Temsirolimus, An mTOR Inhibitor, In Combination with Low-Dose Clofarabine in Older Patients with Advanced Acute Myeloid Leukemia: Results of a Phase 2 GIMEMA Study (AML-1107)

Elderly patients with refractory or relapsed AML have a dismal prognosis and new treatments are needed for these patients.The PI3K/AKT signaling pathway is frequently dysregulated in AML and contributes to cell proliferation and survival through activation of the mTOR kinase and its downstream effectors. mTOR inhibition with Sirolimus or its analogs, such as Temsirolimus, has been associated with clinical responses in AML and may enhance the sensitivity of leukemic cells to cytotoxics. Clofarabine is a second-generation nucleoside analog with activity in AML. Based on this, a multicenter, phase 2, open label, two-stage study was conducted to assess the efficacy and safety of Temsirolimus in combination with low-dose Clofarabine as salvage therapy for older pts with AML.

Eligible were pts older than 60 years of age with first relapse or primary refractory AML. Induction consisted of a single course of Clofarabine 20 mg/m2 iv d 1–5 and Temsirolimus 25 mg (flat dose) iv d 1, 8 and 15; a second course was allowed in pts achieving PR. Pts entering CR/CRi receive up to 12 monthly courses of maintenance with Temsirolimus (25 mg iv d 1 and 8 per course). The primary endpoint was complete remission with (CR) or without (CRi) hematopoietic recovery; secondary endpoints were overall survival, disease-free survival and toxicity. Pre and post-therapy bone marrow samples were obtained from a subset of pts to assess biomarkers.

Accrual began April 2009 and was completed in June 2010. To date, 52 of 54 enrolled pts are evaluable for response and toxicity (1 too early; 1 died pre-therapy): median age 70 yrs (range 60–78); 58% males; 17 pts with primary refractory AML; 35 pts with AML in first relapse (duration of CR1 < 6 mos 34%, ≥ 6 mos 66%); cytogenetics (MRC criteria): favorable in 4, intermediate in 37, adverse in 6, and unavailable in 5 pts. In all, 11 pts (21%; 95% CI 11–35%) have achieved CR (n=4) or CRi (n=7); 1 achieved PR; 7 (13%) died within 30 days of induction therapy (3 from infection, 3 from disease progression, 1 from cerebrovascular accident); 33 were resistant. CR or CRi was achieved in 9/35 pts (26%) in first relapse, and 2/17 (12%) with primary refractory disease. CR+CRi rates among: age < 70 and ≥ 70, 19% and 25%; first CR duration shorter and longer than 6 mos, 17% and 30%; favorable, intermediate, adverse and unknown cytogenetics, 50%, 22%, 0% and 20%. The median duration of remission for the 11 responders was 3.5 mos; 7 pts have relapsed to date and 4 (2 CR, 2 CRi) are currently maintaining a response at 2+, 4+, 11+ and 12+ mos from remission. With a median follow-up of 5 mos (range 0.3–14), the median overall survival for the entire population was 4.3 mos, and for responders 7.6 mos. Besides myelosuppression, most common grade 3–4 adverse events included infection (48%), febrile neutropenia (35%), transaminase elevation (11%), nausea and vomiting (8%), and fatigue (8%). Median times to recovery of neutrophils to 500/cmm and platelets to 50,000/cmm in responders were 28 and 32 days, respectively. Inhibition of phospho-S6RP, a downstream effector of mTOR, was documented in 12/21 (57%) pts analysed, and correlated with an improved rate of clinical response: 7/12 (58%) responded vs 0/9 pts with no detectable target inhibition.

These data indicate that a regimen combining Temsirolimus with low-dose Clofarabine can be safely administered to elderly pts with advanced AML. Encouraging anti-leukemic activity was recorded in this difficult-to-treat patient population, particularly in pts showing evidence of an on-target effect on mTOR signaling. Further investigation of this novel regimen as front-line therapy in older pts with AML considered unsuitable for intensive chemotherapy is planned.

Off Label Use: Clinical trial investigating Clofarabine and Temsirolimus in patients with acute myeloid leukemia.