Fludarabine and Cyclophosphamide in Treating Patients Who Are Undergoing Donor Stem Cell Transplant for Chronic Lymphocytic Leukemia or Waldenstrom's Macroglobulinemia

OBJECTIVES:

Primary

• Determine the feasibility and safety of induction therapy comprising fludarabine and cyclophosphamide followed by allogeneic stem cell transplantation in patients with high-risk B-cell chronic lymphocytic leukemia or lymphoplasmocytic lymphoma (Waldenstrom's macroglobulinemia).

Secondary

• Determine the incidence and kinetics of clinical and molecular remissions in patients treated with this regimen.
• Determine event-free and overall survival of patients treated with this regimen.
• Determine the duration of clinical and molecular remission in relation to the underlying cytogenetic deviation in patients treated with this regimen.
• Determine the kinetics and extent of lympho-hematopoietic donor chimerism in patients treated with this regimen.

OUTLINE: This is a multicenter, open-label, nonrandomized, pilot study.

• Cytoreductive therapy: Patients receive up to 3 courses of cytoreductive therapy comprising fludarabine IV and cyclophosphamide IV on days 1-3 (with or without rituximab IV on day 1). Patients refractory to fludarabine-containing therapy may receive alemtuzumab IV for 12 weeks OR any other cytotoxic salvage regimen for cytoreduction.
• Conditioning regimen: Patients receive 1 of the following conditioning regimens*:

NOTE: *Patients who did not achieve partial response after cytoreductive therapy receive regimen 3.

• Regimen 1: Patients receive fludarabine IV and cyclophosphamide IV on days -7 to -3. If stem cells are collected from an unrelated donor, patients also receive anti-thymocyte globulin (ATG) IV on days -4 to -1.
• Regimen 2: Patients undergo total-body irradiation on day -9. Patients then receive alemtuzumab IV on days -8 to -4 and fludarabine IV and cyclophosphamide IV on days -6 to -2.
• Regimen 3: Patients receive fludarabine IV on days -7 to -3, busulfan IV or orally on days -7 to -5, and cyclophosphamide IV on days -3 to -2. If stem cells are collected from an unrelated donor, patients also receive ATG on days -3 to -1.

• Allogeneic peripheral blood stem cell transplantation (PBSCT): Patients undergo allogeneic PBSCT on day 0. Patients receive filgrastim (G-CSF) subcutaneously daily starting on day 5 and continuing until blood count recover.
• Graft-versus-host-disease (GVHD) prophylaxis: Patients receive cyclosporine IV beginning on day -1 and continuing until approximately day 100. Patients treated with conditioning regimen 1 or 3 also receive methotrexate IV on days 1, 3, and 6 OR oral mycophenolate mofetil twice daily on days 0-50. Patients with evidence of residual disease at least 4 weeks after completion of cyclosporine undergo donor lymphocyte infusion (DLI).
• DLI: The donor T-lymphocytes are collected from the PBSCT donor without prior G-CSF mobilization. Patients receive DLI every 8 weeks in the presence of residual disease and the absence of GVHD.

After completion of study treatment, patients are followed periodically.

PROJECTED ACCRUAL: A total of 70 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Diagnosis of B-cell chronic lymphocytic leukemia or lymphoplasmocytic lymphoma (Waldenstrom's macroglobulinemia)

• Must have poor prognostic features and low probability of successful autografting, defined by one of the following criteria:

• Progressive disease with unfavorable cytogenetics (deletion or mutation of critical regions on chromosomes 11q and/or 17p [p53]; and/or unmutated status of the immunoglobulin V_H gene region; and/or usage of the V_H 3-21 gene), defined as 1 of the following:

• Doubling of lymphocyte count or nodal involvement within 3 months or less
• Progressive decline of platelet count and/or hemoglobin values defining Binet stage C disease (or to 50% or less of baseline values within 3 months) not due to immune mechanisms
• Symptomatic splenomegaly
• Discomfort or imminent complications due to large tumor masses
• B symptoms
• Refractory disease or early relapse (within 12 months) after treatment with a fludarabine-containing regimen
• Relapsed after autologous stem cell transplant (SCT)
• Insufficient stem cell harvest for intended autologous SCT
• Presence of a clonal CDR III rearrangement detected by polymerase chain reaction
• No Richter's syndrome
• HLA-identical sibling or unrelated donor available

PATIENT CHARACTERISTICS:

• ECOG performance status ≤ 1
• Creatinine clearance > 60 mL/min
• SGOT, SGPT, and bilirubin < 2 times normal
• Normal cardiac function determined by ECG and echocardiographic examination
• Inspiratory vital capacity, FEV_1, and DLCO > 50% of predicted
• No serious localized or systemic infections
• No other concurrent malignant disease
• No impaired organ function
• No uncontrolled diabetes
• No uncontrolled hypertension
• Not pregnant or nursing
• Fertile patients must use effective contraception
• No HIV infection
• No hepatitis B or C infection
• No concurrent alcohol or drug abuse
• No dementia or altered mental status that would preclude giving informed consent

PRIOR CONCURRENT THERAPY:

• Not specified