Clinical characteristics and molecular profiling of SF3B1-mutated myelodysplastic syndrome (MDS) in a real-world practice

Abstract Introduction SF3B1-mutated myelodysplastic syndrome (MDS) is now recognized as a distinct subtype in the latest World Health Organization (WHO) Classification. They are generally associated with an indolent course and favorable prognosis. However, recent data suggest that specific SF3B1 variants may portend a worse prognosis 1,2. The aim of the study is to describe SF3B1-mutated MDS patients in a single tertiary center in Singapore, and secondarily to see whether there is a prognostic difference between variants. Methods We retrospectively identified MDS patients with SF3B1 variants on next-generation sequencing (NGS) performed from 1 November 2021 to 31 October 2024 at Singapore General Hospital. Extracted genomic DNA and RNA from bone marrow or blood samples were amplified, and library preparation was performed with the Oncomine Myeloid Research assay (ThermoFisher Scientific) to interrogate 40 DNA genes and 29 fusion driver genes. NGS libraries were sequenced on the Ion GeneStudio S5 System (ThermoFisher Scientific) and analyzed using in-house bioinformatics pipelines and the Ion Reporter software. The hematological parameters, mutation profiles, and disease outcomes were evaluated. Results Nineteen MDS patients had SF3B1 variantsidentified by NGS. Patients were most likely male (14 men compared to 5 women) with a median age of 72 years (interquartile range 59, 78). The cohort composed of Chinese (69%), Indian (26%), and Malay (5%) races. Baseline hematological parameters on diagnosis were a median (interquartile range, IQR) hemoglobin of 9.00 (7.60, 9.70) g/dL, absolute neutrophil count (ANC) 2.25 (1.10, 3.70) x 109/L, and platelet count of 196 (99, 356) x109/L. Thirteen of the 19 patients had 5% blasts on the initial bone marrow aspirate, and five out of 19 had 15% or more ringed sideroblasts. Ten variants of SF3B1 were found, with the top 3 most prevalent being K7000E (40%), K666N (15%), and K666T (10%). One patient had 2 different SF3B1 variants: K700E and T663I. Median variant allele frequency (VAF) was 28 (IQR 11, 39)%. All the variants were missense variants. Ten out of 19 (53%) patients had 1 or more co-mutations. Patients with a higher number of co-mutations had less favorable IPSS-M scores and worse disease outcome. Seven of the 19 patients received treatment for MDS – 4 received a hypomethylating agent, 1 was recruited onto the MBG453 trial (Tim-3 Antibody), 2 received intensive chemotherapy, and one went on to receive allogeneic hematopoietic stem cell transplant. At a median follow-up of 19.5 months, two out of 19 patients progressed to acute myeloid leukemia (AML) and 1 patient died. Conclusion There is heterogeneity in disease outcome for MDS patients with different SF3B1 variants. In our study, SF3B1 variant type was not associated with adverse disease outcome. However, due to the small sample size, our study may not have sufficiently captured the diversity of SF3B1 mutations (e.g. E592K). We demonstrated that the number and type of co-mutations affected the prognosis of patients. Identifying these features is crucial for risk stratification and personalized treatment in MDS. ReferencesChoi IY, Ling J, Zhang J, Helmenstine E, Dalton WB et al; The E592K variant of SF3B1 creates unique RNA missplicing and associates with high-risk MDS without ring sideroblasts. 2023 Apr 14:rs.3.rs-2802265.Brian Dalton, Eric Helmenstine, Lisa Pieterse, et al; The K666N mutation in SF3B1 is associated with increased progression of MDS and distinct RNA splicing, Blood Advances, Volume 4, Issue 7, 2020