SF3B1 mutation identifies a distinct subset of myelodysplastic syndrome with ring sideroblasts

Luca Malcovati, Mohsen Karimi, Elli Papaemmanuil, Ilaria Ambaglio, Martin Jädersten, Monika Jansson, Chiara Elena, Anna Gallì, Gunilla Walldin, Matteo G Della Porta, Klas Raaschou-Jensen, Erica Travaglino, Klaus Kallenbach, Daniela Pietra, Viktor Ljungström, Simona Conte, Emanuela Boveri, Rosangela Invernizzi, Richard Rosenquist, Peter J Campbell, Mario Cazzola, Eva Hellström Lindberg

Refractory anemia with ring sideroblasts (RARS) is a myelodysplastic syndrome (MDS) characterized by isolated erythroid dysplasia and 15% or more ring sideroblasts in the bone marrow. Ring sideroblasts are found also in other MDS subtypes, such as refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD-RS). A high prevalence of somatic mutations of SF3B1 has been reported in these conditions. To identify mutation patterns that affect disease phenotype and clinical outcome, we performed a comprehensive mutation analysis in 293 patients with a myeloid neoplasm and 1% or more ring sideroblasts. SF3B1 mutations were detected in 129/159 cases (81%) of RARS or RCMD-RS. Among other patients with ring sideroblasts, lower prevalence of SF3B1 mutations and higher prevalence of mutations in other splicing factor genes were observed (P<.001). In multivariable analyses, patients with SF3B1 mutations showed significantly better overall survival (HR .37, P=.003) and lower cumulative incidence of disease progression (HR=0.31, P=.018) compared with SF3B1-unmutated cases. The independent prognostic value of SF3B1 mutation was retained when the analyses were restricted to MDS subgroups without excess blasts, as well as to sideroblastic categories (RARS and RCMD-RS). Among SF3B1-mutated patients, coexisting mutations in DNA methylation genes were associated with multilineage dysplasia (P=.015) but had no effect on clinical outcome. TP53 mutations were frequently detected in patients without SF3B1 mutation, and were associated with poor clinical outcome. Thus, SF3B1 mutation identifies a distinct MDS subtype that is unlikely to develop detrimental subclonal mutations and is characterized by indolent clinical course and favorable outcome.