New MDS Subtype Recognized Based on Presence of Common Genetic Variant

The International Working Group for the Prognosis of MDS has identified a distinct subtype of myelodysplastic syndromes based on the presence of SF3B1, a nonheritable genetic mutation that causes the disease.

Luca Malcovati, MD

The International Working Group for the Prognosis of MDS (IWG-PM) has identified a distinct subtype of myelodysplastic syndromes (MDS) based on the presence of SF3B1, a nonheritable genetic mutation that causes the disease; this mutation is found in approximately 1 in every 4 patients with MDS, according to a report published in the journal Blood.1,2

For the study, investigators consulted the dataset of the IWG-PM, which included 3479 patients with MDS and a known SF3B1 mutation status from 18 centers or networks. Based on available evidence and results from the IWG dataset analysis, the following diagnostic criteria for SF3B1-mutant MDS were proposed: cytopenia as defined by standard hematologic values; somatic SF3B1 mutation; isolated erythroid or multilineage dysplasia (with or without ring sideroblasts [RS]); bone marrow blasts of <5% and peripheral blood blasts of <1%; and World Health Organization (WHO) criteria for MDS with isolated del(5q), MDS/MPN-RS-T or other MDS/MPN, and primary myelofibrosis or other MPN are not met.

Additionally, the following genetic lesions represent exclusion criteria for the proposed entity because of their negative prognostic value and distinct interaction with SF3B1 mutations: poor-risk genetic features, including monosomy; abnormalities of chromosome 3q26, leading to aberrant gene fusions and EVI1 overexpression, and complex karyotype defined as ≥3 chromosomal abnormalities; co-occurring RUNX1 and/or EZH2 mutations.

In patients with clonal cytopenia of undetermined significance, the presence of a SF3B1 mutation is linked with subsequent development of overt MDS with ring sideroblasts (MDS-RS), according to the authors of the report; this suggests that the genetic lesion offers presumptive evidence of MDS in the setting of persistent unexplained cytopenia.

Patients with SF3B1-mutant MDS are thought to have a relatively good prognosis and they might respond to treatment with luspatercept-(Reblozyl), a drug that has been found to be an effective option for anemia in patients with lower-risk MDS3 and to eliminate the need for transfusion in some transfusion-dependent patients with MDS-RS.4

The FDA approved luspatercept-aamt in April 2020 for the treatment of anemia failing an erythropoiesis stimulating agent and requiring ≥2 red blood cell units over 8 weeks in adult patients with very low- to intermediate-risk MDS-RS or with MDS/myeloproliferative neoplasm with RS and thrombocytosis.

"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 investigator Luca Malcovati, MD, of the University of Pavia Medical School, said in a press release. "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."

Patients reported in this dataset were originally classified according to the WHO criteria of 2008. These data show that SF3B1 mutations are enriched in the RARS category, accounting for 82% of cases, as well as in the refractory cytopenia with multilineage dysplasia and ringed sideroblasts (RCMD-RS) category, accounting for 75% of cases. Additionally, SF3B1 mutations were also found in 9% of patients with refractory cytopenia with unilineage dysplasia (RCUD) or RCMD.

Investigators found that when compared with SF3B1-unmutated MDS, SF3B1-mutated MDS display significantly lower hemoglobin values, which is consistent with a high degree of ineffective erythropoiesis, higher neutrophil and platelet counts, and lower bone marrow blasts (P <.001). Notably, 89% and 86% of patients with SF3B1-mutant MDS have normal or nearly normal neutrophil and platelet counts, respectively, at the time of the registration into the IWG dataset.

Forty-four percent of patients with SF3B1-mutated MDS were female while 56% were male, translating to a male to female ratio that is close to 1:1, according to study authors. This profile proves to be similar to what is generally observed with MDS with del(5q), the only genetically-defined MDS subtype to date.

Results from an analysis of the largest cohort of patients with SF3B1-mutated MDS to date demonstrated that the mutation retained an independent positive prognostic value in multivariable analyses, including demographic and disease-related factors; this value was confirmed when investigators focused the analyses on sideroblastic categories. However, in those with MDS who also had excess blasts, the mutation did not retain a significant impact on survival and risk of disease progression.5

These data were confirmed in the IWG dataset in that the SF3B1 mutation identifies a subgroup of patients with MDS with a favorable prognosis (P <.001). A stratified analysis of Prognostic Risk Category Clinical Outcomes (IPSS-R) showed that this positive prognostic value is substantial within very low and low IPSS-R categories; the value is not retained within intermediate (P = .66) and high- or very high-risk subgroups (P = .11).

