A Phase II Study of Azacitidine and Sirolimus for the Treatment of Acute Myeloid Leukemia (AML) Refractory to or Not Eligible for Intensive Chemotherapy or High Risk Myelodysplastic Syndrome (MDS)
2017
Abstract Background: The treatment of relapsed, refractory, or frail patients with AML is largely palliative and survival outcomes are poor. Fit patients with high risk MDS also do poorly with intensive chemotherapy. Therapeutic choices for both groups include supportive care only or hypomethylating agents (HMA) like azacitidine. Previous work by our group has demonstrated constitutive activation of the AKT/mammalian target of rapamycin (mTOR) pathway in AML and MDS. Given this, we explored the combination of azacitidine and sirolimus, an inhibitor of mTORC1, in relapsed/refractory/unfit AML and upfront high-risk MDS. Methods: Subjects had either de novo or relapsed AML (Arm A) or high risk MDS (Arm B) as defined by WHO criteria and must have been unsuitable for intensive therapy based on comorbidities. Prior therapy with HMA was allowed. Patients received an oral loading dose of sirolimus 12mg on day 1, and then 4 mg daily for 9 doses, from days 2 to 10 with azaciditine 75mg/m2 IV or SC from days 4-10 every 28 days. Best clinical response by 6 months was assessed using IWG criteria. Samples for pharmacodynamic analysis were drawn prior to treatment with sirolimus on day 1, and then again prior to dosing of azacitidine on day 4. As a marker of mTOR pathway activation, ribosomal S6 phosphorylation (pS6) was assessed by flow cytometry on blast-gated samples using previously described methods. Results: At the time of this analysis, a total of 25 patients in the AML arm (Arm A) and 20 in the MDS arm (Arm B) were enrolled and received at least one cycle of therapy. Toxicity was similar to previous reports with azacitidine alone. Average age of patients on Arm A was 71 years. Nineteen of the 25 AML patients (76%) had high risk cytogenetics, and 6 (24%) had intermediate risk. Seven AML (28%) patients had relapsed or refractory disease. One of 25 (4%) patients on arm A had a complete response (CR), 5 (20%) had a partial response (PR), 13 (52%) had stable disease (SD), and 4 (16%) had progressive disease (PD). Two patients (8%), both high risk, were lost to follow up after one cycle. Of the 19 patients in arm A with high risk cytogenetics, 2 (10%) achieved a PR, 11 (58%) had SD, and 4 (22%) had PD. Of the 6 with intermediate risk cytogenetics, 1 patient had a CR, 3 had a PR, and 2 had SD. Three patients on arm A subsequently underwent allogeneic stem cell transplantation, 2 of whom are alive and in CR 1323 and 1123 days after transplant. Median overall survival (OS) for arm A was 213 days. In the MDS arm (Arm B), all 20 patients (average age of 70) had RAEB-1 or 2. Four (20%) had prior HMA therapy. Four (20%) had a marrow CR, 3 (15%) had a PR, 6 (30%) had SD, and 4 (20%) had PD. Three (15%) died before response could be assessed. Five patients in Arm B subsequently underwent allogeneic stem cell transplantation. Median OS was 206 days. Pharmacodynamic samples from 27 patients (15 in Arm A and 12 in Arm B) were analyzed. Patients were classified as having baseline pS6 if pS6 was detected in >5% of blasts in a sample. In arm A, 9/15 had baseline pS6, with an average of 18.6 % (range 4.4 to 49%) blasts with pS6. After sirolimus administration, 7/9 patients with baseline pS6 had a >40% reduction in the percentage of pS6 blasts. In Arm B, as most MDS samples did not have a clear blast gate by SSC/CD45, non-lymphoid populations were gated based on CD34+CD117+. Cases with a clear blast gate via CD45/SSC were confirmed using CD34, CD33 and CD117. Baseline pS6 was detected in 12/12 MDS patients, with an average of 37% (Range 8-96%) of blasts with pS6. Only 5/12 MDS patients had >40% reduction in pS6 blasts after sirolimus. Correlation with clinical response is ongoing. Summary: Sirolimus and azacitidine appears to be a safe and effective combination for elderly, relapsed/refractory AML and upfront high risk MDS. Measurement of pS6+ marrow blasts by flow cytometry is, to our knowledge, the first assessment of a biomarker of mTORC1 inhibition ever performed in MDS. Overall, these results confirm that mTORC1 is constitutively activated in immature cells from patients with AML and high risk MDS and suggest that patients with MDS are more likely to have pS6 at baseline than AML patients. Sirolimus inhibited pS6 phosphorylation only in a subset of AML and high risk MDS patients. Given these promising results, continued exploration of the inhibition of mTORC1 in AML and MDS is warranted. Disclosures Carroll: Astellas Pharmaceuticals: Research Funding; Incyte Pharmaceuticals: Research Funding. Porcu: Kiowa: Research Funding; Galderma: Research Funding; Cell Medica: Research Funding; Kura: Research Funding; Tetralogic: Research Funding; Miragen: Research Funding; Innate Pharma: Research Funding; Celgene: Research Funding.
Keywords:
- Correction
- Source
- Cite
- Save
- Machine Reading By IdeaReader
0
References
0
Citations
NaN
KQI