Triplet Combination Yields Encouraging Activity for Newly Diagnosed Secondary AML, MDS, or CMML After Failure of Hypomethylating Agents

Results from a Single-Center Phase 1/2 Trial

Findings from a phase 1/2 trial published in the Journal of Hematology & Oncology indicated that the triplet combination of azacitidine, venetoclax, and pevonedistat yielded encouraging efficacy among older patients with newly diagnosed secondary acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), or chronic myelomonocytic leukemia (CMML) after failure of hypomethylating agents.

Nicholas J Short, MD, The University of Texas MD Anderson Cancer Center, Houston, Texas, and coauthors describe a need for updated treatment for both patients with AML and MDS, as secondary AML leads to “poorer response to conventional therapies and shorter survival,” and patients with high-risk MDS have a “median overall survival (OS) of only 4 to 6 months, and there is no standard of care for this population.” 

Preclinical data suggests potential synergies when combining pevonedistat, a first-in-class, small molecular inhibitor of the NEDD8-activating enzyme, with azacitidine and venetoclax. In this trial, the study authors aimed to investigate the efficacy and safety of this triplet combination among older adults diagnosed with secondary AML, MDS, or CMML, after prior hypomethylating agent (HMA) therapy. The primary end points for phase 2 were the complete response (CR) and CR with incomplete count recovery (CRi) rates in the AML cohort, as well as the overall response rate in the MDS/CMML cohort. 

A total of 40 patients with newly diagnosed secondary AML (n = 32) or MDS/CMML (n = 8) after HMA failure were included in this study. Azacitidine was administered at 75 mg/m2 on days 1 through 7, venetoclax at a maximum dose of 200 to 400 mg on days 1 through 21 to the AML cohort, or on days 1 through 14 to the MDFS/CMML cohort, and pevonedistat at 20 mg/m2 on days 1, 3, and 5, for up to 24 cycles. Among the AML cohort, 84% exhibited adverse risk cyto-molecular features, including 47% with TP53 mutations or MECOM rearrangements. The CR/CRi rate was 66%, with a median OS of 8.1 months. In the MDS/CMML cohort, 87% were high or very high risk by the Revised International Prognostic Scoring System (IPSS-R). The overall response rate was 75%. 

In terms of safety, the most common grade 3 to 4 adverse events included infection (35%), febrile neutropenia (25%), and hypophosphatemia (23%). An exploratory analysis revealed early upregulation of NOXA expression and subsequent decreases in MCL-1 and FLIP, which was consistent with preclinical mechanistic studies of pevonedistat. CD36 upregulation was also detected, which was noted as a potential factor of therapeutic resistance. 

Dr Short and colleagues concluded, “The triplet combination of azacitidine, venetoclax and pevonedistat shows encouraging activity in this very poor-risk population of patients with AML, MDS or CMML.”

“A randomized phase 2 study of azacitidine, venetoclax and pevonedistat versus azacitidine and venetoclax in patients with newly diagnosed AML who are unfit for intensive chemotherapy has fully accrued (NCT04266795) and will help to clarify the potential role of pevonedistat in this population,” they added. 

Source: 

Short NJ, Muftuoglu M, Ong F, et al. A phase 1/2 study of azacitidine, venetoclax and pevonedistat in newly diagnosed secondary AML and in MDS or CMML after failure of hypomethylating agents. J Hematol Oncol. Published online July 8, 2023. doi:10.1186/s13045-023-01476-8