There is a critical unmet need for novel treatments for higher-risk myelodysplastic syndromes (MDS), higher-risk chronic myelomonocytic leukemia (CMML), and low-blast (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.

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).

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.

In summary, this randomized, proof-of-concept phase 2 study demonstrated clinical efficacy with pevonedistat + azacitidine in patients with higher-risk MDS and LB-AML. The OS, EFS, and ORR benefits were particularly promising among patients with higher-risk MDS, as was the OS benefit in LB-AML. The addition of pevonedistat to azacitidine resulted in a comparable safety profile to azacitidine alone, no increased myelosuppression, and azacitidine dose intensity was maintained.

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