This phase II trial studies how well fludarabine phosphate with radiation therapy and rituximab followed by donor stem cell infusions work in treating patients with high-risk chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) with low side effects. Nonmyeloablative stem cell transplants use low doses of chemotherapy (fludarabine phosphate) and radiation to suppress the patient's immune system enough to prevent rejection of the donor's stem cells. Following infusion of donor stem cells, a mixture of the patient's and the donor's stem cells will exist and is called "mixed chimerism". Donor cells will attack the patient's leukemia. This is called the "graft-versus-leukemia" effect. Rituximab will be given 3 days before and three times after infusing stem cells to help in controlling CLL early after transplant till the "graft-versus-leukemia" takes control. Further, rituximab could augment the "graft-versus-leukemia" effect by activating donor immune cells and hence improve disease control. Sometimes the transplanted cells from a donor can also attack the body's normal cells. Giving cyclosporine and mycophenolate mofetil after the transplant may stop this from happening.
PRIMARY OBJECTIVES: I. Determine whether nonmyeloablative conditioning and allogeneic hematopoietic cell transplantation (HCT) improves survival at 18 months for patients with fludarabine (fludarabine phosphate)-refractory, fludarabine/cyclophosphamide/rituximab (FCR)-failed, or del 17p CLL over that of historical controls (45% at 18 months) given CAMPATH-1H (alemtuzumab). SECONDARY OBJECTIVES: I. Estimate the overall response rate (complete remission \[CR\] + partial remission \[PR\]) by standard morphologic, flow cytometric, and molecular techniques. II. Assess the rate of relapse/progression. III. Define incidences of regimen-related toxicities (RRT) and infections within the first 100 days and the incidence of transplant-related mortality (TRM) within the first year. IV. Estimate incidences of grade II-III and III-IV acute graft-versus-host disease (GVHD) and chronic GVHD. V. Determine whether the addition of rituximab to the nonmyeloablative conditioning and allogeneic HCT improves survival at 18 months over our historical data (57% at 18 months). VI. Determine the incidence of serious adverse events with the addition of rituximab in comparison to historical data of unrelated nonmyeloablative HCT. VII. Evaluate the pharmacokinetics of rituximab. VIII. Evaluate B-cell and T-cell immune reconstitution in comparison to historical data of unrelated nonmyeloablative HCT. IX. Describe donor and host polymorphisms of the FCgammaRIIIa receptor and cluster of differentiation (CD)32 and evaluate their impact on disease response and relapse. X. Investigate the mechanism of disease resistance in relapsed/nonresponding patients. XI. Isolate donor cytotoxic T lymphocytes specific for host minor histocompatibility antigens. OUTLINE: Patients receive a conditioning regimen comprising fludarabine phosphate intravenously (IV) on days -4 to -2 and rituximab IV on days -3, 10, 24, and 38. Patients undergo single fraction low-dose total-body irradiation (TBI) on day 0. After completion of TBI, patients undergo allogeneic hematopoietic stem cell transplantation (HSCT) on day 0. Patients then receive rituximab IV on days 10, 24, and 38. Patients receive an immunosuppressive regimen comprising cyclosporine orally (PO) twice daily (BID) on days -3 to 56 followed by a taper to day 180 (related recipients) or on days -3 to 100 followed by a taper to day 180 (unrelated recipients). Patients also receive mycophenolate mofetil PO BID on days 0-27 (related recipients) or three times daily (TID) on days 0-40 followed by a taper to day 96 (unrelated recipients). After completion of study treatment, patients are followed up at 6 months, 1 year, 18 months, 2 years, and then annually thereafter.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
66
Undergo HSCT
Given PO
Given IV
Correlative studies
Given PO
Undergo HSCT
Correlative studies
Given IV
Undergo TBI
Mayo Clinic
Rochester, Minnesota, United States
VA Puget Sound Health Care System
Seattle, Washington, United States
Fred Hutch/University of Washington Cancer Consortium
Seattle, Washington, United States
Rigshospitalet University Hospital
Copenhagen, Denmark
University of Torino
Torino, Italy
Overall Survival
Number of participants surviving post-transplant
Time frame: At 18 months
Comparison of Survival, Serious Adverse Events, and B-cell and T-cell Immune Reconstitution With Historical Data
Time frame: At 18 months
Number of Participants With Relapse/Progression
Relapse/Progression criteria for CLL Progressive disease: ≥1 of: Physical exam/imaging studies ≥50% increase or new, circulating lymphocytes by morphology and/or flow cytometry ≥50% increase, and lymph node biopsy w/ Richter's transformation. Relapsed disease: Criteria of progression occurring 6 months after achievement of complete or partial remission.
Time frame: Day 84
Graft-versus-leukemia Analysis by Mechanism of Disease Resistance in Relapsed or Non-responding Patients and Isolation of Donor Cytotoxic T Lymphocytes Specific for Host Minor Histocompatibility Antigens
Time frame: Day 84
Number of Participants With Grade II-III and III-IV Acute GVHD and Chronic GVHD
Number of patients who developed acute GVHD post-transplant. Grade I +1 to +2 skin rash, No gut or liver involvement Grade II +1 to +3 skin rash, +1 gastrointestinal involvement and/or +1 liver involvement Grade III +2 to +4 gastrointestinal involvement and/or +2 to +4 liver involvement with or without a rash Grade IV Pattern and severity of GVHD similar to grade 3 with extreme constitutional symptoms or death The diagnosis of chronic GVHD requires at least one manifestation that is distinctive for chronic GVHD as opposed to acute GVHD. In all cases, infection and others causes must be ruled out in the differential diagnosis of chronic GVHD.
Time frame: Up to 1 year
Number of Participants With Regimen-related Toxicity and Infections
Reported using the adapted National Cancer Institute Common Toxicity Criteria.
Time frame: Within the first 100 days
Number of Participants With Treatment-related Mortality
Number of subjects expired without disease progression/relapse.
Time frame: Up to 1 year
Rituxan Concentration
Median rituxan level at days 60, 84, 180, and 1 year.
Time frame: Days 60, 84, 180, and 1 year
Number of Patients Achieving Complete Response and Partial Response (Overall Response Rate)
Complete Remission (CR): Imaging studies (Xray, CT, MRI) (nodes, liver, and spleen): Normal Peripheral blood by flow cytometry: No clonal lymphocytes Bone marrow by morphology: No nodules; or if present, nodules are free from CLL cells by immunohistochemistry Duration: ≥2 months CR with minimal residual disease Peripheral blood or bone marrow by flow cytometry: \>0 - \<1 CLL cells/1000 leukocytes (0.1%) Partial Remission (PR): Both criteria: Absolute lymphocyte count in peripheral blood: ≥50% decrease Physical exam/Imaging studies (nodes, liver, and/or spleen): ≥50% decrease Duration: ≥2 months
Time frame: Up to 1 year
Donor and Host Polymorphisms of the FCgammaRIIIa Receptor and CD32 and Their Impact on Disease Response and Relapse
Number of participants without progressive disease and surviving at one year. Participants with FCgammaRIIIa receptor vs participants without FCgammaRIIIa receptor.
Time frame: 1 Year
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