A phase I study of the mammalian target of rapamycin inhibitor sirolimus and MEC chemotherapy in relapsed and refractory acute myelogenous leukemia.

Authors

• Alexander E Perl
• Margaret T Kasner
• Donald E Tsai
• Dan T Vogl
• Alison W Loren
• Stephen J Schuster
• David L Porter
• Edward A Stadtmauer
• Steven C Goldstein
• Noelle V Frey
• Sunita D Nasta
• Elizabeth O Hexner
• Jamil K Dierov
• Cezary R Swider
• Adam Bagg
• Alan M Gewirtz
• Martin Carroll
• Selina M Luger

Publication/Presentation Date

11-1-2009

Abstract

PURPOSE: Inhibiting mammalian target of rapamycin (mTOR) signaling in acute myelogenous leukemia (AML) blasts and leukemic stem cells may enhance their sensitivity to cytotoxic agents. We sought to determine the safety and describe the toxicity of this approach by adding the mTOR inhibitor, sirolimus (rapamycin), to intensive AML induction chemotherapy.

EXPERIMENTAL DESIGN: We performed a phase I dose escalation study of sirolimus with the chemotherapy regimen MEC (mitoxantrone, etoposide, and cytarabine) in patients with relapsed, refractory, or untreated secondary AML.

RESULTS: Twenty-nine subjects received sirolimus and MEC across five dose levels. Dose-limiting toxicities were irreversible marrow aplasia and multiorgan failure. The maximum tolerated dose (MTD) of sirolimus was determined to be a 12 mg loading dose on day 1 followed by 4 mg/d on days 2 to 7, concurrent with MEC chemotherapy. Complete or partial remissions occurred in 6 (22%) of the 27 subjects who completed chemotherapy, including 3 (25%) of the 12 subjects treated at the MTD. At the MTD, measured rapamycin trough levels were within the therapeutic range for solid organ transplantation. However, direct measurement of the mTOR target p70 S6 kinase phosphorylation in marrow blasts from these subjects only showed definite target inhibition in one of five evaluable samples.

CONCLUSIONS: Sirolimus and MEC is an active and feasible regimen. However, as administered in this study, the synergy between MEC and sirolimus was not confirmed. Future studies are planned with different schedules to clarify the clinical and biochemical effects of sirolimus in AML and to determine whether target inhibition predicts chemotherapy response.

Volume

15

Issue

21

First Page

6732

Last Page

6739

ISSN

1557-3265

Published In/Presented At

Perl, A. E., Kasner, M. T., Tsai, D. E., Vogl, D. T., Loren, A. W., Schuster, S. J., Porter, D. L., Stadtmauer, E. A., Goldstein, S. C., Frey, N. V., Nasta, S. D., Hexner, E. O., Dierov, J. K., Swider, C. R., Bagg, A., Gewirtz, A. M., Carroll, M., & Luger, S. M. (2009). A phase I study of the mammalian target of rapamycin inhibitor sirolimus and MEC chemotherapy in relapsed and refractory acute myelogenous leukemia. Clinical cancer research : an official journal of the American Association for Cancer Research, 15(21), 6732–6739. https://doi.org/10.1158/1078-0432.CCR-09-0842

Disciplines

Medicine and Health Sciences

PubMedID

19843663

Department(s)

Hematology-Medical Oncology Division

Document Type

Article