SF3B1 mutated MDS: Blast count, genetic co-abnormalities and their impact on classification and prognosis

Recently, MDS with mutated SF3B1 and blast count <5% was proposed as distinct entity with favorable prognosis by the international working group for the prognosis of MDS (IWG-PM), the 5th edition of the WHO classification and the International Consensus Classification. To further characterize this entity with respect to the genomic landscape, AML transformation rate and clinical outcome, we analyzed 734 MDS patients by whole genome sequencing. SF3B1 mutations were identified in 31% (n = 231), most frequently accompanied by TET2 mutations (29%). 144/231 (62%) SF3B1(mut) samples fulfilled entity criteria proposed by IWG-PM (SF3B1ent). These cases were associated with longer survival, lower AML transformation rate, normal karyotypes and harbored less accompanying mutations compared to SF3B1(mut) samples not falling into the proposed SF3B1 entity (SF3B1nent). Of SF3B1(mut) cases 7% (15/231; SF3B1ent: 3/144 [2%]; SF3B1nent: 12/87 [14%]) progressed to AML compared to 15% SF3B1 wild-type patients (75/503). Of these 15 SF3B1(mut) cases, 10 (67%) showed RUNX1 mutations at MDS or AML stage. Multivariate analysis revealed that del(5q) and RUNX1 mutations were independent negative prognostic factors for overall survival, while blast count >5% was not. In conclusion, SF3B1(mut) MDS has a favorable prognosis independent of blast count if karyotype and RUNX1 mutations are considered.