease No CNS involvement PATIENT CHARACTERISTICS: Age: 18 to 64 Performance status: See Disease Characteristics Life expectancy: Not specified Hematopoietic: Absolute neutrophil count greater than 1,000/mm^3 Platelet count greater than 50,000/mm^3 Hepatic: Bilirubin less than 2.0 mg/dL unless history of Gilbert's disease or pattern consistent with Gilbert's disease Hepatitis B surface antigen and hepatitis C antibody negative No chronic, active, or persistent hepatitis Renal: Creatinine no greater than 1.5 mg/dL OR Creatinine clearance greater than 60 mL/min No chronic renal insufficiency Cardiovascular: Ejection fraction at least 50% by echocardiogram or MUGA scan No myocardial infarction within the past 6 months No unstable angina No cardiac arrhythmias except chronic atrial fibrillation Other: Not pregnant or nursing Negative pregnancy test Fertile patients must use effective barrier contraception HIV negative No other medical illness that would preclude study No uncontrolled infection No other malignancy within the past 5 years except curatively treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix PRIOR CONCURRENT THERAPY: Biologic therapy: No prior biologic therapy for malignancy Chemotherapy: No prior chemotherapy for malignancy Endocrine therapy: Prior steroids allowed if received no more than 1 week of therapy Radiotherapy: No prior radiotherapy for malignancy Surgery: No prior surgery for malignancy Other: No other prior therapy for malignancy

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Induction R-CHOPac Therapy for patients with B-Cell Lymphoma<br>Patients received 4 cycles if accelerated R-CHOP (cyclophosphamide. doxorubicin, vincristine and prednisone + rituximab) followed by 3 cycles ICE (ifosfamide, carboplatin and etoposide) consolidation therapy. | Biological: filgrastim<br> <br> Biological: rituximab<br> <br> Drug: carboplatin<br> <br> Drug: cyclophosphamide<br> <br> Drug: doxorubicin hydrochloride<br> <br> Drug: etoposide<br> <br> Drug: ifosfamide<br> <br> Drug: prednisone<br> <br> Drug: vincristine sulfate<br> <br> Procedure: peripheral blood stem cell transplantation<br> <br> Radiation: radiation therapy<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival | Kaplan-Meier estimates will be used to verify the progression free survival. | 2 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
stage I adult diffuse large cell lymphoma, stage III adult diffuse large cell lymphoma, stage IV adult diffuse large cell lymphoma, contiguous stage II adult diffuse large cell lymphoma, noncontiguous stage II adult diffuse large cell lymphoma