Determinants of survival after failure of frontline venetoclax plus hypomethylating agent therapy in 356 patients with newly diagnosed acute myeloid leukemia

Venetoclax (Ven) in combination with hypomethylating agents (HMA) has become the standard frontline therapy for elderly or unfit patients with newly diagnosed acute myeloid leukemia (ND-AML). Despite impressive initial response rates demonstrated in the pivotal phase III VIALE-A trial, disease progression or relapse occurred in 42% of patients receiving Ven plus azacytidine [ 1 ]. Long-term follow-up of VIALE-A (median 43.2 months) confirmed a median OS of 14.7 months with Ven-azacitidine versus 9.6 months with placebo-azacitidine (HR 0.58; p < 0.001), and a 24-month OS rate of 37.5%. Nonetheless, most patients eventually experienced treatment failure highlighting the need for more effective therapeutic strategies [ 2 ]. Prior reports characterizing outcomes after frontline Ven+HMA failure have documented a dismal median overall survival (OS) of 2.4 months, with particularly poor outcomes in patients who did not receive salvage therapy [ 3 ]. A recent European real-world cohort of 67 patients similarly reported a median OS of 2.3 months following Ven-HMA failure, with only 30% of patients eligible to receive salvage therapy and a salvage overall response rate of 23%. Notably, no difference in OS was observed between patients who received salvage treatment and those who did not (2.2 vs. 4 months; p = 0.22), further reflecting the dismal outcomes in this setting and highlighting significant disparities in treatment accessibility across healthcare systems [ 4 ]. Another study demonstrated that survival following treatment failure was inferior in patients receiving frontline Ven-HMA compared with those treated with upfront intensive chemotherapy [ 3 ]. In our previously published single-institution experience of 71 ND-AML patients with Ven+HMA failure, TP53 , K/NRAS , and ASXL1 mutations emerged as independent predictors of inferior survival; however, the small sample size, limited salvage therapy data, and molecular profiling at failure which was available in only 18 patients restricted broader applicability [ 5 ]. Herein, we report the largest real-world cohort of 356 ND-AML patients with frontline Ven+HMA failure, characterizing the molecular landscape through paired next-generation sequencing (NGS) in 137 patients, and defining outcomes following salvage therapy in 170 patients.