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

Author:

Palmisiano Neil1,Jeschke Grace2,Wilde Lindsay1,Alpdogan Onder1,Carabasi Matthew1,Filicko-O’Hara Joanne1,Grosso Dolores1,Klumpp Thomas1,Martinez Ubaldo1,Wagner John1,Carroll Martin P.2ORCID,Perl Alexander2,Kasner Margaret1ORCID

Affiliation:

1. Division of Hematology and Oncology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA

2. Department of Medicine, Division of Hematology and Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA

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.

Funder

Abramson Cancer Center

Thomas Jefferson University’s Sidney Kimmel Cancer Center Cancer Center

Publisher

MDPI AG

Subject

Cancer Research,Oncology

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