Splicing factor mutations clearance and outcomes in clonal myeloid neoplasms: a referral center experience

Splicing factor (SF) mutations (SF3B1, SRSF2, U2AF1, and ZRSR2) are implicated in the pathogenesis of myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML). However, additional cytogenetic aberrations or driver mutations are typically required for the development of AML, raising questions about the utility of SF mutation persistence as a marker of measurable residual disease (MRD). We conducted a retrospective review of adult patients treated at UIHC from 2016 to 2025. Logistic and Cox regression models assessed the impact of clinical and molecular factors on composite complete remission (CR), allogeneic stem cell transplantation (HSCT), AML transformation, and overall survival (OS). Among 95 patients (AML, N = 57; MDS/CMML, N = 38) who received treatment of cytoreductive potential, SF mutations became undetectable in 22 AML and 8 MDS/CMML patients. In AML, post-treatment SF mutation status was associated with receipt of HSCT, but not with CR or OS. In MDS/CMML, SF mutation clearance was associated with CR, but not the receipt of HSCT or OS. Median OS was 27.2 vs. 17.2 months in AML and 16.7 vs. 23.7 months in MDS/CMML for clearance versus persistence groups, respectively. These findings suggest that SF mutation clearance does not significantly impact OS but may influence other clinical outcomes in patients with myeloid neoplasms harboring SF mutations.