Donor Stem Cell Transplant in Treating Patients With High-Risk Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

Study Overview
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Brief Summary
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RATIONALE: Giving low doses of chemotherapy before a donor stem cell transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. Also, monoclonal antibodies, such as rituximab, can find cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells. The donated stem cells may replace the patient's immune cells 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, sirolimus, and methotrexate after the transplant may stop this from happening. PURPOSE: This phase II trial is studying how well donor stem cell transplant works in treating patients with high-risk chronic lymphocytic leukemia or small lymphocytic lymphoma.

Detailed Description
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OBJECTIVES: Primary To determine if this treatment can improve 2-year current progression-free survival (PFS) in the early disease cohort compared to historical controls. Specifically, we plan to study whether we can achieve 2-year PFS ≥ 70% and to exclude 2 year PFS ≤ 50% Secondary To determine whether in the advanced disease cohort we can achieve 2-year current PFS ≥ 50% and to exclude 2-year PFS ≤ 30% To assess objective response rate. To assess the incidence of grade 2-4 and 3-4 acute graft-vs-host disease (GVHD). To assess the incidence of extensive chronic GVHD. To assess the incidence of treatment-related mortality at 100 days and 1 year To assess overall survival To assess donor chimerism for CD3+ cells at 1 and 2 years after transplantation To investigate the presence of donor antigen-specific T-cell clones before and after withdrawal of immune suppression. To compare the relapse profiles of patients with T-cell responses against CLL to those whose CLL cells are not reactive To prospectively examine the impact of high-risk genomic features and immune-based single nucleotide polymorphisms on response, toxicity, and 2-year PFS to reduced intensity allogeneic stem cell transplant OUTLINE: This is a multicenter study. Preparative regimen: Patients receive 1 of 2 preparative regimens at the discretion of the participating institution. Preparative regimen 1: Patients receive rituximab IV on days -7, -1, 7, and 14 and fludarabine phosphate IV over 30 minutes and busulfan IV over 3 hours on days -5 to -2. . Preparative regimen 2: Patients receive rituximab IV on days -7, -1, 7, and 14, fludarabine phosphate IV over 30 minutes on days -5 to -2, and cyclophosphamide IV over 1-2 hours on days -5 to -3. Patients with matched unrelated donors also receive anti-thymocyte globulin IV over 4-6 hours on days -6 to -4. Graft-vs-host disease (GVHD) prophylaxis: Patients who receive preparative regimen 1 may receive either GVHD prophylaxis regimen 1 or 2; patients who receive preparative regimen 2 may only receive GVHD prophylaxis regimen 2. GVHD prophylaxis regimen 1: Patients receive tacrolimus either orally or IV and oral sirolimus beginning on day -2 and continuing until day 60, followed by a taper until day 180. Patients also receive methotrexate IV on days 1, 3, and 6. GVHD prophylaxis regimen 2: Patients receive tacrolimus either orally or IV beginning on day -2 and continuing until day 60, followed by a taper until day 180. Patients also receive methotrexate IV on days 1, 3, 6, and 11. Transplantation: Patients undergo allogeneic peripheral blood stem cell transplantation on day 0. Maintenance therapy: Patients receive rituximab IV at 3, 6, 9, and 12 months after transplantation. Peripheral blood and bone marrow aspirate samples may be collected periodically for correlative laboratory studies. Patients are followed up periodically for a maximum of 5 years from study entry.

Official Title
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Phase II Study of Reduced-Intensity Allogeneic Stem Cell Transplant for High-Risk Chronic Lymphocytic Leukemia (CLL)

Conditions
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Leukemia, Lymphoma

Intervention / Treatment
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* Biological: rituximab
* Drug: busulfan
* Drug: cyclophosphamide
* Drug: fludarabine phosphate
* Drug: methotrexate
* Drug: sirolimus
* Drug: tacrolimus
* Procedure: allogeneic stem cell transplant


