A phase I study of pevonedistat, azacitidine, and venetoclax in patients with relapsed/refractory acute myeloid leukemia

• Published in: Haematologica (Roma) Vol. 109; no. 9; pp. 2864 - 2872
• Main Authors: Murthy, Guru Subramanian Guru, Saliba, Antoine N, Szabo, Aniko, Harrington, Alexandra, Abedin, Sameem, Carlson, Karen, Michaelis, Laura, Runaas, Lyndsey, Baim, Arielle, Hinman, Alex, Maldonado-Schmidt, Sonia, Venkatachalam, Annapoorna, Flatten, Karen S, Peterson, Kevin L, Schneider, Paula A, Litzow, Mark, Kaufmann, Scott H, Atallah, Ehab
• Format: Journal Article
• Language: English
• Published: Italy Fondazione Ferrata Storti 01-09-2024; Ferrata Storti Foundation
• Subjects: Acute Myeloid Leukemia; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Azacitidine - administration & dosage; Azacitidine - adverse effects; Azacitidine - therapeutic use; Bridged Bicyclo Compounds, Heterocyclic - administration & dosage; Bridged Bicyclo Compounds, Heterocyclic - adverse effects; Bridged Bicyclo Compounds, Heterocyclic - therapeutic use; Cyclopentanes; Drug Resistance, Neoplasm; Female; Humans; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - mortality; Male; Middle Aged; Naphthyridines - administration & dosage; Naphthyridines - therapeutic use; Pyrimidines - administration & dosage; Pyrimidines - adverse effects; Pyrimidines - therapeutic use; Recurrence; Sulfonamides - administration & dosage; Sulfonamides - therapeutic use; Treatment Outcome
• ISSN: 0390-6078; 1592-8721; 1592-8721
• DOI: 10.3324/haematol.2024.285014

Azacitidine/venetoclax is an active regimen in patients with newly diagnosed acute myeloid leukemia (AML). However, primary or secondary resistance to azacitidine/venetoclax is an area of unmet need and overexpression of MCL1 is suggested to be a potential resistance mechanism. Pevonedistat inhibits MCL1 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, open-label 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 doses of 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 in five of seven (71.4%) patients who had not previously been treated with the hypomethylating agent/venetoclax. No measurable residual disease was detected in 80.0% of the patients who achieved complete remission. 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).