Randomized phase 2 trial of pevonedistat plus azacitidine versus azacitidine for higher-risk MDS/CMML or low-blast AML

Abstract

There is a critical unmet need for novel treatments for higher-risk myelodysplastic syndromes (MDS), higherrisk chronic myelomonocytic leukemia (CMML), and lowblast (LB) acute myeloid leukemia (AML). For patients ineligible for stem cell transplant (SCT), standard therapy with hypomethylating agents, such as azacitidine and decitabine, is not curative, with most patients relapsing within 2 years [1–3]. Pevonedistat is the first small-molecule inhibitor of the neural precursor cell expressed, developmentally downregulated 8 (NEDD8)-activating enzyme (NAE); NAE facilitates conjugation of the small ubiquitin-like protein, NEDD8, which activates cullin-RING E3 ubiquitin ligases (CRLs) [4–6]. Inhibition of NAE by pevonedistat prevents degradation of CRL substrates integral to tumor cell growth, proliferation, and survival, thereby leading to cancer cell death [4–6]. Pevonedistat+ azacitidine demonstrated preclinical synergistic antitumor activity in AML xenografts and was well tolerated in patients with untreated AML, with promising clinical activity [7]. Based on these results, this phase 2, multicenter, global, randomized, controlled, open-label trial (NCT02610777) compared pevonedistat+ azacitidine versus single-agent azacitidine in patients with higher-risk MDS/CMML and LB-AML who had not previously received a hypomethylating agent. The study enrolled adults with morphologically confirmed higher-risk MDS, non-proliferative CMML, or LB-AML (20–30% myeloblasts in bone marrow); these patients were eligible for enrollment because the diseases are part of the higher-risk MDS spectrum, and were included in the pivotal randomized study that demonstrated significant improvement in overall survival (OS) with azacitidine versus conventional care regimens [3, 8, 9]. Patients with MDS/CMML were required to have very-high, high, or intermediate risk according to the revised international prognostic scoring system (IPSS-R);