Journal Article

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

Kantarjian, Hagop, Borthakur, Gautam, Jain, Nitin, Qiao, Wei, Issa, Ghayas C., Garcia-Manero, Guillermo, Daver, Naval, Montalban-Bravo, Guillermo, Ohanian, Maro, Nasr, Lewis, Cortes, Jorge, Dinardo, Courtney D., Bose, Prithviraj, Andreeff, Michael, Ong, Faustine, Short, Nicholas J., Muftuoglu, Muharrem, Huang, Xuelin, Patel, Keyur P., Ravandi, Farhad, Jabbour, Elias, Macaron, Walid, Alvarado, Yesid, Abramova, Regina, Basyal, Mahesh, Delumpa, Ricardo, Kanagal-Shamanna, Rashmi

2023

Overview

Background Pevonedistat is a first-in-class, small molecular inhibitor of NEDD8-activating enzyme that has clinical activity in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Preclinical data suggest synergy of pevonedistat with azacitidine and venetoclax. Methods This single-center, phase 1/2 study evaluated the combination of azacitidine, venetoclax and pevonedistat in older adults with newly diagnosed secondary AML or with MDS or chronic myelomonocytic leukemia (CMML) after failure of hypomethylating agents. Patients received azacitidine 75 mg/m 2 IV on days 1–7, venetoclax at maximum dose of 200-400 mg orally on days 1–21 (AML cohort) or days 1–14 (MDS/CMML cohort) and pevonedistat 20 mg/m 2 IV on days 1, 3 and 5 for up to 24 cycles. The primary endpoints for the phase 2 portion of the study were the CR/CRi rate in the AML cohort and the overall response rate (CR + mCR + PR + HI) in the MDS/CMML cohort. Findings Forty patients were enrolled (32 with AML and 8 with MDS/CMML). In the AML cohort, the median age was 74 years (range 61–86 years), and 27 patients (84%) had at least one adverse risk cyto-molecular feature, including 15 (47%) with a TP53 mutation or MECOM rearrangement; seventeen patients (53%) had received prior therapy for a preceding myeloid disorder. The CR/CRi rate was 66% (CR 50%; CRi 16%), and the median overall survival (OS) was 8.1 months. In the MDS/CMML cohort, 7 patients (87%) were high or very high risk by the IPSS-R. The overall response rate was 75% (CR 13%; mCR with or without HI 50%; HI 13%). The most common grade 3–4 adverse events were infection in 16 patients (35%), febrile neutropenia in 10 patients (25%) and hypophosphatemia in 9 patients (23%). 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. Upregulation of CD36 was observed, which may have contributed to therapeutic resistance. Conclusions The triplet combination of azacitidine, venetoclax and pevonedistat shows encouraging activity in this very poor-risk population of patients with AML, MDS or CMML. Trial registration ClinicalTrials.gov (NCT03862157).

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Acute myeloid leukemia / Aged / Aged, 80 and over / Analysis / Antineoplastic Combined Chemotherapy Protocols - adverse effects / Azacitidine - adverse effects / Bone marrow / Cancer Research / CD36 antigen / Chemotherapy / Chronic myelomonocytic leukemia / Clinical trial / Clinical trials / Elderly / Enzymes / FLIP protein / Flow cytometry / Hematology / Humans / Hypophosphatemia / Leukemia / Leukemia, Myeloid, Acute - diagnosis / Leukemia, Myelomonocytic, Chronic - drug therapy / Mcl-1 protein / Medical prognosis / Medicine / Medicine & Public Health / Middle Aged / Mutation / Myelodysplastic syndrome / Myelodysplastic syndromes / Myelodysplastic Syndromes - drug therapy / Myeloid diseases / Myelomonocytic leukemia / Neutropenia / Oncology / Protein neddylation / Proteins / Remission (Medicine) / Therapy / Treatment Outcome / Tumor proteins