RATIONALE: Giving chemotherapy, such as clofarabine and melphalan, before a donor stem cell
transplant helps stop the growth of cancer or abnormal cells. It also helps stop the
patient's immune system from rejecting the donor's stem cells. When the healthy stem cells
from a donor are infused into the patient, they may help the patient's bone marrow make stem
cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells
from a donor can make an immune response against the body's normal cells. Giving
cyclosporine and mycophenolate mofetil after the transplant may stop this from happening.
PURPOSE: This phase I trial is studying the side effects and best dose of clofarabine when
given together with high-dose melphalan followed by a donor stem cell transplant in treating
patients with acute myeloid leukemia, acute lymphocytic leukemia, or myelodysplastic
- 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
- To assess the efficacy of this regimen in facilitating engraftment in these patients.
- To perform correlative laboratory studies of engraftment, immune reconstitution, and
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.
- 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
- 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
- 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
- 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
- At least 4 weeks since prior chemotherapy
- At least 24 hours since prior hydroxyurea for blast count control