S0501 Fludarabine, Melphalan, and Donor Stem Cell Transplant Followed By Tacrolimus and Methotrexate in Treating Patients for Relapsed Lymphoma

Study Overview
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Brief Summary
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RATIONALE: Giving low doses of chemotherapy, such as fludarabine and melphalan, before a donor bone marrow or peripheral blood stem cell transplant helps stop the growth of cancer cells. It also stops the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune system and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving tacrolimus and methotrexate after transplant may stop this from happening. PURPOSE: This phase II trial is studying how well giving fludarabine together with melphalan followed by tacrolimus and methotrexate works in treating patients who are undergoing a donor stem cell transplant for relapsed lymphoma.

Detailed Description
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OBJECTIVES: Determine the 1-year progression-free and overall survival rate in patients with relapsed Hodgkin's or non-Hodgkin's lymphoma after prior autologous stem cell transplantation treated with a nonmyeloablative conditioning regimen comprising fludarabine and melphalan followed by allogeneic bone marrow or peripheral blood stem cell transplantation and immunosuppression comprising tacrolimus and methotrexate. Determine treatment-related mortality in patients treated with this regimen. Determine the toxic effects of this regimen in these patients. Determine engraftment of donor hematopoietic stem cells, as measured by hematopoietic recovery and donor-derived hematopoiesis (determined by T cell and neutrophil specific chimerism) at 2, 3, 6, and 12 months, in patients treated with this regimen. Determine the incidence of acute and chronic graft-versus-host disease in patients treated with this regimen. OUTLINE: This is a multicenter study. Patients are stratified according to diagnosis (Hodgkin's lymphoma vs non-Hodgkin's lymphoma). Patients receive fludarabine IV over 1 hour on days -6 to -2 and melphalan IV over 15-20 minutes on days -3 and -2. Patients undergo allogeneic peripheral blood stem cell or bone marrow transplantation on day 0. Patients receive oral tacrolimus twice daily beginning on day -3 and continuing until day 100 followed by a taper to day 180. Patients also receive methotrexate IV on days 1, 3, and 7. Treatment continues in the absence of disease progression or unacceptable toxicity. After completion of study transplantation, patients are followed at 1 and 3 months, 1 year, and then annually for up to 4 years. PROJECTED ACCRUAL: A total of 50 patients will be accrued for this study within 2 years.

Official Title
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Nonmyeloablative Allogeneic Stem Cell Transplantation For Relapsed Hodgkin's or Non-Hodgkin's Lymphoma After Autologous Transplantation ( A BMT Study)

Conditions
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Lymphoma

Intervention / Treatment
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* Drug: fludarabine phosphate
* Drug: melphalan
* Drug: methotrexate
* Drug: tacrolimus
* Procedure: allogeneic bone marrow transplantation
* Procedure: peripheral blood stem cell transplantation


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of lymphoma of 1 of the following types: Diffuse large B-cell lymphoma Follicular lymphoma Grades 1, 2, or 3 Primary mediastinal lymphoma Mantle cell lymphoma Small lymphocytic lymphoma Hodgkin's lymphoma Transformed lymphoma Relapsed after prior autologous bone marrow transplantation (BMT) More than 180 days post BMT Received ≥ 1 course of chemotherapy after BMT relapse Achieved a complete response OR a partial response to chemotherapy Largest residual tumor dimension ≤ 2 cm No clinical or laboratory evidence of CNS involvement by lymphoma HLA-identical donor available, meeting 1 of the following criteria: Sibling donor with 5/6 or 6/6 alleles matching by genotyping No monozygotic identical twins Unrelated donor with 10/10 alleles matching by genotyping PATIENT CHARACTERISTICS: Age 18 and over Performance status Zubrod 0-2 Life expectancy Not specified Hematopoietic Not specified Hepatic Not specified Renal Not specified Cardiovascular LVEF ≥ 40% by MUGA or 2-D echocardiogram (2-D ECHO) No significant cardiac abnormalities by MUGA or 2-D ECHO No uncompensated coronary artery disease by ECG or physical exam None of the following within the past 6 months: Myocardial infarction Unstable angina Uncontrolled atrial fibrillation None of the following within the past 3 months: Severe peripheral vascular disease Venous stasis ulcers Deep venous or arterial thrombosis No uncontrolled hypertension Pulmonary DLCO (corrected) and total lung capacity ≥ 40% of predicted No requirement for continuous supplemental oxygen Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception HIV negative No AIDS No active bacterial, viral, or fungal infection No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix No history of uncontrolled seizures No diabetic ulcers within the past 3 months PRIOR CONCURRENT THERAPY: Biologic therapy See Disease Characteristics No more than 1 prior bone marrow transplantation Chemotherapy See Disease Characteristics More than 21 days since prior chemotherapy and recovered Endocrine therapy Not specified Radiotherapy More than 4 weeks since prior radiotherapy Surgery More than 4 weeks since prior major surgery except placement of a venous access device

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nonmyeloablative allogeneic stem cell transplant<br>Patients are given fludarabine 30 mg/m^2 on days -6 to -2 and melphalan 70 mg/m^2 on days -3 and -2, then transplanted with donor peripheral blood stem cells or harvested bone marrow stem cells on day 0. Patients are then given post-transplant immunosuppression consisting of tacrolimus 0.06 mg/kg/day on days -3 to 100 and methotrexate 5 mg/m^2 on days 1, 3, and 7. | Drug: fludarabine phosphate<br>* 30 mg/m^2 on days -6 to -2 (2-6 days before transplant).<br>Drug: melphalan<br>* 70 mg/m^2 on days -3 and -2 (2-3 days before transplant).<br>Drug: methotrexate<br>* 5 mg/m^2 on days 1, 3, and 7 post-transplant.<br>Drug: tacrolimus<br>* 0.03 mg/kg bid on days -3 to 100 post-transplant.<br>Procedure: allogeneic bone marrow transplantation<br>* if donor bone marrow stem cells are harvested<br>Procedure: peripheral blood stem cell transplantation<br>* if donor peripheral blood stem cells are harvested<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | PFS rate at 1 year. | 1, 3, and 12 months after protocol treatment, then every 3 months for 1 year, every 6 months for year 2, then annually thereafter until 5 years after registration | 
| Overall Survival | OS rate at 1 year. | 1, 3, and 12 months after protocol treatment, then every 3 months for 1 year, every 6 months for year 2, then annually thereafter until 5 years after registration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent adult Hodgkin lymphoma, recurrent small lymphocytic lymphoma, recurrent mantle cell lymphoma, recurrent grade 1 follicular lymphoma, recurrent grade 2 follicular lymphoma, recurrent grade 3 follicular lymphoma, recurrent adult diffuse large cell lymphoma