The impact of secondary-type mutations in newly diagnosed acute myeloid leukemia treated with venetoclax and decitabine or azacitidine.

Abstract

e19048 Background: The recently revised risk classification schema in ELN 2022 for acute myeloid leukemia (AML) now includes a more prominent presence of secondary-type mutations (STMs): ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, and ZRSR2. However, the risk classification schema of ELN 2022 is based on the outcomes of patients treated with intensive chemotherapy. The impact of STMs in patients treated with lower-intensity venetoclax-based strategies is unknown. Furthermore, IDH and NPM1 mutations are associated with a significant survival benefit in those treated with venetoclax-based strategies, but it is unknown how these mutations impact outcomes when they cooperate with STMs. The purpose of this study was to determine the impact of STMs included in ELN 2022 and cooperating mutations on lower-intensity venetoclax-based strategies. Methods: We retrospectively analyzed 79 patients with AML treated with front-line venetoclax and a hypomethylating agent (HMA; decitabine or azacitidine) at VCU Massey Cancer Center from January 1, 2018 to January 1, 2022. We excluded nine patients without available NGS at diagnosis. We recorded doses and dates of chemotherapy regimens, molecular profiles at diagnosis, and overall survival. We analyzed survival by the Kaplan-Meier method and compared groups with the Mantel-Cox test. The date of death was used to calculate overall survival; patients were censored at the date of the last contact. Results: We identified 32 patients with STMs and compared them to 38 patients without STMs; the median overall survival was nonsignificantly shorter in those with STMs (5.3 m. with STMs versus 8.2 m. without, p = 0.323). The presence of mutated TP53, RAS, or FLT3-ITD appeared to be associated with shorter overall survival in patients with STMs: co-mutated STMs with TP53, RAS, or FLT3-ITD had an overall survival of 2.6 m. compared to 8.6 m. for those with STMs but no additional adverse mutations ( p = 0.093). However, when we excluded patients with mutated TP53, NRAS, KRAS, and FLT3-ITD, there was no significant difference in overall survival in those with and without STMs (8.5 m. with STMs versus 14.7 m. without, p = 0.323). The presence of STMs did not appear to reduce the favorable prognosis associated with IDH mutations without cooperating mutated TP53, RAS, or FLT3-ITD (20.0 m. with STMs versus 23.4 m. without STMs, p = 0.493). Conclusions: While the presence of secondary-type mutations was associated with shorter survival, the association was nonsignificant in those treated with front-line venetoclax + HMA. Additionally, the presence of STMs did not appear to worsen survival in patients that respond favorably to venetoclax-based strategies, such as IDHmut AML. These findings, together with those of larger studies, may contribute to a refined risk classification schema for patients treated with lower-intensity strategies.

Venetoclax Resistance in Acute Myeloid Leukemia

“…As a result, the ELN 2022 classifies these AML cases in the poor-risk group [ 55 ]. Nevertheless, the impact of these gene mutations are less clearly defined in the context of VEN-AZA treatment [ 53 , 56 ]. For example, ASXL1 mutations confer VEN sensitivity in preclinical models but not in clinical studies [ 57 , 58 ].…”