Venetoclax and hypomethylating agents in acute myeloid leukemia: Mayo Clinic series on 86 patients

Abstract

Venetoclax and hypomethylating agent (HMA) combination therapy is FDA-approved for elderly or unfit acute myeloid leukemia (AML) patients unable to withstand intensive chemotherapy. The primary objective of the current study was to impart our institutional experience with the above regimen, outlining response, survival outcomes, and its determinants amongst 86 treatment-naïve and relapsed/refractory AML patients. A total of 44 treatment-naïve AML patients, median age 73.5 years, enriched with secondary, therapy related and ELN adverse risk disease (n = 27) were studied. The CR/CRi rates of 50% (22 of 44 patients) were superior to 23% in a matched AML cohort treated with HMA alone (P = .005). Response rates were similar with TP53, FLT3, NPM1 and IDH mutations (P = .31). Moreover, CEPBA mutations (P = .03) and neutropenia (P = .05) emerged as predictors of complete response. Survivalwas prolonged in patients achieving CR/CRi (17 vs 3 months without CR/CRi, P < .001; conversely adverse ELN risk portended inferior survival. Amongst 42 relapsed/refractory AML patients, half received ≥2 prior therapies excluding transplant, and 15 (35.7%) had received HMA. A group of 14 patients (33.3%) attained CR/CRi; age > 65 years, AML with myelodysplasia, JAK2, DNMT3A, and BCOR mutations predicted complete response. Survival distinctions were based on CR/CRi (median survival 15 vs 3 months with/without CR/CRi; P < .001), and TP53 mutation status (P = .04). In summary, we corroborate existing reports demonstrating superior response and prolonged survival with venetoclax and HMA in treatment-naïve and relapsed/refractory AML patients regardless of genotype. Additionally, we identify unique predictors of response to therapy which require validation. 1 | INTRODUCTION Venetoclax in combination with either a hypomethylating agent (HMA) or low dose cytarabine (LDAC) gained FDA approval in November 2018 for newly diagnosed AML patients that are elderly >75 years or unfit for intensive induction regimens. 1,2 The above regimen is being increasingly utilized over the last 2 years, since the vast majority of AML patients are elderly with median age at diagnosis of 68 years. 3-7 Mechanistically venetoclax functions as a selective inhibitor of B-cell leukemia/lymphoma-2 (BCL-2), an anti-apoptotic protein which is overexpressed in leukemia stem cells (LSCs). 8 Functional studies have demonstrated that venetoclax in concert with azacitidine impacts the tricarboxylic acid cycle (TCA) cycle with reduction in α-ketoglutarate and increased succinate levels resulting in inhibition

Venetoclax plus hypomethylating agent in blast‐phase myeloproliferative neoplasm: preliminary experience with 12 patients

“…The overall and CR rates seen in our present patients with BP‐MPN were similar to those recently reported in a pivotal study of elderly unfit patients with AML treated up‐front with venetoclax + HMA, with an OR rate of 68% 5 . Similarly, we recently reported an OR rate of 77% with CR/CRi rate of 56% in 44 newly diagnosed treatment naïve patients with AML with high‐risk disease that included adverse karyotype and therapy related AML 6 . In the latter study, the CR/CRi rate amongst 42 relapsed/refractory cases was 36%.…”

Acute myeloid leukemia after age 70 years: A retrospective comparison of survival following treatment with intensive versus HMA ± venetoclax chemotherapy

“…Whereas, HMA-based combinations with venetoclax or other mutation-targeted agents are reasonable alternatives for those with unfavorable karyotype. 2,7 Whether or not combining venetoclax or other mutation targeting agents with intensive chemotherapy extends additional value remains to be determined. Myelodysplastic syndromes are associated with bone marrow inflammation driven by myeloid-derived suppressor cells (MDSCs) and regulatory T (T reg ) cells.…”

“…Therefore, until additional information from prospective controlled studies that are stratified for cytogenetic risk groups becomes available, it is reasonable to consider intensive chemotherapy for fit AML patients over age 70 years and with favorable or intermediate risk karyotype. Whereas, HMA-based combinations with venetoclax or other mutation-targeted agents are reasonable alternatives for those with unfavorable karyotype 2,7.…”

Efficacy of Venetoclax Combined with Decitabine-Based Treatment for Heavily Pre-Treated Relapsed or Refractory AML Patients in a Real-World Setting

“…DiNardo CD, 3 DiNardo CD, 16 Yinjun Lou 18 Erika Morsia 19 FLT3-ITD DiNardo CD. 16 Aldoss I, 15 Yinjun Lou, 18 Erika Morsia 19 Goldberg AD, 12 ORR rate was 44.5 ) %, CR/CRi was 39.8 (12-51) %. Compared with previous data, our study obtained the similar results, of which the ORR was 45.5% and the CR rate was 40.9%, although these RR-AML patients were heavily pre-treated.…”

“…We reviewed twelve published literatures from 2017 to 2020 on the treatment of R/R AML with venetoclax combined with hypomethylating agents. 3,4,[12][13][14][15][16][17][18][19][20][21] The reported IDH1/2. DiNardo CD, 3 DiNardo CD, 16 Yinjun Lou 18 Erika Morsia 19 FLT3-ITD DiNardo CD.…”