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Clofarabine in combination with a standard remission induction regimen (cytosine arabinoside and idarubicin) in patients with previously untreated intermediate and bad-risk acute myelogenous leukemia (AML) or high-risk myelodysplastic syndrome (HR-MDS): phase I results of an ongoing phase I/II study of the leukemia groups of EORTC and GIMEMA (EORTC GIMEMA 06061/AML-14A trial)

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Abstract

This study aims to determine the maximum tolerated dose (MTD) of clofarabine combined with the EORTC-GIMEMA 3 + 10 induction regimen (idarubicin + cytosine arabinoside) in adults with untreated acute myelogenous leukemia or high-risk myelodysplastic syndrome. In this phase I trial, 25 patients (median age 56 years) received 5 days of clofarabine as 1-h infusion (arm A) or push injection (arm B) at the dose level of 5 × 10 or 5 × 15 mg/m2/day in an algorithmic dose escalation 3 + 3 design. A consolidation course (intermediate dose cytosine arabinoside, idarubicin) was planned for patients in complete remission (CR). Primary endpoint was safety and tolerance as measured by dose limiting toxicity (DLT); secondary endpoints were response rate, other grade III/IV toxicities, and hematological recovery after induction and consolidation. Five DLTs were observed (in arm A: one DLT at 10 mg/m2/day, three at 15 mg/m2/day; in arm B: one DLT at 15 mg/m2/day). Three patients receiving 15 mg/m2/day were withdrawn due to adverse events not classified as DLT. Prolonged hypoplasia was observed in five patients. CR + complete remission with incomplete recovery were achieved in 21 patients (11/12 (92 %) receiving clofarabine 10 mg/m2/day; 10/13 (77 %) receiving clofarabine 15 mg/m2/day). Clofarabine, 5 × 10 mg/m2/day, resulted in one DLT and no early treatment withdrawals. MTD of clofarabine combined with cytosine arabinoside and idarubicin is 5 × 10 mg/m2/day.

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Acknowledgments

This publication was supported by Fonds Cancer (FOCA) from Belgium. We thank the EORTC Headquarters staff who contributed to this trial as well: Aurore Theys (Data Manager), Filip Beeldens and Hilde Breyssens (Project Managers), and Sandrine Marreaud (Head of Medical Department). Genzyme, Cambridge, MA, USA, provided an educational grant and clofarabine free of charge.

Conflict of interest

Roelof Willemze has been a member of the Scientific Advisory Board of Genzyme concerning clofarabine. The other authors have nothing to disclose with respect to clofarabine.

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Authors and Affiliations

  1. Department of Hematology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands

    R. Willemze & C. J. M. Halkes

  2. EORTC Headquarters, Brussels, Belgium

    S. Suciu, L. Meert, M. Karrasch & J. Rapion

  3. Radboud University Medical Center, Nijmegen, The Netherlands

    P. Muus & T. de Witte

  4. University “Sapienza”, Rome, Italy

    G. Meloni

  5. GIMEMA Data Center, Rome, Italy

    M. Vignetti

  6. Tor Vergata University Hospital, Rome, Italy

    S. Amadori

  7. Hopital Saint Antoine, Paris, France

    J. P. Marie

Authors
  1. R. Willemze
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  2. S. Suciu
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  3. P. Muus
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  4. C. J. M. Halkes
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  5. G. Meloni
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  6. L. Meert
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  7. M. Karrasch
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  8. J. Rapion
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  9. M. Vignetti
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  10. S. Amadori
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  11. T. de Witte
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  12. J. P. Marie
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Corresponding author

Correspondence to R. Willemze.

Additional information

NCT number 00838240 EudraCT 2006-004912-28

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Willemze, R., Suciu, S., Muus, P. et al. Clofarabine in combination with a standard remission induction regimen (cytosine arabinoside and idarubicin) in patients with previously untreated intermediate and bad-risk acute myelogenous leukemia (AML) or high-risk myelodysplastic syndrome (HR-MDS): phase I results of an ongoing phase I/II study of the leukemia groups of EORTC and GIMEMA (EORTC GIMEMA 06061/AML-14A trial). Ann Hematol 93, 965–975 (2014). https://doi.org/10.1007/s00277-014-2056-6

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  • DOI: https://doi.org/10.1007/s00277-014-2056-6

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