Participation Criteria
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Eligibility Criteria
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Patient Eligibility: Diagnosis of B-cell chronic lymphocytic leukemia or B-cell small lymphocytic lymphoma. Diagnosis should be according to International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 Criteria Early Disease Cohort - Patients in the early disease cohort must include one or more of the following: FISH showing deletion 17p in ≥ 20% of cells (either at diagnosis or any time prior to study entry) either alone or in combination with other cytogenetic abnormalities FISH showing del 11q in ≥ 20% of cells (either at diagnosis or any time prior to study entry) either alone or in combination with other cytogenetic abnormalities, unless the patient has achieved a complete remission by IWCLL 2008 which includes CT scan, bone marrow morphology and flow cytometry Failure to achieve a partial response with initial chemotherapy, but with lack of progression. These patients may receive a second therapy to improve their response prior to transplant. Patients who, at the time of first progression, have a 17p deletion by FISH in ≥ 20% of cells, either alone or in combination with other cytogenetic abnormalities. The duration of the first progression is not specified. In addition, patients in the early disease cohort must have all of the following: Received at least 2 cycles of induction therapy. It is expected that most patients will receive at least 4 months of therapy prior to enrollment, but this is not required. Suggested regimens include but are not limited to the following: fludarabine plus rituximab, fludarabine, cyclophosphamide plus rituximab, pentostatin, cyclophosphamide plus rituximab, bendumustine plus rituximab, or alemtuzumab alone or in combination with other agents. Patients may receive no more than 2 different regimens prior to proceeding to transplantation. Nodes ≤ 5 cm Advanced Disease Cohort - Patients in the advanced disease cohort must include one or more of the following: FISH showing deletion 17p in ≥ 20% of cells (regardless of interval from initial therapy) either alone or in combination with other cytogenetic abnormalities First progression < 24 months after completing therapy. This includes progression on initial therapy. Second or subsequent progression In addition, patients in the advanced disease cohort must have all of the following: Stable disease or better by the Revised IWCLL 2008 NCI Criteria to their most recent chemotherapy Nodes ≤ 5 cm Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2 Age Requirement - Patients must be between ≥ 18 and < 70 years of age Cytotoxic Chemotherapy or Alemtuzamab - There must be at least 4 weeks after day 1 of the last cycle of cytotoxic chemotherapy, or alemtuzamab. Human Immunodeficiency Virus (HIV) Status - Patients must have no HIV infection. Allogeneic transplantation in the HIV patient population is not well-defined and there are likely to be requirements for concomitant anti-HIV therapy and anti-GVHD therapy that would create potentially dangerous pharmacokinetic interactions among the different agents that could constrain therapeutic options for controlling both HIV and GVHD. Hepatitis B and C - Patients must have no Hepatitis B sAg, anti-HBc or HCV. Diffusion capacity of carbon monoxide DLCO must be ≥ 40% predicted Left ventricular ejection fraction (LVEF) by Echocardiogram (ECHO) or Multiple gated acquisition (MUGA) must be ≥ 30% Diabetes or Serious Infection - Patients must have no uncontrolled diabetes mellitus or active uncontrolled serious infections Pregnancy and Nursing Status - Patients must be non-pregnant and non-nursing. Treatment under this protocol would expose a fetus to significant risks. Women of childbearing potential should have a negative pregnancy test prior to study entry. Women and men of reproductive potential should agree to use an appropriate method of birth control throughout their participation in this study due to the teratogenic potential of the therapy utilized in this trial. Appropriate methods of birth control include oral contraceptives, implantable hormonal contraceptives (Norplant®), or double barrier method (diaphragm plus condom). Richter's Transformation - Patients must have no history of Richter's transformation. Initial Required Laboratory Values: Serum Creatinine < 2 mg/dL Calculated Creatinine Clearance ≥ 40 mL/min AST < 3 x ULN Total Bilirubin < 2 mg/dL (except for Gilbert's syndrome) Donor Eligibility: Donors may be either a 6/6 HLA-matched related donor by low-resolution typing at HLA A, B, DR. Donors may be an 8/8 HLA-matched unrelated donor at HLA A, B, C, DR. Unrelated donors will be analyzed by molecular typing at both HLA Class I and Class II (A, B, C, DR loci). Syngeneic donors are not eligible Donors must be healthy and must be an acceptable donor as per institutional standards for stem cell donation. There will be no donor age restriction.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 69 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: Treatment (Combination of chemotherapy and transplant)<br>See detailed description | Biological: rituximab<br> <br> Drug: busulfan<br> <br> Drug: cyclophosphamide<br> <br> Drug: fludarabine phosphate<br> <br> Drug: methotrexate<br> <br> Drug: sirolimus<br> <br> Drug: tacrolimus<br> <br> Procedure: allogeneic stem cell transplant<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 2-year Progression-free Survival in Early Disease Participants | Percentage of participants who were alive and progression free at 2 years for participants with early disease stage. The 2 year progression free survival, with 95% confidence interval, was estimated using the Kaplan Meier method. A progression is defined as one of the following events: >= 50% increase in the products of at least two lymph nodes on two consecutive determinations two weeks apart (at least one lymph node must be >= 2 cm); appearance of new palpable lymph nodes. >= 50% increase in the size of the liver and/or spleen as determined by measurement below the respective costal margin; appearance of palpable hepatomegaly or splenomegaly, which was not previously present. > 50% increase in peripheral blood lymphocytes with an absolute increase > 5000/μL. Transformation to a more aggressive histology (i.e., Richter's syndrome or prolymphocytic leukemia with >= 56% prolymphocytes). | 2 years post-registration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response |  | 5 years post-registration | 
| Acute Graft-vs-host Disease (GVHD) |  | 5 years post-registration | 
| Chronic GVHD |  | 5 years post-registration | 
| Treatment-related Mortality |  | 6 months post-transplant | 
| Overall Survival |  | 5 years post-registration | 
| Chimerism for CD3 |  | 5 years post-registration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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refractory chronic lymphocytic leukemia, stage I chronic lymphocytic leukemia, stage II chronic lymphocytic leukemia, stage III chronic lymphocytic leukemia, stage IV chronic lymphocytic leukemia, B-cell chronic lymphocytic leukemia, contiguous stage II small lymphocytic lymphoma, noncontiguous stage II small lymphocytic lymphoma, recurrent small lymphocytic lymphoma, stage I small lymphocytic lymphoma, stage III small lymphocytic lymphoma, stage IV small lymphocytic lymphoma