A Phase I Trial of Sirolimus with “7&3” Induction Chemotherapy in Patients with Newly Diagnosed Acute Myeloid Leukemia

SIMPLE SUMMARY: Relapsed or refractory AML remains common and difficult to treat, with no standard of care. Therefore, improving upfront therapy to prevent relapse in younger AML patients who are candidates for aggressive chemotherapy is an imperative. The PI3K/AKT/mTOR pathway helps regulate a variety of cellular processes, including protein synthesis, cell cycle progression and apoptosis. Unlike many therapeutic targets valid in only a subset of patients, this pathway demonstrates broad activation across a wide variety of subtypes of AML. Sirolimus is a highly mTORC1-selective allosteric kinase inhibitor that has been extensively studied in a wide variety of malignancies, including myeloid malignancies, and is approved as antirejection prophylaxis in solid organ transplantation. We examined levels of pS6 (a marker of activation of this pathway) at baseline and after exposure to sirolimus in patient samples, and here we report on the pharmacodynamic and clinical results of our phase 1 trial. ABSTRACT: Chemotherapy remains a primary treatment for younger AML patients, though many relapse. Data from our group have shown that highly phosphorylated S6 in blasts may predict response to sirolimus given with chemotherapy. We report the results of a phase I study of this combination in newly diagnosed AML and the pharmacodynamic analysis of pS6 before and after treatment. Subjects received sirolimus (12 mg on day 1, 4 mg daily, days 2–10), then idarubicin and cytarabine (days 4–10). Response was assessed at hematologic recovery or by day 42 using a modified IWG criteria. Fifty-five patients received sirolimus. Toxicity was similar to published 7 + 3 data, and 53% had high-, 27% intermediate-, and 20% favorable-risk disease. Forty-four percent of the high-risk patients entered into CR/CRp. Seventy-nine percent of the intermediate-risk subjects had a CR/CRp. All favorable-risk patients had a CR by day 42; 9/11 remained alive and in remission with a median follow-up of 660 days. Additionally, 41/55 patients had adequate samples for pharmacodynamic analysis. All patients demonstrated activation of S6 prior to therapy, in contrast to 67% seen in previous studies of relapsed AML. mTORC1 inhibition was observed in 66% of patients without enrichment among patients who achieved remission. We conclude that sirolimus and 7 + 3 is a well-tolerated and safe regimen. mTORC1 appears to be activated in almost all patients at diagnosis of AML. Inhibition of mTORC1 did not differ based on response, suggesting that AML cells may have redundant signaling pathways that regulate chemosensitivity in the presence of mTORC1 inhibition.