Ring Sideroblasts and SF3B1 Mutations in Myelodysplastic Syndromes (MDS): Are They Two Faces of the Same Coin? a Study on Behalf of the MDS Clinical Research Consortium (MDS CRC)

Introduction

Recurrent somatic mutations in SF3B1, a gene encoding a spliceosome component, have been identified in patients (pts) with myelodysplastic syndromes (MDS). SF3B1 mutations (MT) are more commonly detected in pts with ring sideroblast (RS) morphology and are associated with favorable outcome. The proposed 2016 World Health Organization (WHO) MDS classification categorizes pts with >5% RS and SF3B1 MT as MDS with RS, in contrast to prior WHO classifications which required ≥15% RS regardless of genotype. In this study, we explored the prognostic value of RS and SF3B1 MT and assessed the validity of the new proposal.

Methods

We identified 471 pts with MDS and known SF3B1 mutational status from MDS CRC institutions. RS were assessed as present or absent (RS +/-) based on bone marrow aspirate reports (n=157); in cases where quantitative data on RS% were available (n=41), pts were grouped in the 5-15% RS group or > 15% RS group. Survival was calculated from time of diagnosis. Cox regression analysis was used to estimate hazard ratios for overall survival (OS) and AML free survival (AFS), which was defined as time to death or AML transformation, respectively. Chi-squared and Wilcoxon tests were used to test for differences in categorical and continuous distributions, respectively.

Results:

Among 471 pts with known SF3B1 mutational status, 76 (16%) had MT. Pts with MT had lower-risk International Prognostic Scoring System (IPSS) scores compared to SF3B1 wild-type (WT; 79% vs 57%, p < .001). Among pts with MT, 50% had RS + compared to 19% RS + in the WT group (p < .001). MT were independently associated with better OS (HR 0.48, p= .001) and longer AFS (HR 0.5, p <.005) after adjusting for age and IPSS.

We compared outcomes of four groups: WT/RS-, MT/RS-, WT/RS+, and MT/ RS +. Adjusting for age and IPSS, pts with MT/RS + had the best outcome, with hazard ratios for AFS of 4.2 for WT/RS- vs. MT/RS+ (p =.018), 4.1 for MT/RS- vs. MT/RS+ (p =.045), and 5.1 for WT/RS+ vs. MT/RS+ (p= .01).

We compared 7 pts with 5-15% RS to 22 pts with >15% RS. Among patients with RS 5-15%, 4/7 pts (57%) were classified as MDS with excess blasts compared to 24% for those RS >15% (p=.09). Pts with 5-15% RS were more likely to be thrombocytopenic (5/7, 71%) compared to >15% RS (29%, p=.04). One patient (14%) with 5-15% RS had MT compared to 12 (55%) pts with > 15% RS, p= .06. In Cox regression analysis using the RS 5-15% group as the reference, the hazard ratio for RS > 15% for AFS was 0.26 (p = .034) and the hazard ratio for MT for AFS was 0.08 (p= .002).

Conclusions

SF3B1 somatic mutations in MDS are commonly associated with RS, better OS and longer AML-free survival. Patients with RS and MT had a significantly better outcome than those with either isolated RS or MT, or neither. These data support incorporation of SF3B1 mutation status into the WHO classification regardless of RS percent, though with differentiation for those with RS and MT.