SF3B1-mutant MDS as a distinct disease subtype: a proposal from the International Working Group for the Prognosis of MDS

Abstract

The 2016 revision of the World Health Organization classification of tumors of hematopoietic and lymphoid tissues is characterized by a closer integration of morphology and molecular genetics. Notwithstanding, the myelodysplastic syndrome (MDS) with isolated del(5q) remains so far the only MDS subtype defined by a genetic abnormality. Approximately half of MDS patients carry somatic mutations in spliceosome genes, with SF3B1 being the most commonly mutated one. SF3B1 mutation identifies a condition characterized by ring sideroblasts (RS), ineffective erythropoiesis, and indolent clinical course. A large body of evidence supports recognition of SF3B1-mutant MDS as a distinct nosologic entity. To further validate this notion, we interrogated the data set of the International Working Group for the Prognosis of MDS (IWG-PM). Based on the findings of our analyses, we propose the following diagnostic criteria for SF3B1-mutant MDS: (1) cytopenia as defined by standard hematologic values, (2) somatic SF3B1 mutation, (3) morphologic dysplasia (with or without RS), and (4) bone marrow blasts <5% and peripheral blood blasts <1%. Selected concomitant genetic lesions represent exclusion criteria for the proposed entity. In patients with clonal cytopenia of undetermined significance, SF3B1 mutation is almost invariably associated with subsequent development of overt MDS with RS, suggesting that this genetic lesion might provide presumptive evidence of MDS in the setting of persistent unexplained cytopenia. Diagnosis of SF3B1-mutant MDS has considerable clinical implications in terms of risk stratification and therapeutic decision making. In fact, this condition has a relatively good prognosis and may respond to luspatercept with abolishment of the transfusion requirement.

Figure 1.

Patterns of the mutations observed in MDS patients reported to the data set of the International Working Group for MDS. (A) Distribution of somatic lesions in the analyzed genes according to the WHO category. Each column represents an individual patient sample. (B) Distribution of somatic lesions in the analyzed genes in patients with MDS-RS with or without SF3B1 mutation. CMML, chronic myelomonocytic leukemia; RA, refractory anemia; RAEB, refractory anemia with excess blasts; RCUD, refractory cytopenia with unilineage dysplasia; unk, unknown.

Figure 2.

Tridimensional scatterplot of SF3B1-mutated and unmutated MDS with RS according to bone marrow dysplastic features. Red dots identify MDS associated with SF3B1 mutation, whereas blue dots identify MDS unmutated for SF3B1. The degree of dysmyelopoiesis and dysmegakaryopoiesis is measured as percentage of lineage dysplastic cells.

Figure 3.

Effect of current WHO classification criteria on OS of patients with SF3B1-mutated MDS. (A) OS of patients with SF3B1-mutated MDS according to the presence of single-lineage (blue curve, n = 267) or multilineage (red curve, n = 171) dysplasia (P = .4). (B) OS of patients with SF3B1-mutated MDS according to bone marrow blasts <5% (blue curve, n = 341) or ≥5% (red curve, n = 85) (P < .001).

Figure 4.

OS of patients with MDS classified according to SF3B1 mutation status. (A) OS of the whole MDS population according to SF3B1 mutation status. Patients with SF3B1-mutated MDS (red curve, n = 769) have a significantly longer survival compared with SF3B1-unmutated MDS patients (blue curve, n = 2555) (P < .001). (B) OS of SF3B1-mutated (red curve, n = 267) and unmutated (blue curve, n = 54) patients with RARS (P < .001). (C) OS of SF3B1-mutated (red curve, n = 171) and unmutated (blue curve, n = 56) patients with RCMD-RS (P = .003). (D) OS of patients with SF3B1-mutated RARS or RCUD (red curve, n = 287) compared to SF3B1-unmutated patients with RARS (blue curve, n = 54) (P < .001). This group overlaps the category of MDS-RS-SLD according to 2016 WHO criteria, except that it comprises occasional patients with SF3B1-mutation and <5% RS. (E) OS of patients with SF3B1-mutated RCMD-RS or RCMD (red curve, n = 189) compared to SF3B1-unmutated patients with RCMD-RS (blue curve, n = 56) (P = .003). This group overlaps the category of MDS-RS-MLD according to 2016 WHO criteria, except that it comprises occasional patients with SF3B1-mutation and <5% RS.(F) OS of SF3B1-mutated (red curve, n = 77) and unmutated patients (blue curve, n = 823) with MDS-EB (P = .34).

Figure 5.

OS of patients with SF3B1-mutant MDS according to additional somatic mutations. (A) OS by isolated SF3B1 mutation (n = 201, blue curve) vs SF3B1 mutation associated with additional somatic mutations within SF3B1-mutated MDS without excess blasts (SF3B1 plus 1 additional mutation, n = 192, red curve; 2 additional mutations, n = 66, green curve; ≥3 additional mutations, n = 23, purple curve) (including patients sequenced for all of the following 15 genes: SF3B1, TET2, DNMT3A, SRSF2, ASXL1, RUNX1, TP53, EZH2, JAK2, U2AF1, IDH1, IDH2, CBL, NRAS, and ETV6). (B-C) OS and cumulative incidence of AML evolution of SF3B1-mutated MDS without excess blasts according to RUNX1 mutation status (mutated, n = 21, red curve; unmutated, n = 505, blue curve) (P < .001). Cumulative incidence of AML evolution was estimated with a competing risk approach, considering death for any cause as a competing event. (D) OS of SF3B1-mutated MDS without excess blasts according to EZH2 mutation status (mutated, n = 20, red curve; unmutated, n = 499, blue curve) (P = .003).

Figure 6.

Frequency of cooccurring or mutually exclusive mutated genes in SF3B1-mutated or unmutated MDS in the IWG data set. (A) Most frequent cooccurring or mutually exclusive mutated genes in SF3B1-mutant MDS in the IWG data set. Red and blue bars represent relative frequencies (percentage) of mutated genes in SF3B1-mutated and SF3B1-wild-type MDS, respectively. Red or blue gene labels indicate significantly higher frequencies of the comutated gene in SF3B1-mutated or SF3B1-wild-type MDS, respectively (P values ranging from .019 to <.001). (B) Most frequent cooccurring or mutually exclusive mutated genes in SF3B1-wild-type vs SF3B1-mutant MDS-RS in the IWG data set. Blue and red bars represent relative frequencies (percentage) of mutated genes in SF3B1-wild-type and SF3B1-mutant MDS-RS, respectively. Blue or red gene labels indicate significantly higher frequencies of the comutated gene in SF3B1-wild-type or SF3B1-mutant MDS-RS, respectively (P values ranging from .047 to .002).

Figure 7.

Survival and risk of leukemic evolution of patients classified within the proposed entity of MDS with mutated SF3B1. (A) OS of patients classified within the proposed entity of MDS with mutated SF3B1 (n = 486). (B) Cumulative incidence of AML evolution of evaluable patients (n = 52) classified within the proposed entity of MDS with mutated SF3B1. Cumulative incidence of AML evolution was estimated with a competing risk approach, considering death for any cause as a competing event.