Azacitidine, venetoclax, and pevonedistat showed “encouraging” activity in a “very poor risk” population of patients with acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), or chronic myelomonocytic leukemia (CMML), according to a recent study.
Nicholas Short, MD, of the University of Texas MD Anderson Cancer Center, and colleagues conducted the study because “preclinical data suggest synergy of pevonedistat with azacitidine and venetoclax.”
The single-center phase I/II study evaluated the triplet combination after hypomethylating agent failure in 40 older adults with newly diagnosed secondary AML (n=32), MDS, or CMML (n=8).
In the cohort of patients with AML, the median age was 74 years and nearly all (84%) patients had at least one adverse risk cytomolecular feature, including 47% who had a TP53 mutation or 3q26 rearrangement. Around half (53%) received prior therapy for a preceding myeloid disorder. In the cohort of patients with MDS or CMML, nearly all (87%) were considered high risk or very high risk by the Revised International Prognostic Scoring System.
All patients received azacitidine 75 mg/m2 intravenously on days one through seven. Patients with AML received venetoclax at a maximum dose of 200 mg to 400 mg orally on days one through 21. Patients with MDS or CMML received venetoclax at a maximum dose of 200 mg to 400 mg orally on days one through 14. All patients received pevonedistat 20 mg/m2 intravenously on days one, three, and five. Patients received up to 24 cycles of treatment.
The primary endpoints of the phase II portion of the study were the rate of complete response (CR) and CR with incomplete hematologic recovery in the cohort of patients with AML and the overall response rate (ORR) in the cohort of patients with MDS or CMML.
In the cohort of patients with AML, 50% had a CR, while 16% had a CR with incomplete hematologic recovery. The median overall survival (OS) was 8.1 months.
In the cohort of patients with MDS or CMML, the ORR was 75%, with a CR in 13% of patients, a marrow CR with or without hematologic improvement in 50%, and hematologic improvement in 13%.
The study’s investigators also conducted a biomarker analysis using serial peripheral blood and bone marrow samples they collected from patients in the AML cohort.
“In an exploratory analysis, early upregulation of NOXA expression was observed, with subsequent decrease in MCL-1 and FLIP, findings consistent with preclinical mechanistic studies of pevonedistat,” Dr. Short and colleagues wrote. “Upregulation of CD36 was observed, which may have contributed to therapeutic resistance.”
Infection was the most common grade 3 to 4 adverse event (AE), occurring in 35% of patients. Other common grade 3 to 4 AEs included febrile neutropenia in 25% and hypophosphatemia in 23%.
“The triplet combination of azacitidine, venetoclax and pevonedistat shows encouraging activity in this very poor-risk population of patients with AML, MDS or CMML,” Dr. Short and colleagues concluded.
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. 2023;16(1). doi:10.1186/s13045-023-01476-8