Clinical outcomes in spliceosome-mutant myelodysplastic neoplasms and Acute Myeloid Leukemia

Abstract Spliceosomes facilitate the removal of non-coding introns from precursor messenger RNA via a macromolecular complex to form mature mRNA transcripts. Somatic mutations in genes encoding splicing factors are commonly seen in myeloid malignancies, especially in myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML). The most common spliceosome mutations include RNA splicing factor 3B subunit 1 (SF3B1), serine and arginine-rich splicing factor 2 (SRSF2), U2 small nuclear RNA auxiliary factor 1 (U2AF1), and zinc finger CCC-H type, RNA binding motif and serine/arginine-rich 2 (ZRSR2). AML bearing spliceosome mutations is considered an adverse risk, while MDS bearing SF3B1 mutations harbors a favorable prognosis with lower risk of disease progression. The impact of the other spliceosome mutations on MDS progression is less well-defined. Our group has previously reported on the hematologic, cytogenetic, and molecular characteristics of a smaller subset of these patients. This study aims to evaluate the differential impact of spliceosome mutations on survival outcomes in the context of varying treatment modalities. Methods: We conducted an observational study of 97 patients with mutations in one or more spliceosome genes (SRSF2, U2AF1, SF3B1, ZRSR2) from the UMass Chan Leukemia Registry. Patients with overt myeloid neoplasm were included. Patients with clonal hematopoiesis involving spliceosome mutations were excluded. Clinical data, including demographics, treatment type (hypomethylating agents (HMA), cytotoxic therapy, targeted therapy, or no treatment), and outcomes, were longitudinally collected. Outcomes were analyzed based on therapy type and time-to-event endpoints, inclusive of overall survival, with stratification by mutational subsets. Results: A total of 97 patients were retrospectively analyzed, of whom 69% were male, with the median age being 76 years, and non-Hispanic White (92%). The median overall survival (OS) in the entire cohort was 29 (18-40) months. Patients harboring the U2AF1 mutation had the shortest median OS of 15 months, while patients harboring the SF3B1 mutations had the longest median OS of 52 months, although these differences were not significant (p = 0.26). Median OS were 18 months, 20 months, and 71 months for patients treated with HMA, cytotoxic chemotherapy, and targeted therapies, respectively, and 24 months for those who did not receive treatment. There was no statistically significant difference (p = 0.11). Within each mutational subtype, there were no significant differences in survival based on the type of treatment received. Discussion: This study adds to existing literature on the impact of spliceosome mutations on survival outcomes and response to therapy in MDS and AML. In our cohort the subtype of spliceosome mutation had no significant impact on median OS which was similar at 27 months, compared to the 35 months described in the literature for AML. It is well characterized that SF3B1 mutations in MDS, commonly associated with ring sideroblasts, portend a good prognosis and a lower risk of progression to AML. We observed a trend towards longer OS in the SF3B1 subgroup, suggesting that our study may have been underpowered to detect a true difference. We also observed no significant differences in survival based on treatment type in the entire cohort as well as within mutation subgroups. It has been described that patients with AML characterized by spliceosome mutations have similar outcomes to patients with AML without these mutations when treated with intensive chemotherapy and HMA combinations. The impact of targeted therapies is less well known. A limitation of our study is that only 13 of 97 patients in our cohort were treated with targeted agents. Of these, only 3 received luspatercept, an agent that promotes late-stage erythropoiesis and has shown improved outcomes in patients with SF3B1-mutant myeloid neoplasms. In the future, we would like to expand this cohort over multiple centers to better assess the impact of targeted agents on survival outcomes and to aid in prognostic refinement among the 4 major spliceosome mutations.