Clofarabine and High-Dose Melphalan Followed by Donor Stem Cell Transplant in Patients With Acute Myeloid Leukemia, Acute Lymphocytic Leukemia, or Myelodysplastic Syndromes

OBJECTIVES:

• To determine the maximum tolerated dose and toxicities of clofarabine when administered with high-dose melphalan as a conditioning regimen in patients undergoing allogeneic stem cell transplantation for acute myeloid leukemia, acute lymphocytic leukemia, or myelodysplastic syndromes.
• To assess the efficacy of this regimen in facilitating engraftment in these patients.
• To perform correlative laboratory studies of engraftment, immune reconstitution, and therapeutic outcomes.

OUTLINE: This is a dose-escalation study of clofarabine. Patients are stratified according to age (< 18 years vs ≥ 18 years).

• Reduced-intensity conditioning regimen: Patients receive clofarabine IV over 30 minutes on days -9 to -5 and high-dose melphalan IV over 30 minutes on day -4.

Cohorts of 3-6 patients receive escalating doses of clofarabine until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD.

• Allogeneic stem cell transplantation: Patients undergo allogeneic stem cell transplantation on day 0.
• Graft-versus-host disease (GVHD) prophylaxis: Patients receive cyclosporine IV over 10 hours or orally twice daily beginning on day -1 and continuing until day 90-100, followed by a taper in the absence of GVHD. Patients also receive mycophenolate mofetil IV or orally twice daily beginning on day 0 and continuing until day 28, followed by a taper in the absence of GVHD.

Patients undergo blood and/or bone marrow sample collection periodically for correlative laboratory studies. Samples are examined for markers of immune reconstitution (i.e., CD8+ T lymphocytes, CD4+ T lymphocytes, NK cells, B cells, and monocytes) by flow cytometry and for diversity of the reconstituted T-cell repertoire by PCR-based T-cell receptor repertoire analysis. Samples are also examined for gene expression of hRRM2 and markers of apoptosis (i.e., Bcl-2, Bid, NFkB2, and Bcl-3) by real-time RT-PCR and for markers of ribonucleotide reductase inhibition (i.e., dCTP levels in circulating peripheral blood mononuclear cells).

After completion of study therapy, patients are followed periodically for up to 5 years.

DISEASE CHARACTERISTICS:

• Diagnosis of one of the following:

• Acute myeloid leukemia
• Acute lymphocytic leukemia
• Myelodysplastic syndromes
• Disease meets 1 of the following criteria:

• In first complete remission (CR)
• In second CR
• In relapse
• No more than 50% blasts in bone marrow
• Not deemed eligible for standard transplantation regimens by the attending physician, or at high risk for relapse
• No suspected or proven CNS leukemia
• HLA-matched (6/6) sibling donor available

PATIENT CHARACTERISTICS:

• Karnofsky performance status 50-100%
• Glomerular filtration rate (pediatric patients) or creatinine clearance ≥ 60 mL/min OR serum creatinine < 1.5 times upper limit of normal (ULN)
• Serum bilirubin ≤ 2.0 mg/dL
• AST and ALT ≤ 2.5 times ULN
• LVEF ≥ 50% by ECHO or MUGA scan
• DLCO or FEV_1 ≥ 40% predicted
• Not pregnant
• Negative pregnancy test
• No concurrent uncontrolled illness including, but not limited to, any of the following:

• Ongoing, active, or poorly controlled infection
• Symptomatic congestive heart failure
• Unstable angina pectoris
• Cardiac arrhythmia
• Poorly controlled pulmonary disease
• Psychiatric illness/social situation that would limit compliance with study requirement
• No active cytomegalovirus (CMV) or fungal disease
• HIV negative

PRIOR CONCURRENT THERAPY:

• Recovered from prior intensive chemotherapy (pediatric patients)
• At least 100 days since prior autologous stem cell transplantation
• At least 100 days since prior radiotherapy administered as part of a transplantation conditioning regimen
• At least 4 weeks since prior chemotherapy
• At least 24 hours since prior hydroxyurea for blast count control