OnlySF3B1Mutation involving K700E (And Not Other Codons), Independently Predicts Overall Survival in Myelodysplastic Syndromes
Authors: Kanagal-Shamanna Rashmi , Montalban-Bravo Guillermo , Sasaki Koji , Jabbour Elias , Bueso-Ramos Carlos , Wei Yue , Chien Kelly , Kadia Tapan , Ravandi Farhad , Borthakur Gautam , Soltysiak Kelly A. , Daver Naval , Darbaniyan Faezeh , Routbort Mark , Patel Keyur , Medeiros L. Jeffrey , Pierce Sherry , Kantarjian Hagop , Garcia-Manero Guillermo 
Published: September 2020

ABSTRACTBackgroundSF3B1mutations (SF3B1mut) in myelodysplastic syndromes (MDS) frequently involve codon K700E and have a favorable prognosis. The prognostic effect of non-K700ESF3B1mutis uncertain.MethodsWe analyzed the clinical-pathologic features and outcomes of a single-institutional series of 94SF3B1mutand 415SF3B1wtnewly diagnosed untreated MDS patients and explored the differences between K700E and non-K700E subgroups.FindingsNinety-four (19%) patients hadSF3B1mut: median age, 74 years. Fifty-five (60%) patients carried K700E. Recurrent non-K700E mutations (39, 40%) included R625, H662 and K666. Compared toSF3B1mutK700E, non-K700E patients had a lower median ANC (1·8 vs. 2·4, p=0·005) and were frequently “high” R-IPSS (revised International Prognostic Scoring System) [7(19%) vs. 2(4%), p=0·031]. Non-K700E MDS frequently associated withRUNX1(26% vs. 7%, p=0·012) and exclusively withBCOR, IDH2, andSRSF2mutations. There was no significant difference in karyotype orSF3B1variant allele frequency. Most (∼80%) were treated with hypomethylating agents.SF3B1muthad superior overall survival (OS) thanSF3B1wtin all MDS categories [not-reached vs. 25·2 months, p=0·0003], low-grade MDS, and MDS with ring sideroblasts (MDS-RS). Compared toSF3B1wt,SF3B1mutK700E had superior outcomes in all MDS categories (25 months vs. not-reached, p=0·0001), low-grade MDS, and MDS-RS, but no significant difference was seen with non-K700E. By multivariate analysis, absence ofSF3B1mutK700E (not non-K700E) independently associated with prognosis.InterpretationSF3B1mutMDS show distinct clinical and mutational profiles, with K700E showing a significantly better OS compared to non-K700E mutations andSF3B1wt. Our study highlights the importance ofSF3B1mutation type in MDS risk assessment.Data Sharing StatementThe datasets generated during and/or analyzed during the current study are not publicly available due to patient privacy concerns but are available from the corresponding author on reasonable request.Research in ContextEvidence before this studyWe designed this study based on the collective evidence from a systematic search of the literature for outcomes of patients MDS withSF3B1mutations (SF3B1mut) from January 2013 to June 2020. Both the International Working Group for the Prognosis of MDS (IWG-PM) proposal and 2016 revisions to the World Health Organization (WHO) Classification of Myelodysplastic Syndromes recognizeSF3B1mutMDS with <5% blasts (or ring sideroblasts >5% for WHO) as a distinct sub-category, in the absence of other unfavorable features. This was largely based on favorable prognostic outcomes, a distinct gene expression profile, and association with ring sideroblasts. However, the natural history ofSF3B1mutMDS is heterogeneous. A high proportion ofSF3B1mutations occur within codon K700, leading to large-scale mRNA downregulation due to branch point recognition error, while the rest occur outside of this codon. The downstream functional effects ofSF3B1mutations outside of the K700 codon are unclear. The clinical course ofSF3B1mutMDS patients likely depends on the type ofSF3B1mutation and other features such as variant allele frequency, concomitant gene mutations, and karyotype. Until now, the effects of the different types ofSF3B1mutations were largely unknown.Added value of this studyIn this study, we report distinctive clinicopathologic characteristics and outcomes of MDS patients withSF3B1mutations segregated based on mutation type: K700E vs. non-K700E. We show that ∼40% ofSF3B1mutated MDS patients have non-K700E mutations. Non-K700ESF3B1mutMDS have distinct clinico-pathologic features, such as lower ANC and frequent association with mutations inRUNX1, BCOR, IDH2, andSRSF2. There was no significant difference in karyotype orSF3B1variant allele frequency. Importantly, K700ESF3B1mutMDS had superior overall survival compared toSF3B1wt, in all MDS, low-grade MDS, and MDS with ring sideroblasts, but no significant difference was seen with non-K700E. By multivariate analysis, absence ofSF3B1mutK700E, but not non-K700E, independently associated with prognosis.Implications of all the available evidenceTo the best of our knowledge, this is the first study to report these findings from a single-institutional series of MDS primarily treated with hypomethylating agents. Our study highlights the importance of determining theSF3B1mutation type in MDS risk assessment. These findings are important in light of the recent FDA approval of luspatercept based on the results of the MEDALIST trial that suggested sustained hematological responses inSF3B1mutMDS patients.