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 x 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. Leukemia (2011) 25, 599-605; doi:10.1038/leu.2010.319; published online 21 January 2011