Venetoclax Abrogates the Prognostic Impact of Splicing Factor Gene Mutations in Newly Diagnosed Acute Myeloid Leukemia.

Mutations in splicing factor (SF) genes SRSF2, U2AF1, SF3B1 and ZRSR2 are now classified as adverse risk (AR) in the European LeukemiaNet 2022 risk stratification for acute myeloid leukemia (AML). The prognostic impact of SF mutations in AML has been predominantly derived from younger patients treated with intensive (INT) therapy. We evaluated 994 patients with newly diagnosed AML, including 266 (27%) with a SFmut. Median age was 67 years overall, with SFmut pts older at 72 years. SRSF2 (=140, 53%) was the most common amongst SFmut. Amongst patients treated with INT therapy, median relapse-free survival (RFS) (9.6 versus 21.4 months, p=0.04) and overall survival (OS)(15.9 versus 26.7 months, p=0.06) were shorter for the SFmut compared to SFwt patients, however this significance abrogated when evaluating patients who received venetoclax with INT therapy (RFS 15.4 versus 20.3 months, p=0.36 and OS 19.6 versus 30.7 months, p=0.98). In patients treated with low-intensity (LI) therapy, median RFS (9.3 versus 7.7 months, p=0.35) and OS (12.3 versus 8.5 months, p=0.14) were similar for SFmut and SFwt patients, and outcomes improved in all groups with the receipt of venetoclax. On multivariate analysis, SFmut did not affect the hazards of relapse and death for INT therapy arm, arms but reduced both these hazards in the LI therapy arm. In this large AML dataset with >60% of patients receiving venetoclax with LI/ INT therapy, SFmut did not demonstrate independent prognostic impact. Newer prognostic models that consider LI therapy and the use of venetoclax amongst other factors are warranted.