SF3B1 Variant in MDS Found to Identify Distinct Disease Entities


An international working group of experts in myelodysplastic syndromes proposed the recognition of the SF3B1 variant as a distinct nosologic entity based on the presence of a non-inheritable genetic mutation that causes the disease.

For the first time, an international working group of experts in myelodysplastic syndromes (MDS) proposed the recognition of the SF3B1 variant as a distinct nosologic entity based on the presence of a non-inheritable genetic mutation that causes the disease.1

SF3B1 mutation identifies a condition which is characterized by ring sideroblasts, ineffective erythropoiesis, and indolent clinical course.

The report, published in Blood, suggested that the mutation is found in approximately 1 in every 5 patients with MDS. About half of patients with MDS carry somatic mutations, and SF3B1 is the most commonly mutated. 

“Diagnosis of SF3B1-mutant MDS has considerable clinical implications in terms of risk stratification and therapeutic decision making,” the working group wrote. “In fact, this condition has a relatively good prognosis and may respond to luspatercept (Reblozyl) with abolishment of transfusion requirement.”

The team of experts analyzed the results of several previous studies that they suggested support the hypothesis that SF3B1-mutated MDS is a distinct subtype of the disease. Additionally, they also examined records from a large international database of patients with MDS, in which 795 patients carried the SF3B1 mutation and 2,684 did not. 

Based on the findings of their analyses, the working group came up with a proposed diagnostic criteria for SF3B1-mutant MDS. The criteria includes cytopenia as defined by standard hematologic values, somatic SF3B1 mutation, morphologic dysplasia (with or without ring sideroblasts), and bone marrow blasts <5% and peripheral blood blasts <1%. Moreover, selected concomitant genetic lesions represent exclusion criteria for the proposed entity. 

“This study represents an important step forward in the ability to diagnose MDS on the basis of genetic features, and this is paving the way to obtain a diagnosis without the need to analyze bone marrow,” lead author Luca Malcovati, MD, of the University of Pavia Medical School in Italy, said in a press release.2 “Patients who carry this genetic variant may benefit from treatment with an approved drug, luspatercept. In addition, other potential new treatments that directly target this genetic mutation are in the early stages of development and may benefit patients in the future.”

A phase III clinical trial recently demonstrated that a high proportion of patients with MDS who carried the SF3B1 mutation responded to treatment with luspatercept.3 The agent was approved by the FDA in November 2019 to treat anemia in patients with a rare blood disorder. 

In the double-blind, placebo-controlled trial, patients with very-low-risk, low-risk, or intermediate-risk MDS with ring sideroblasts who had been receiving regular red-cell transfusion were randomized to receive either luspatercept at a dose of 1.0 up to 1.75 mg per kilogram of body weight or placebo, administered subcutaneously every 3 weeks. The primary endpoint was transfusion independence for 8 weeks or longer during weeks 1 through 24, and the key secondary endpoint was transfusion independence for 12 weeks or longer, assessed during both weeks 1 through 24 and weeks 1 through 48. 

Overall, 229 patients were enrolled, with 153 randomly assigned to receive luspatercept and 76 to receive placebo. Transfusion independence for 8 weeks or longer was observed in 38% of the patients in the luspatercept group, compared to 13% of those in the placebo group (P < 0.001). Moreover, a higher percentage of those in the luspatercept group than those in the placebo group met the secondary end point (28% vs 8% for weeks 1 through 24, and 33% vs 12% for weeks 1 through 48; P < 0.001 for both comparisons). 

The most common adverse events (of any grade) associated with luspatercept included fatigue, diarrhea, asthenia, nausea, and dizziness. However, the incidence of adverse events decreased over time.

According to Malcovati and his team, there are a number of other genetic variants that may occur in MDS in addition to the SF3B1 mutation. Further, Malcovati indicated that the presence of these additional mutations may suggest more aggressive forms of the disease. However, Malcovati also noted that MDS with these additional genetic features would be excluded from the proposed new subtype of SF3B1-mutated disease.


1. Malcovati L, Stevenson K, Papaemmanuil E, et al. SF3B1-mutant myelodysplastic syndrome as a distinct disease subtype - A proposal of the International Working Group for the Prognosis of Myelodysplastic Syndromes (IWG-PM). Blood. doi:10.1182/blood.2020004850.

2. New MDS Subtype Proposed Based on Presence of Genetic Mutation [news release]. Washington. Published April 29, 2020. hematology.org/newsroom/press-releases/2020/new-mds-subtype-proposed-based-on-presence-of-genetic-mutation. Accessed May 11, 2020. 

3. Fenaux P, Platzbecker U, Mufti GJ, et al. Luspatercept in Patients with Lower-Risk Myelodysplastic Syndromes. N Engl J Med. doi:10.1056/NEJMoa1908892. 

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