Addition of the mammalian target of rapamycin inhibitor, everolimus, to consolidation therapy in acute myeloid leukemia: experience from the UK NCRI AML17 trial

Abstract

As part of the UK NCRI AML17 trial, adult patients with acute myeloid leukemia in remission could be randomized to receive the mammalian target of rapamycin inhibitor everolimus, sequentially with post-induction chemotherapy. Three hundred and thirty-nine patients were randomised (2:1) to receive everolimus or not for a maximum of 84 days between chemotherapy courses. The primary endpoint was relapse-free survival. At 5 years there was no difference in relapse-free survival [29% versus 40%; odds ratio 1.19 (0.9-1.59) P=0.2], cumulative incidence of relapse [60% versus 54%: odds ratio 1.12 (0.82-1.52): P=0.5] or overall survival [45% versus 58%: odds ratio 1.3 (0.94-1.81): P=0.11]. The independent Data Monitoring Committee advised study termination after randomization of 339 of the intended 600 patients because of excess mortality in the everolimus arm without any evidence of beneficial disease control. The delivery of the everolimus dose was variable, but there was no evidence of clinical benefit in patients with adequate dose delivery compared with no treatment. This study suggests that the addition of mammalian target of rapamycin inhibition to chemotherapy provides no benefit.

Figure 1.

CONSORT diagram. APL: acute promyelocytic leukemia; CEP-701: lestaurtinib; CBF: core-binding factor; MTOR: mammalian target of rapamycin;

Figure 2.

Compliance with treatment. AE: adverse event; LFT: liver fuction tests.

Figure 3.

Toxicities associated with treatment in courses 2 and 3. (A) Course 2 (B) Course 3.

Figure 4.

Relapse, death in remission, relapse-free survival and overall survival within the everolimus randomisation: (A) Cumulative incidence of relapse; (B) cumulative incidence of death in remission; (C) relapse-free survival; (D) overall survival.