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A Phase I Study of the Mammalian Target of Rapamycin Inhibitor Sirolimus and MEC Chemotherapy in Relapsed and Refractory Acute Myelogenous Leukemia
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, sirolimu...
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Published in: | Clinical cancer research 2009-11, Vol.15 (21), p.6732-6739 |
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Main Authors: | , , , , , , , , , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
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Online Access: | Get full text |
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Summary: | 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. (Clin Cancer Res 2009;15(21):6732–9) |
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ISSN: | 1078-0432 1557-3265 |
DOI: | 10.1158/1078-0432.CCR-09-0842 |