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Ferrata Storti Foundation
Acute Myeloid Leukemia
Addition of the mammalian target of rapamycin inhibitor, everolimus, to consolidation therapy in acute myeloid leukemia: experience from the UK NCRI AML17 trial
Haematologica 2018 Volume 103(10):1654-1661
Alan K Burnett,1 Emma Das Gupta,2 Steve Knapper,3 Asim Khwaja,4 Marion Sweeney, 3Lars Kjeldsen,5 Timothy Hawkins,6 Sophie E Betteridge,7 Paul Cahalin,8 Richard E Clark,9 Robert K Hills9 and Nigel H Russell2 on behalf of the UK NCRI AML Study Group
1Formerly Department of Haematology, Cardiff University School of Medicine, UK; 2Department of Haematology, Nottingham University Hospital NHS Trust, UK; 3Department of Haematology, University Hospital of Wales, Cardiff, UK; 4University College, London Cancer Institute, UK; 5Department of Haematology, Rigshospitalet, Copenhagen, Denmark; 6Department of Haematology, Auckland City Hospital, New Zealand; 7Centre for Trials Research, Cardiff University School of Medicine, UK; 8Department of Haematology, Blackpool Victoria Hospital, UK and 9Department of Haematology, Royal Liverpool University Hospital, UK
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, sequen- tially with post-induction chemotherapy. Three hundred and thirty-nine patients were randomised (2:1) to receive everolimus or not for a maxi- mum 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], cumula- tive 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.
Introduction
The majority (70-85%) of younger patients with acute myeloid leukemia (AML) will enter complete morphological remission with any one of a variety of induction treatments. However, nearly half will relapse. It is being increasingly recognized that a substantial proportion of those subjects in morphological remission do actu- ally have residual disease, as determined by techniques of minimal/measurable residual disease assessment (flow cytometry or quantitative polymerase chain reac- tion1,2). In our previous studies we endeavored to define the optimum post-remis- sion chemotherapy. To date we have concluded that, apart from transplantation, following two induction courses of anthracycline-containing therapy, two consoli- dation courses of cytarabine (Ara-C) is adequate.3 One of the aims of the UK NCRI AML17 trial was to explore the effects of a further reduction in the total number of chemotherapy courses from four to three, as well as the addition of molecularly tar- geted treatments to consolidation therapy. Among these was the incorporation of the inhibitor of the mammalian target of rapamycin (mTOR), everolimus.
Correspondence:
akburnett719@gmail.com
Received: January 24, 2018. Accepted: July 4, 2018. Pre-published: July 5 2018.
doi:10.3324/haematol.2018.189514
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/10/1654
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