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. 2022 Dec;36(12):2894-2902.
doi: 10.1038/s41375-022-01728-5. Epub 2022 Oct 19.

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

Sandra Huber  1 , Torsten Haferlach  1 , Manja Meggendorfer  1 , Stephan Hutter  1 , Gregor Hoermann  1 , Constance Baer  1 , Wolfgang Kern  1 , Claudia Haferlach  2
Affiliations

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

Sandra Huber et al. Leukemia. 2022 Dec.

Abstract

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%) SF3B1mut 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 SF3B1mut samples not falling into the proposed SF3B1 entity (SF3B1nent). Of SF3B1mut 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 SF3B1mut 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, SF3B1mut MDS has a favorable prognosis independent of blast count if karyotype and RUNX1 mutations are considered.

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Conflict of interest statement

CH, WK, and TH declare part ownership of Munich Leukemia Laboratory (MLL). SH, HS, MM, GH, and CB are employed by the MLL.

Figures

Fig. 1
Fig. 1. Distribution and OS of SF3B1 mutations in MDS.
A Frequency of SF3B1 mutations in the entire MDS cohort; wt wild-type, mut mutated. B Proportion of SF3B1mut cases within different MDS entities (red: mutated; gray: wild-type). C WHO 2017 entities of SF3B1mut MDS. D OS of patients with mutated (n = 231; red) vs. wild-type (n = 503; gray) SF3B1 within the entire MDS cohort. E OS of MDS-RS-SLD patients with mutated (n = 43; red) vs. wild-type (n = 8; gray) SF3B1. F OS of MDS-RS-MLD patients with mutated (n = 128; red) vs. wild-type (n = 21; gray) SF3B1. G OS of MDS 5q- patients with mutated (n = 21; red) vs. wild-type (n = 86; gray) SF3B1. H OS of MDS-EB-1 patients with mutated (n = 25; red) vs. wild-type (n = 124; gray) SF3B1. I OS of MDS-EB-2 patients with mutated (n = 12; red) vs. wild-type (n = 139; gray) SF3B1.
Fig. 2
Fig. 2. Categorization and OS of SF3B1mut samples.
A WHO 2017 entities of SF3B1mut samples and classification into the IWG-PM proposed SF3B1 entity (SF3B1ent) or non-SF3B1 entity (SF3B1nent). B OS of patients with mutated SF3B1 fulfilling criteria for proposed SF3B1 entity (n = 144; green) or not (n = 87; brown) vs. wild-type SF3B1 (n = 503; gray) (p < 0.001). C Comparison of SF3B1mut MDS diagnoses based on the currently used revised 4th edition of the WHO (WHO 2017) and the IWG-PM criteria (middle) to the corresponding MDS diagnoses considering the upcoming 5th edition of WHO (WHO 2022; left) and the International Consensus Classification (ICC; right).
Fig. 3
Fig. 3. Variant allelic frequencies (VAFs) of 231 SF3B1mut samples.
A SF3B1 VAFs with respect to the different entities; n (mutations) = 236. B Characteristics of cases having only one SF3B1 mutation and a VAF below 15%.
Fig. 4
Fig. 4. Molecular characterization of SF3B1mut MDS patients.
Illustration of all 231 samples, each column represents one patient. Genes (gray: wild-type; red: mutated) as well as the WHO entity (incl. SF3B1ent) are given for each patient. Light green: SF3B1ent patients with isolated SF3B1 mutation; VAF variant allelic frequency.
Fig. 5
Fig. 5. Genetics of MDS patients with mutated SF3B1 progressing to AML.
A Molecular characterization of SF3B1mut patients progressing to AML at MDS stage (n = 15). Each column represents one patient, numbered 1–15. Number in brackets indicate that molecular data at AML stage is not available. Genes (gray: wild-type; red: mutated), WHO 2017 entities and SF3B1ent/nent are given for each patient. ent entity, nent non-entity, VAF variant allelic frequency. B Cumulative incidence of AML transformation of SF3B1 mutated (n = 15; red) vs. wild-type (n = 75; gray) patients.
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