Interestingly, the positive prognostic value of the SF3B1 mutation was also confirmed within those with refractory anemia with ring sideroblasts (RARS; P <.001) and those with refractory cytopenia with multilineage dysplasia and ringed sideroblasts (RCMD-RS; P = .003). In order for investigators to estimate the prognostic effect of the mutation in 2016 MDS-RS categories, they created 2 groups of patients: those with RARS and SF3B1-mutated RCUD, and those with RCMD-RS and SF3B1-mutated RCMD. When compared with the respective 2016 categories, these groups contained some patients with a SF3B1 mutation and less than 5% of patients with RS. The prognostic value of the mutation was fully confirmed within the category of single-lineage (P <.001) and multilineage dysplasia (P = .003), according to the investigators.

"Taken together, these data suggest that within MDS-RS, SF3B1 mutation represents a classification criterion stronger than single- or multilineage dysplasia, and concur to support the recognition of MDS with mutated SF3B1 as distinct disease entity," the investigators wrote.

Investigators also noted that in patients with SF3B1-mutated MDS, progression to higher-risk disease or acute myeloid leukemia occurs with a relatively low frequency. With the IWG dataset, investigators were able to validate and expand on those observations by evaluating the prognostic value of co-occurring cytogenetic abnormalities and somatic mutations present in the largest group of patients with SF3B1-mutated MDS to date.

Their analysis showed that overall, only 3% of patients with SF3B1-mutated MDS reported in the IWG dataset had a poor or very poor risk karyotype per Revised International Prognostic Scoring System (IPSS-R) stratification. In fact, the percentage was reduced to 1% in patients without excess blasts. Within this subset, a significant effect of IPSS-R poor or very poor cytogenetic risk versus very low, low, or intermediate risk groups was observed on overall survival (OS; P = .032, P = .007, and P = 0.49, respectively). Within those with IPSS-R poor or very poor cytogenetic risk, the negative prognostic value of monosomy 7 was also confirmed (n = 7, P <.001).

Moreover, investigators also took a closer look at the relationship between SF3B1 mutation and del(5q) and found that these mutations have been reported in approximately 20% of patients with MDS with isolated del(5q). The co-occurrence of SF3B1 and del(5q) proved to be consistent with the prevalence of this genotype within the IWG dataset. When investigators analyzed the clinical outcome of patients with MDS and isolated del(5q), no significant difference in OS was observed (P = .57). Additionally, the presence or absence of del(5q) did not substantially effect the survival of patients with SF3B1-mutated MDS without excess of blasts (P = .40).

Patients with SF3B1-unmutated MDS-RS appear to be heterogeneous, have less favorable prognosis, and an obscure molecular basis. Additional efforts are needed to clarify the pathophysiology of these disorders, concluded the authors of the study.


  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) [published online ahead of print, 2020 Apr 29]. Blood. 2020; doi:10.1182/blood.2020004850
  2. New MDS subtype proposed based on presence of genetic mutation. News release. American Society of Hematology; April 29, 2020. Accessed May 06, 2020.
  3. Platzbecker U, Germing U, Götze KS, et al. Luspatercept for the treatment of anaemia in patients with lower—risk myelodysplastic syndromes (PACE-MDS): a multicentre, open-label phase 2 dose-finding study with long-term extension study. Lancet Oncol. 2017;10:1338-1347. doi:10.1016/S1470-2045(17)30615-0
  4. Fenaux P, Platzbecker U, Mufti GJ, et al. The Medalist trial: results of a phase 3 randomized, double-blind, placebo-controlled study of luspatercept to treat anemia in patients with very low-, low-, or intermediate-risk myelodysplastic syndromes (MDS) with ring sideroblasts (RS) who require red blood cell (RBC) transfusions. Blood. 2018;132(suppl 1). doi:10.1182/blood-2018-99-110805
  5. Malcovati L, Karimi M, Papaemmanuil E, et al. SF3B1 mutation identifies a distinct subset of myelodysplastic syndrome with ring sideroblasts. Blood. 2015;126(2):233-241. doi:10.1182/blood-2015-03-633537