Alemtuzumab Plus Fludarabine and Melphalan With or Without Cyclosporine, Mycophenolate Mofetil, and Low-Dose Total-Body Irradiation Therapy Followed by Donor Peripheral Stem Cell Transplant in Treating Patients With Hematologic Cancer

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.

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)* with an inadequate response to imatinib 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

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