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Therapy

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

Leukemia volume 25, pages 599–605 (2011)Cite this article

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Abstract

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/m2 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/m2 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/m2 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.

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Acknowledgements

This study was supported in part by research funding from Genzyme Inc. Pharmacoanalytical work was performed by the Clinical Pharmacology Analytical Laboratory of the Indiana University Melvin and Bren Simon Cancer Center and supported by Institutional grant P30 CA082709.

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  1. Division of Hematology and Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA

    S S Farag, L L Wood, J E Schwartz, S Srivastava, R P Nelson Jr, M J Robertson & R Abonour

  2. Blood and Bone Marrow Transplantation Program, Indiana University Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA

    S S Farag, L L Wood, J E Schwartz, S Srivastava, R P Nelson Jr, M J Robertson, R Abonour, A Secrest, E Cox, J Baute, C Sullivan & K Kane

  3. Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA

    D R Jones

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Correspondence to S S Farag.

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SF has received research support from Genzyme Inc., and Honoraria from Genzyme Inc. and Otsuka Pharmaceuticals.

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Farag, S., Wood, L., Schwartz, J. et al. 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. Leukemia 25, 599–605 (2011). https://doi.org/10.1038/leu.2010.319

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