Primary Outcome Measures:
- Maximum tolerated dose [ Designated as safety issue: Yes ]
- Dose-limiting toxicity as assessed by NCI CTCAE v3.0 and the Modified Bearman scale [ Designated as safety issue: Yes ]
- Graft failure or rejection [ Designated as safety issue: Yes ]
Secondary Outcome Measures:
- Efficacy [ Designated as safety issue: No ]
- Correlative laboratory studies of engraftment, immune reconstitution, and therapeutic outcomes [ Designated as safety issue: No ]
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 -7 to -3 and high-dose melphalan IV over 30 minutes on day -2.
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.