RATIONALE: Monoclonal antibodies such as alemtuzumab can locate cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells. Donor stem cell transplantation may be able to replace immune cells that were destroyed by chemotherapy and radiation therapy. Sometimes the transplanted cells from a donor are rejected by the body’s normal cells. Giving alemtuzumab, fludarabine, and melphalan with or without cyclosporine, mycophenolate mofetil, and low-dose total-body irradiation before transplantation may prevent this from happening.

PURPOSE: Phase I/II trial to study the effectiveness of giving alemtuzumab, fludarabine, and melphalan with or without cyclosporine, mycophenolate mofetil, and total-body irradiation before donor peripheral stem cell transplantation in treating patients who have relapsed or refractory hematologic cancer.

Condition	Treatment or Intervention	Phase
acute leukemia atypical chronic myeloid leukemia chronic leukemia myelodysplastic and myeloproliferative disease Non-Hodgkin's Lymphoma plasma cell neoplasm	Drug: alemtuzumab  Drug: allogeneic lymphocytes  Drug: cyclosporine  Drug: fludarabine  Drug: melphalan  Drug: mycophenolate mofetil  Drug: sargramostim  Procedure: antibody therapy  Procedure: biological response modifier therapy  Procedure: bone marrow ablation with stem cell support  Procedure: chemotherapy  Procedure: colony-stimulating factor therapy  Procedure: cytokine therapy  Procedure: graft versus host disease prophylaxis/therapy  Procedure: graft versus tumor induction  Procedure: monoclonal antibody therapy  Procedure: peripheral blood stem cell transplantation  Procedure: radiation therapy  Procedure: supportive care/therapy	Phase I Phase II

OBJECTIVES:

• Determine the ability of a reduced-intensity conditioning regimen comprising alemtuzumab, fludarabine, and melphalan with or without cyclosporine, mycophenolate mofetil, and low-dose total body radiotherapy followed by haplotype-mismatched, KIR class I epitope-mismatched CD34-positive allogeneic peripheral blood stem cell transplantation to facilitate engraftment by day 35 post-transplantation in at least 85% of patients with relapsed, refractory, or poor-risk hematological malignancies.
• Determine the risk of graft-versus-host-disease in patients treated with these regimens.
• Determine, preliminarily, the efficacy of these regimens, in terms of progression-free survival, in these patients.
• Correlate outcomes, engraftment, and progression-free survival with the number of detectable alloreactive natural killer cell clones before transplantation and after engraftment in patients treated with these regimens.
• Determine immune reconstitution in patients treated with these regimens.

OUTLINE: This is a multicenter, pilot study. Patients are initially treated with conditioning regimen A. If adequate donor engraftment is not achieved, subsequent patients are treated with conditioning regimen B.

• Conditioning regimen A: Patients receive alemtuzumab IV over 2 hours on days -14 to -12; fludarabine IV over 30 minutes on days -7 to -3; and melphalan IV over 20-30 minutes on day -2.
• Conditioning regimen B: Patients receive oral or IV cyclosporine twice daily and oral or IV mycophenolate mofetil twice daily on days -15 to 0. Patients also receive alemtuzumab, fludarabine, and melphalan as in conditioning regimen A. Patients undergo low-dose total body irradiation twice daily on days -2 and -1. All patients undergo allogeneic, T-cell-depleted, CD34-positive peripheral blood stem cell transplantation on day 0. Patients receive sargramostim (GM-CSF) subcutaneously beginning on day 1 and continuing until blood counts recover.

Patients are followed every 3 months for 1 year and then every 6 months for 5 years.

PROJECTED ACCRUAL: A total of 14-56 patients (14-28 per regimen) will be accrued for this study.

