A Phase I Study of the Mammalian Target of Rapamycin Inhibitor Sirolimus and MEC Chemotherapy in Relapsed and Refractory Acute Myelogenous Leukemia

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. (Clin Cancer Res 2009;15(21):6732-9) Although intensive combination chemotherapy is effective in temporizing acute myelogenous leukemia (AML) in most treated patients, the majority of those who achieve complete remission (CR) subsequently relapse and ultimately die of their disease (1-3). More than 30 years of combination chemotherapy clinical trials have failed to substantially improve survival in AML, leading to efforts to develop targeted therapeutics for this disease. We and others have concentrated on identifying agents or signaling inhibitors that target AML cells and AML stem cells without additional toxicity to normal hematopoietic cells. Some of these agents seem to be cytotoxic by themselves (4-9), whereas others alter the response of AML cells to chemotherapy (10, 11). The most extensively studied drugs in this class are the FLT3 inhibitors, for which clinical trials are ongoing (12-16). Use of FLT3 inhibitors has been studied primarily in patients with FLT3 mutations, which are known to confer a (12,15,17,18).Phosphatidylinositol-3′-kinase (PI3K) is a potential novel therapeutic target in AML. The role of PI3K signaling in leukemia has been studied in both murine models and primary human cells. Yilmaz et al. studied a murine leukemia model that conditionally induces activated PI3K signaling in hematop...

Antileukaemic effect of PI3K‐mTOR inhibitors in acute myeloid leukaemia‐gene expression profiles reveal CDC25B expression as determinate of pharmacological effect

“…PI3K and mTOR inhibitors have now entered clinical trials in AML (Yee et al, 2006;Perl et al, 2009;Chapuis et al, 2010a;Park et al, 2010). However, despite their theoretical potential as antileukaemic agents, their clinical effects have been limited and the reasons for this are unknown.…”

Utility of mTOR Inhibition in Hematologic Malignancies

“…The authors suggested that higher doses of rapamycin or a combination of mTOR inhibitors may increase the chances of driving these patients into remission [36]. A phase I study examined rapamycin in combination with mitoxantrone, etoposide, and cytarabine in 29 patients with AML [37]. Six of 27 patients who completed chemotherapy experienced a clinical response (complete response [CR] or partial response [PR]).…”

Perspectives on inhibiting mTOR as a future treatment strategy for hematological malignancies

“…56 Accordingly, previous clinical studies have revealed the low clinical benefit of rapalogs either alone 64 or in combination with high-dose chemotherapies 65 in refractory/relapsed cases of AML. However, although the anti-leukemic activity of the rapalogs has produced largely disappointing results in clinical practice, in vitro studies are ongoing to identify compounds that may function synergistically with them in AML, as reported for the use of histone deacetylases inhibitors (Table 1).…”