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A phase I study of imatinib mesylate in combination with chlorambucil in previously treated chronic lymphocytic leukemia patients

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Abstract

Purpose

The tyrosine kinase inhibitor, imatinib, has the potential to indirectly inhibit DNA repair. This mechanism of action has been shown to mediate sensitization to chlorambucil in chronic lymphocytic leukemia (CLL). To evaluate this effect in vivo, we performed a phase I study of chlorambucil combined with imatinib in relapsed CLL patients.

Methods

The three dose levels studied included imatinib at 300, 400, or 600 mg/day. Imatinib was given on days 1–10, and chlorambucil (8 mg/m2 daily) was given on days 3–7 of a 28-day cycle (up to 6 cycles).

Results

Eleven patients participated in this study. Low-grade gastrointestinal toxicities were observed in a dose-dependent manner. Forty-five percent of patients responded (two unconfirmed CRs and three PRs). Two responding patients were fludarabine refractory. The in vitro IC50 of chlorambucil alone or in the presence of 5 μM imatinib in CLL lymphocytes correlated with the decrease in lymphocyte counts on day 15. Imatinib plasma concentrations achieved in patients were in the range of those effective in in vitro sensitization studies.

Conclusion

The combination of chlorambucil and imatinib in patients with previously treated CLL was well tolerated and showed evidence of clinical efficacy. Based on our results, we recommend the 400 mg daily dose of imatinib on days 1–10 with 8 mg/m3 chlorambucil on days 3–7 every 28 days as the phase II dose. This represents the first clinical trial examining the potential synergy between a tyrosine kinase inhibitor and a conventional alkylating agent for the treatment of CLL.

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Acknowledgments

We wish to thank Novartis for funding this investigator-initiated clinical trial and in part the associated laboratory correlative studies. This project was also supported by the Leukemia & Lymphoma Society (LP). Please note that authors JH and SA contributed equally to this manuscript. This work was funded by Novartis Pharmaceutical Canada Inc. Author LP has previously acted as a consultant on advisory boards for Novartis.

Author information

Authors and Affiliations

  1. Lady Davis Institute for Medical Research, Sir Mortimer B Davis—Jewish General Hospital, Montreal, QC, Canada

    Jonathan Hebb, Sarit Assouline, Caroline Rousseau, Stephen Caplan, Lilian Amrein, Raquel Aloyz & Lawrence Panasci

  2. Hôpital Charles Lemoyne, Greenfield Park, QC, Canada

    Pierre DesJardins

  3. Departments of Medicine and Pharmacology and Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA

    Merrill J. Egorin

Authors
  1. Jonathan Hebb
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  2. Sarit Assouline
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  3. Caroline Rousseau
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  4. Pierre DesJardins
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  5. Stephen Caplan
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  6. Merrill J. Egorin
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  7. Lilian Amrein
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  8. Raquel Aloyz
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  9. Lawrence Panasci
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Corresponding author

Correspondence to Lawrence Panasci.

Additional information

This manuscript is dedicated to the memory of Dr. Merrill J. Egorin.

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Hebb, J., Assouline, S., Rousseau, C. et al. A phase I study of imatinib mesylate in combination with chlorambucil in previously treated chronic lymphocytic leukemia patients. Cancer Chemother Pharmacol 68, 643–651 (2011). https://doi.org/10.1007/s00280-010-1530-7

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  • DOI: https://doi.org/10.1007/s00280-010-1530-7

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