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Acute Myeloid Leukemia
Synergistic activity of IDH1 inhibitor BAY1436032 with azacitidine in IDH1 mutant acute myeloid leukemia
Anuhar Chaturvedi,1 Charu Gupta,1 Razif Gabdoulline,1 Nora M. Borchert,1 Ramya Goparaju,1 Stefan Kaulfuss,2 Kerstin Görlich,1 Renate Schottmann,1 Basem Othman,1 Julia Welzenbach,3 Olaf Panknin,2 Markus Wagner,2 Robert Geffers,4 Arnold Ganser,1 Felicitas Thol,1 Michael Jeffers,5
Ferrata Storti Foundation
Haematologica 2021 Volume 106(2):565-573
Andrea Haegebarth2 and Michael Heuser1
1Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany; 2Bayer AG, Berlin, Germany; 3Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany; 4Genome Analytics Research Group, Helmholtz Center for Infection Research, Braunschweig, Germany and 5Bayer AG, Whippany, NJ, USA
ABSTRACT
Mutant isocitrate dehydrogenase 1 (mIDH1) inhibitors have shown single-agent activity in relapsed/refractory acute myeloid leukemia (AML), even though most patients eventually relapse. We evaluated the efficacy and molecular mechanism of the combination treatment with azacitidine, which is currently the standard of care in older AML patients, and mIDH1 inhibitor BAY1436032. Both compounds were evaluated in vivo as single agents and in combination with sequential (azac- itidine, followed by BAY1436032) or simultaneous application in two human IDH1 mutated AML xenograft models. Combination treatment sig- nificantly prolonged survival compared to single agent or control treatment (P<0.005). The sequential combination treatment depleted leukemia stem cells by 470-fold. Interestingly, the simultaneous combination treatment depleted leukemia stem cells by 33,150-fold compared to control mice. This strong synergy is mediated through inhibition of MAPK/ERK and Rb/E2F signaling. Our data strongly argues for the concurrent application of mIDH1 inhibitors and azacitidine and predicts improved outcome of this regimen in IDH1 mutated AML patients.
Introduction
In acute myeloid leukemia (AML) patients, mutated isocitrate dehydrogenase 1 (IDH1) is found in about 6-10% of patients1,2 at amino acid arginine 132 in the active site where isocitrate and NADPH bind.3 Whereas the enzymatic function of mutant IDH to convert isocitrate to α-ketoglutarate is impaired, it gains a neomorphic func- tiontoconvert α-ketoglutaratetoR-2-hydroxyglutarate(R-2HG),whichinduceshis- tone- and DNA hypermethylation through inhibition of demethylation, and leads to a block in cellular differentiation thus promoting tumorigenesis.3-6 IDH1 mutant-spe- cific (mIDH1) inhibitors have emerged as a potent tool for the treatment of IDH1 mutant AML. A recent report on the first clinical IDH1 inhibitor ivosidenib as a single agent in IDH1-mutated relapsed or refractory AML showed an overall response rate of 41.6% and a complete remission rate of 21.6% with a median duration of response of 8.2 months.7 While these results are promising in this difficult to treat patient setting, they also suggest that mIDH1 inhibitors should be combined with other agents to improve efficacy.
A possible mechanism of synergy in IDH1 mutant AML is the reversal of DNA methylation by hypomethylating agents. 5-azacitidine (AZA) is a hypomethylating agent and can activate key epigenetically silenced pathways in AML cells, leading to an arrest of AML cell proliferation.8 The AZA-AML-001 study showed that azaciti- dine has clear activity in AML as monotherapy in patients with unfavorable cytoge- netics.9 Therefore, a successful reversal of IDH1 mutant induced DNA hypermethy- lation in AML cells represents a window of opportunity to enhance the efficacy of mIDH1 inhibitors. We have previously shown that BAY1436032 is a highly effective
Correspondence:
MICHAEL HEUSER
heuser.michael@mh-hannover.de
ANUHAR CHATURVEDI
chaturvedi.anuhar@mh-hannover.de
Received: September 9, 2019. Accepted: March 26, 2020. Pre-published: April 2, 2020.
https://doi.org/10.3324/haematol.2019.236992
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