Background: The initial treatment of FLT3 wild type acute myeloid leukemia (AML) has not significantly changed since induction therapy with Ara-C and anthracyclines was first developed. Preclinical data suggests constitutive activation of the AKT3/mammalian target of rapamycin (mTOR) pathway may play a role in pathogenesis of this disease in a subset of AML patients. Previous data from our group has shown that the presence of phosphorylated ribosomal S6 (pS6) in AML blasts as detected by flow cytometry may predict response to the combination of sirolimus and induction chemotherapy. Here we report the clinical and pharmacodynamics results of a phase II study of the combination of these drugs.
Methods: Subjects had newly diagnosed AML based on WHO criteria. Subjects received oral sirolimus starting on day 1 (12 mg loading dose) then 4 mg daily on days 2-10 with idarubicin 12mg/m2 days 4-7 and cytarabine 100mg/m2 days 4-10. Clinical response was assessed at hematologic recovery or by day 42 using IWG for response. Samples for pharmacodynamic studies of blasts were drawn prior to treatment with sirolimus on day 1, and then again prior to dosing of idarubicin and cytarabine on day 4. Assessment of pS6 on gated blasts, a biomarker of mTORC1 activation, was assessed by flow cytometry using previously described methods.
Results: 55 patients enrolled on this trial received sirolimus with an average age of 58 years. Toxicity was similar to published 7+3 data and prolonged aplasia without recovery was not observed. Twenty-nine patients (53%) had high risk cytogenetic or molecular mutations, 15 (27%) had intermediate risk disease, and 11 (20%) patients had lower risk disease. As a whole, 35 patients (64%) entered into CR or CRp, 1 had a PR, 17 (27%) were non-responders. Two (4%) patients (ages 64 and 71) died during induction. Thirteen (45%) patients with high risk disease had a CR or CRp, 14 (48%) were non-responders, and 2 died in induction. Of the 15 subjects with intermediate risk disease, 11 (79%) patients had a CR or CRp, 1 had a partial response, and 3 were non-responders. All low risk patients had a CR, and 9 of 11 are alive and in remission at the time of censoring of data with a median time on study of 674 days. One patient with low risk disease subsequently relapsed, went to stem cell transplant, and is currently in CR. Two patients with low risk disease refused to proceed with standard of care consolidation; of these, 1 is alive and in remission 946 days from study entry, and 1 died in relapse. Fifteen patients (27%) subsequently underwent allogeneic stem cell transplantation in CR, and 8 (53%) are still alive an average of 358 days after transplant.
Thirty-seven of 55 patients had adequate samples for pharmacodynamic analysis. Surprisingly, all patients demonstrated activation of ribosomal S6 prior to therapy in contrast to 67% positivity seen in previous studies that focused on patients with relapsed AML. mTORC1 was inhibited greater than 40% in 28/37 (76%) of patients. Inhibition did not correlate with either overall survival or age of patients.
Conclusions: Sirolimus and 7+3 is a well-tolerated regimen. mTORC1 appears to be activated in almost all patients at the time of diagnosis of AML as assessed by flow cytometric assessment of ribosomal S6. Inhibition of mTORC1 did not correlate with response, suggesting that AML cells may have redundant signaling pathways that regulate chemosensitivity when mTORC1 is inhibited. Given the large percentage of samples with mTORC1 activation in this upfront AML study, future research into dual mTORC inhibitors may prove valuable.
Carroll: Astellas Pharmaceuticals: Research Funding; Incyte Pharmaceuticals: Research Funding. Porcu: Innate Pharma: Research Funding; Kura: Research Funding; Miragen: Research Funding; Kiowa: Research Funding; Galderma: Research Funding; Tetralogic: Research Funding; Cell Medica: Research Funding; Celgene: Research Funding. Perl: Arog Pharmaceuticals: Consultancy; Novartis: Other: Advisory Board; Pfizer: Other: Advisory Board; Seattle Genetics: Other: Advisory board; Asana Biosciences: Other: Scientific advisory board; Astellas: Consultancy; Daiichi Sankyo: Consultancy; Actinium Pharmaceuticals: Other: Scientific Advisory Board.
Asterisk with author names denotes non-ASH members.