Ages Eligible for Study:  18 Years   -   60 Years,  Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Histologically confirmed hematological malignancy of 1 of the following types:
• Acute myeloid leukemia meeting at least 1 of the following criteria:
• Poor-risk cytogenetics, including -5, 5q-, -7, 7q-, 11q23, and Philadelphia (Ph) chromosome-positive in first or subsequent complete remission (CR)
• Relapsed or primary refractory disease with ≤ 10% blasts in the peripheral blood and ≤ 20% blasts in the bone marrow
• Standard-risk cytogenetics in second CR AND autologous transplantation is not feasible
• Standard-risk cytogenetics in third or subsequent CR
• Acute lymphoblastic leukemia meeting 1 of the following criteria:
• Second or subsequent CR
• High-risk cytogenetics, including Ph chromosome-positive and t(4:11) in first CR
• Relapsed or primarily refractory disease with ≤ 10% blasts in the peripheral blood and ≤ 20% blasts in the bone marrow
• High-risk myelodysplasia
• International Prognostic Scoring System Score ≥ 2.5
• Chronic myeloid leukemia (CML)* meeting 1 of the following criteria:
• Second or subsequent chronic phase
• Accelerated phase NOTE: *Patients with CML in blast crisis (> 30% promyelocytes and myeloblasts in the bone marrow) are not eligible
• Non-Hodgkin's lymphoma meeting 1 of the following criteria:
• Primarily refractory disease or in refractory relapse
• Relapsed disease after autologous stem cell transplantation
• Chemosensitive relapsed disease without CR to standard salvage therapy AND no option for autologous stem cell transplantation due to blood or marrow involvement or failure to harvest sufficient autologous stem cells
• Chronic lymphocytic leukemia meeting both of the following criteria:
• Stage III or IV disease
• Refractory to fludarabine
• Multiple myeloma meeting 1 of the following criteria:
• Primarily refractory disease or in refractory relapse
• Relapsed disease after autologous stem cell transplantation
• No relapsed disease < 6 months after autologous stem cell transplantation
• No available eligible HLA-matched (i.e., 5 of 6 or 6 of 6 antigen match for HLA-A, -B, and -DR loci) family donor by serological or molecular typing
• Available suitable family donor meeting the following criteria:
• Parent, sibling, or child of the recipient
• ≥ 16 years of age
• Identical for only one HLA haplotype (i.e., haploidentical) AND incompatible at the HLA-A, -B, -C, and -DR loci of the unshared haplotype by serological or molecular typing
• Mismatched with respect to KIR class I epitopes graft-vs-host directional activity
• Mismatching that predicts both graft-vs-host and host-vs-graft bi-directional activity eligible
• No mismatching that predicts only host-vs-graft directional activity

PATIENT CHARACTERISTICS: Age

• 18 to 60

Performance status

• ECOG 0-1

Life expectancy

• Not specified

Hematopoietic

• Not specified

Hepatic

• Bilirubin < 2 times upper limit of normal (ULN)
• AST and ALT < 2 times ULN

Renal

• Creatinine ≤ 2 mg/dL

Cardiovascular

• LVEF > 40% (corrected)

Pulmonary

• DLCO > 50% of predicted

Other

• No active infection requiring oral or IV antibiotics
• HIV negative
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY: Biologic therapy

• See Disease Characteristics

Chemotherapy

• See Disease Characteristics

Endocrine therapy

• Concurrent corticosteroids allowed for adrenal failure, treatment of graft-vs-host disease, or as premedication during study
• No concurrent corticosteroids for antiemesis

Radiotherapy

• Not specified

Surgery

• Not specified

Study chairs or principal investigators

Sherif S. Farag, MD, PhD,  Study Chair,  Arthur G. James Cancer Hospital & Richard J. Solove Research Institute   
Koen Van Besien, MD,  University of Chicago Cancer Research Center   

Study ID Numbers:  CDR0000370797; CALGB-100102
Record last reviewed:  May 2004
Record first received:  June 10, 2004
ClinicalTrials.gov Identifier:  NCT00085449
Health Authority: Unspecified
ClinicalTrials.gov processed this record on 2004-10-20