A phase I study of pevonedistat, azacitidine, and venetoclax in patients with relapsed/refractory acute myeloid leukemia. Haematologica 2024 Apr 04
Date
04/04/2024Pubmed ID
38572562DOI
10.3324/haematol.2024.285014Abstract
Azacitidine/venetoclax is an active regimen in patients with newly diagnosed AML. However, primary or secondary resistance to azacitidine/venetoclax is an area of unmet need and overexpression of MCL-1 is suggested to be a potential resistance mechanism. Pevonedistat inhibits MCL-1 through activation of NOXA, and pevonedistat/azacitidine has previously shown activity in AML. To assess the tolerability and efficacy of adding pevonedistat to azacitidine/venetoclax in relapsed/refractory AML, we conducted a phase I multicenter openlabel study in 16 adults with relapsed/refractory AML. Patients were treated with azacitidine, venetoclax along with pevonedistat intravenously on days 1, 3 and 5 of each 28-day cycle at 10, 15 or 20 mg/m2 in successive cohorts in the dose escalation phase. The impact of treatment on protein neddylation as well as expression of pro-apoptotic BCL2 family members was assessed. The recommended phase II dose of pevonedistat was 20 mg/m2. Grade 3 or higher adverse events included neutropenia (31%), thrombocytopenia (13%), febrile neutropenia (19%), anemia (19%), hypertension (19%) and sepsis (19%). The overall response rate was 46.7% for the whole cohort including complete remission (CR) in 5 of 7 (71.4%) patients who were naïve to the hypomethylating agent/venetoclax. No measurable residual disease (MRD) was detected in 80.0% of the patients who achieved CR. The median time to best response was 50 (range: 23 - 77) days. Four patients were bridged to allogeneic stem cell transplantation. The combination of azacitidine, venetoclax and pevonedistat is safe and shows encouraging preliminary activity in patients with relapsed/refractory AML. (NCT04172844).
Author List
Murthy GSG, Saliba AN, Szabo A, Harrington A, Abedin S, Carlson K, Michaelis L, Runaas L, Baim A, Hinman A, Maldonado-Schmidt S, Venkatachalam A, Flatten KS, Peterson KL, Schneider PA, Litzow M, Kaufmann SH, Atallah EAuthors
Sameem Abedin MD Associate Professor in the Medicine department at Medical College of WisconsinLyndsey Runaas MD Assistant Professor in the Medicine department at Medical College of Wisconsin
Aniko Szabo PhD Professor in the Institute for Health and Equity department at Medical College of Wisconsin
