Early Administration of ATG Followed by Cyclophosphamide, Busulfan and Fludarabine Before a Donor Stem Cell Transplant in Patients With Hematological Cancer

OBJECTIVES:

• To assess the percentage of patients with hematological malignancies or renal cell carcinoma who achieve > 90% donor T-cell chimerism at 30 days after treatment with reduced-intensity conditioning comprising low-dose anti-thymocyte globulin, low-dose cyclophosphamide, busulfan, and fludarabine phosphate followed by allogeneic peripheral blood progenitor cell transplantation from a matched related donor.
• To assess the incidence of severe (grade 3 or 4) acute graft-versus-host disease (GVHD) and extensive chronic GVHD in these patients.
• To assess whether this regimen is associated with reduced transplant-related toxicity and increased tolerability in these patients.
• To assess the overall safety of this conditioning regimen as measured by 6-month transplant-related mortality in these patients.
• To determine the efficacy of this regimen in inducing durable remissions in these patients.

OUTLINE:

• Reduced-intensity conditioning (RIC): Patients receive anti-thymocyte globulin IV over 4-6 hours on day -16 and over 6-8 hours on day -15, fludarabine phosphate IV over 30 minutes on days -7 to -3, busulfan IV over 3 hours on days -4 and -3, and cyclophosphamide IV over 1-2 hours on day -2.
• Transplantation: Patients undergo allogeneic peripheral blood progenitor cell transplantation on day 0.
• Graft-vs-host disease (GVHD) prophylaxis: Patients receive oral tacrolimus every 12 hours on days -1 to 90, followed by a taper until day 150. Patients also receive methotrexate IV on days 1, 3, and 6.

Blood samples are collected periodically for pharmacokinetic studies of anti-thymocyte globulin and PCR analysis for chimerism.

After completion of study therapy, patients are followed periodically for up to 3 years.

DISEASE CHARACTERISTICS:

• Histologically confirmed diagnosis of one of the following:

• Chronic myeloid leukemia (CML)

• Philadelphia chromosome (Ph)- and/or BCR-ABL-positive disease
• In chronic or accelerated phase
• Suboptimal response to imatinib mesylate (i.e., no hematologic complete response by 3 months, no major cytogenetic response by 6 months, or no complete cytogenetic response by 1 year)
• CML in blastic transformation allowed provided patient achieved complete remission (CR) or second chronic phase after treatment with imatinib mesylate or chemotherapy
• Chronic lymphocytic leukemia meeting one of the following criteria:

• Rai stage III or IV disease
• Rai stage I or II disease that failed standard therapy (i.e., disease is progressing after ≥ 1 course of standard therapy)
• Non-Hodgkin lymphoma (NHL) meeting one of the following criteria:

• Indolent NHL

• Clinical stage III or IV disease or bulky stage II disease (i.e., ≥ one lymphoid mass > 5 cm in ≥ one dimension)
• Relapsed after primary therapy OR is refractory to therapy
• Aggressive NHL

• Is not considered curable with standard chemotherapy or autologous stem cell transplantation (i.e., relapsed after autologous stem cell transplantation)
• Chemotherapy-responsive disease
• Multiple myeloma

• Durie-Salmon stage II or III disease

• Durie Salmon stage I disease allowed provided β2 microglobulin level > 3 mg/dL
• Acute myeloid leukemia or acute lymphocytic leukemia

• In CR (defined as < 5% blasts in bone marrow and no circulating blasts) AND has any of the following poor prognostic features:

• WBC > 100,000/mm^3 at presentation
• In second or greater remission
• Adverse-risk cytogenetics (i.e., Ph1-positive, 11q23 translocation, -5, -7, complex translocations, or other recognized adverse-risk cytogenetics)
• Renal cell carcinoma

• Stage IV disease
• Clear cell morphology
• Myelodysplastic syndromes

• Bone marrow blasts ≤ 10% on last bone marrow biopsy prior to transplantation
• Myeloproliferative disease

• Anticipated life expectancy on conventional therapy < 10 years
• No uncomplicated essential thrombocythemia or primary polycythemia
• Hodgkin lymphoma

• Relapsed after ≥ 1 standard-dose chemotherapy regimen
• Not considered curable by autologous stem cell transplantation
• No clinical evidence of active CNS involvement

• Previously treated leptomeningeal disease allowed provided CSF cytology is negative at the time of assessment for transplantation
• Available 6/6 allele match (i.e., HLA-A, B, DRβ1)matched related donor

PATIENT CHARACTERISTICS:

• ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100%
• Bilirubin < 3 times normal (unless abnormality due to malignancy)
• AST and ALT < 3 times normal (unless abnormality due to malignancy)
• Creatinine ≤ 2.0 mg/dL
• LVEF ≥ 40% by MUGA or ECHO
• DLCO ≥ 40% of predicted
• FEV-1 ≥ 50% of predicted
• Not pregnant or nursing
• Fertile patients must use effective contraception
• Deemed to be an appropriate candidate for allogeneic SCT
• No evidence of myocardial infarction within the past 6 months
• No psychological or social condition that may interfere with study participation
• No serious uncontrolled localized or active systemic infection
• No second malignancy within the past 3 years except for completely excised nonmelanotic skin cancer or in situ carcinoma of the cervix
• No chronic inflammatory disorder requiring the continued use of glucocorticoids or other immunosuppressive medications
• No known HIV positivity
• No hypersensitivity to E. coli-derived proteins