Phase I trial and pharmacokinetic study of high-dose clofarabine and busulfan and allogeneic stem cell transplantation in adults with high-risk and refractory acute leukemia.
We conducted a phase I trial to determine the maximum tolerated dose (MTD) of clofarabine with high-dose busulfan followed by allogeneic stem cell transplantation (SCT) in patients with high-risk and refractory acute leukemia. Patients received intravenous busulfan 0.8 mg/kg every 6 h on days -6 to -3 and clofarabine 30-60 mg/m(2) per day on days -6 to -2. Graft-versus-host disease prophylaxis included sirolimus plus tacrolimus (days -2 to +180). A total of 15 patients, median age 48 (30-58) years, with acute leukemia that was relapsed and refractory (n=8), primary refractory (n=6), or in CR2 (n=1), were treated at four clofarabine dose levels: 30 (n=3), 40 (n=3), 50 (n=3) and 60 mg/m(2) per day (n=6) with busulfan. All engrafted, and the MTD was not reached. Grades 3-4 non-hematological toxicities included vomiting (n=3), mucositis (n=9), hand-foot syndrome (n=1), acute renal failure (n=1) and reversible elevation of aspartate aminotransferase/alanine aminotransferase (n=10). The 1-year event-free survival was 53% (95% confidence interval: 33-86%), and the 1-year overall survival was 60% (95% confidence interval: 40-91%). Given the good tolerability and promising results, we recommend clofarabine 60 mg/m(2) per day × 5 days as a phase II dose in combination with busulfan (12.8 mg per kg total dose) for further study as a myeloablative regimen for allogeneic SCT for high-risk acute leukemia.
Division of Hematology and Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA. ssfarag@iupui.edu
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SS
Farag
L L
LL
Wood
J E
JE
Schwartz
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Srivastava
R P
RP
Nelson
M J
MJ
Robertson
R
R
Abonour
A
A
Secrest
E
E
Cox
J
J
Baute
C
C
Sullivan
K
K
Kane
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DR
Jones
D000227:Adenine Nucleotides / Q000008:administration & dosage; D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001087:Arabinonucleosides / Q000008:administration & dosage; D002066:Busulfan / Q000008:administration & dosage; D000077866:Clofarabine; D003131:Combined Modality Therapy; D005260:Female; D006086:Graft vs Host Disease / Q000517:prevention & control*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000628:therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000628:therapy*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000628:therapy*; D012307:Risk Factors; D033581:Stem Cell Transplantation; D015996:Survival Rate; D014018:Tissue Distribution; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D055815:Young Adult
D000227:Adenine Nucleotides; D001087:Arabinonucleosides; D000077866:Clofarabine; D002066:Busulfan