Optimized Donor Selection, Nonmyeloablative BMT for B-cell Lymphomas With Post-transplantation Cy and Rituximab

Study Overview
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Brief Summary
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This phase II trial is studying how well giving fludarabine and cyclophosphamide together with total-body irradiation and rituximab works in treating patients with B-cell lymphoma or chronic lymphocytic leukemia who are undergoing an allogeneic (donor) bone marrow transplant. The type of bone marrow transplant is a less intensive or mini transplant using a relative as the bone marrow donor. The donated bone marrow stem cells may replace the patient's immune system cells and help destroy any remaining cancer (graft-versus-tumor effect). Patients undergoing this type of transplant often have more than one relative who could be a donor. The trial is also studying a new way of choosing amongst possible donors which might improve how the rituximab works.

Detailed Description
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This phase II for relapsed or refractory B-cell malignancies builds on the platform of nonmyeloablative, related-donor, HLA (human leukocyte antigen)-matched or HLA-haploidentical BMT with post-transplantation high-dose cyclosphosphamide administered for prophylaxis of graft-versus-host disease and graft rejection. Rituximab is added to the transplant regimen with the goal of augmenting anti-tumor activity. In patients with B-cell lymphomas, specific polymorphisms in the immunoglobulin Fc receptor have been associated with greater sensitivity to rituximab or rituximab-based therapies, translating in some series into higher response rates and improved progression-free survival. This raises the possibility of selecting donors who carry this permissive polymorphism. This trial identifies and selects donors who have the favorable polymorphism at FcgammaR3A-158, thereby potentially conferring greater sensitivity to rituximab in the host after BMT.

Official Title
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Nonmyeloablative BMT With Post-transplant Cyclophosphamide, Rituximab and Optimized Donor Selection for B-cell Lymphomas

Conditions
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Lymphoma, B-cell Lymphoma, Non Hodgkin Lymphoma, Chronic Lymphocytic Leukemia

Intervention / Treatment
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* Drug: Fludarabine
* Drug: Cyclophosphamide
* Radiation: Total body irradiation
* Drug: Tacrolimus
* Drug: Mycophenolate Mofetil
* Drug: Rituximab
* Biological: Allogeneic Bone Marrow Transplant (BMT)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Poor-risk CD20+, B-cell lymphoma, as follows: Low grade B-cell lymphoma that has failed at least two prior therapies (excluding single agent rituximab), or undergone histologic conversion (if histologic conversion, PR or CR is required): Follicular grade 1 or 2 lymphoma Follicular lymphoma not otherwise specified Marginal zone (or MALT) lymphoma Lymphoplasmacytic lymphoma / Waldenstrom's macroglobulinemia Hairy cell leukemia Small lymphocytic lymphoma / chronic lymphocytic leukemia (SLL/CLL) Low grade B-cell lymphoma, unspecified Nodular lymphocyte-predominant Hodgkin lymphoma Poor-risk small lymphocytic lymphoma or chronic lymphocytic leukemia, defined by a 17p deletion, 11q deletion, or histologic conversion (if histologic conversion, PR or CR is required) Aggressive B-cell non-Hodgkin's lymphoma that has failed at least one prior regimen of multiagent chemotherapy, is in PR (partial remission) or CR (complete remission), and patient is either ineligible for autologous hematopoietic BMT or autologous BMT is not recommended: Follicular grade 3 lymphoma Histoconversion of low-grade B-cell lymphoma (including SLL/CLL) to aggressive B-cell non-Hodgkin's lymphoma Mantle cell lymphoma Diffuse large B-cell lymphoma (excluding primary CNS [central nervous system] lymphoma) Gray zone or composite lymphomas with combined features of primary mediastinal large B-cell and Hodgkin's lymphoma Burkitt's lymphoma/leukemia Atypical Burkitt's lymphoma/leukemia (high grade B-cell lymphoma, unclassified, including that with features intermediate between Burkitt's and diffuse large B-cell lymphoma) Must have a related donor who is at least HLA haploidentical Any previous BMT must have occurred at least 3 months prior Left ventricular ejection fraction at least 35% Bilirubin no more than 3.0 mg/dL (unless due to Gilbert's syndrome), and ALT (alanine aminotransferase) and AST (aspartate aminotransferase) no more than 5 x upper limit of normal FEV1 (forced expiratory volume in one second) and FVC (forced vital capacity) at least 40% of predicted Absence of uncontrolled infection Exclusion Criteria: More than 20% involvement of bone marrow by chronic lymphocytic leukemia Active central nervous system lymphoma ECOG (Eastern Cooperative Oncology Group) performance status greater than 1 (2,3, and 4) HIV positive Pregnant or breastfeeding

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 75 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: Transplant<br>Non-myeloablative allogeneic bone marrow transplant (BMT) with a fludarabine (Flu), cyclophosphamide (Cy), total body irradiation (TBI) preparative regimen and post-transplant Cy, mycophenolate mofetil (MMF), and tacrolimus as GVHD (graft vs host disease) prophylaxis. Rituximab will be given as post-transplant maintenance. | Drug: Fludarabine<br>* Days -6 through -2: 30 mg/m^2 IV daily<br>* Other names: Fludara;Drug: Cyclophosphamide<br>* Days -6 and -5: 14.5 mg/kg IV daily; Days 3 and 4: 50 mg/kg IV daily<br>* Other names: Cy;Radiation: Total body irradiation<br>* Day -1: 200 centigray (cGy) in a single fraction<br>* Other names: TBI;Drug: Tacrolimus<br>* Start on Day 5 through Day 180<br>* Other names: Prograf;Drug: Mycophenolate Mofetil<br>* Days 5 through 35: 15 mg/kg PO three times daily (max 3 g/day)<br>* Other names: CellCept;Drug: Rituximab<br>* Day 30 and every week after for 8 total doses: 375 mg/m^2 IV<br>* Other names: Rituxan;Biological: Allogeneic Bone Marrow Transplant (BMT)<br>* Day 0: Donor bone marrow infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Percentage of participants alive and without relapse or disease progression. | 1 year post-intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Percentage of participants alive with and without relapse. | 2 years post-intervention | 
| Overall Survival | Percentage of participants alive. | 1 year post intervention | 
| Overall Survival | Percentage of participants alive. | 2 years post intervention | 
| Relapse | Percentage of participants alive with relapse or disease progression. | 1 year post intervention | 
| Relapse | Percentage of participants alive with relapse or disease progression. | 2 years post intervention | 
| Non-relapse Mortality | Percentage of participants who died due to BMT-related reasons. | 1 year post intervention | 
| Incidence of Grades II-IV Acute Graft-versus-Host-Disease (GVHD) | Percentage of participants who experienced grade II, III, or IV acute GVHD. Acute GVHD is graded using the Przepiorka criteria. | 1 year post intervention | 
| Incidence of Grades III-IV Acute GVHD | Percentage of participants who experienced grade II, III, or IV acute GVHD. Acute GVHD is graded using the Przepiorka criteria. | 1 year post intervention | 
| Incidence of Chronic GVHD | Percentage of participants who experienced chronic GVHD. Chronic GVHD is graded using NIH consensus criteria and Seattle criteria. | 1 year post intervention | 
| Engraftment | Percentage of patients who engrafted neutrophils and platelets. | Day 60 | 
| Graft Failure | Percentage of participants who failed to engraft. | Day 60 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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lymphoma, non hodgkin lymphoma, allogeneic, bone marrow transplantation, nonmyeloablative, cyclophosphamide, rituximab