Myelodysplastic Syndromes with Concomitant SF3B1 Mutation and Deletion of the Long Arm of Chromosome 5 (SF3B1del5q): Outcomes and Response to Treatment
Authors: Komrokji Rami S. , Schwabkey Zaker I. , Al Ali Najla H. , Aguirre Luis E. , Stahl Maximilian , Ball Somedeb , Mason Emily F. , Savona Michael R. , Santini Valeria , Consagra Angela , Platzbecker Uwe , Kubasch Anne Sophie , Madanat Yazan F , Fenaux Pierre , Zhao Lin-Pierre , Sekeres Mikkael A. , Chandhok Namrata S. , Della Porta Matteo Giovanni , Lanino Luca , DeZern Amy E. , Sallman David , Xie Zhuoer , Padron Eric , Sasaki Koji , Takaoka Kensuke , Jain Akhil , Del Rey Mónica , Diez-Campelo Maria , Garcia-Manero Guillermo 
Published: December 2024

Background
Both MDS-SF3B1 and isolated del(5q) MDS are recognized by WHO and ICC 2022 as unique molecularly-defined MDS entities. Reports including the molecular revised international prognostic scoring system (IPSS-M) indicate that concomitant SF3B1 mutation (MT) with del(5q) is associated with less favorable outcome. SF3B1del5q accounted for 7% of all SF3B1 cases in the IPSS-M cohort. Lenalidomide (Len) is the treatment of choice for isolated del(5q) MDS and luspatercept (Luspa) for MDS-SF3B1. However, there are scarce data about response of SF3B1del5q to either Len or Luspa. Hence, we assessed the hematological response rate to therapies including Len and Luspa among lower-risk (LR) MDS patients (pts) with SF3B1del5q . We also compared outcomes for MDS- SF3B1del5q pts to MDS-SF3B1 and del5qMDS.
Methods
This was a multicenter international retrospective analysis for pts diagnosed with concomitant del5q and SF3B1, less than 5% myeloblasts, no complex karyotype who received at least one line of therapy. Hematological improvement (HI) was defined as hemoglobin (Hgb) increase 1.5 g/dl or more in non-transfusion dependent pts, or red blood cell transfusion independence among transfusion dependent pts. We identified 2 comparison cohorts, MDS-SF3B1 cohort and isolated del5q-MDS cohort to compare baseline characteristics and outcomes.
Results
Among 77 LR-MDS pts with SF3B1del5q, the median age at diagnosis was 70 years (30-87), 74% were female, 97% white and 13% classified as t-MDS. The median Hgb was 9.3 g/dl (5-13), median platelets 250 × 109/L (32-1330) and median ANC 2.01 × 109/L (1-11). The most common other concomitant somatic MT were TP53 (26%), DNMT3A (23%) and TET-2 (21%). The median TP53 VAF was 16% (1-66%). R248W TP53 was most common hot spot (20%).
First-line therapy was Len for 46 pts (61%), erythroid stimulating agents (ESA) for 18 pts (23%), Luspa for 4 pts (5%), hypomethylating agents (HMA) for 6 pts (8%) and other therapies for 2 pts (3%). Among 72 evaluable pts for response, the HI rate to 1st line therapy was 53% (37 pts). The HI rate to Len, ESA, HMA and Luspa was 64%, 42%, 20% and no response respectively as 1st line.
Forty-seven pts received 2nd line therapy, 12 (26%) Len, 4 (9%) Luspa, 22 (47%) HMA, 1 ESA, and 8 (17%) other treatments. Among 39 evaluable pts, the HI rate to 2nd line therapy was 43% (17 Pts). The HI rate was 46% (5/11 pts), 50% (2/4 pts), 47% (8/17 pts) for Len, Luspa and HMA as 2nd line therapy respectively.
Among 38 pts who received ESA at any time, 33 were evaluable for response, and the HI rate was 27% (9pts). Among 60 pts who received Len at any time, 57 were evaluable for response, and the HI rate was 59%. There was no difference in response among TP53 WT (61%) vs 50% for TP53 MT (p=.4). Among 16 pts who received Luspa at any time, the HI rate was 18%. Finally, 37 pts received HMA at any time, 32 evaluable for response, with an HI=37%.
The median overall survival (mOS) for the whole cohort was 66 months (mo) (95%CI 53-79). The mOS was 109 mo for TP53 WT compared to 64 mo for TP53 MT (p=0.22).
We compared the 77 MDS SF3B1del5q cohort to 382 MDS-SF3B1 pts and 133 MDS isolated del5q MDS pts. Outcome for SF3B1del5q MDS pts was closer to del5q MDS and inferior to MDS-SF3B1. HR for OS was 0.67 (95%CI .46-.98) (p=0.038) for MDS-SF3B1 and 0.79 (95% CI 0.51-1.2) (p=.28) for del5q pts compared to SF3B1del5q. Median OS was 66, 82, and 103 mo respectively for SF3B1del5q, del5q, and MDS-SF3B1 (p=0.1). The rate of AML transformation was 20%,12% and 5% respectively, p&lt;.005. Baseline counts and demographics were similar except for more MDS-SF3B1 observed in males. The concomitant MT were different, where more TP53 observed in 26%, 18%, and 2% respectively (p&lt;0.005). No JAK-2 mutations observed in SF3B1del5q group. Higher ESA response was observed among MDS-SF3B1 group, and similar response to Len among del5q and SF3B1del5q.
Conclusions
In this largest retrospective cohort of concomitant SF3B1del5q MDS pts to date, we report mOS of 66 mo, which is better than what was reported in IPSS-M for this group. Contrary to IPSS-M, our analysis was limited to pts with less than 5% myeloblasts. The mOS of SF3B1del5q was still inferior to either isolated del5q or SF3B1 entities and maybe driven by higher rate of concurrent TP53 MT observed. Response to Len was similar to isolated del5q whereas response to Luspa was inferior to MDS-SF3B1 and more observed as 2nd line therapy. Our data suggest that Len should be 1st line therapy for those pts followed by Luspa and HMA.