Outcomes and Treatment Responses to Lenalidomide and Luspatercept in MDS with SF3B1del(5q) Compared With MDS With Isolated SF3B1 and del(5q) Mutations

Participants with myelodysplastic syndromes (MDS) harboring splicing factor 3B subunit 1 mutations with concomitant deletion of the long arm of chromosome 5 (MDS-SF3B1^del5q) demonstrate distinct clinical outcomes and treatment responses compared with participants with isolated (either/or) mutations. Lenalidomide emerged as a preferred first-line therapy for MDS-SF3B1^del5q.

The recently published, large, retrospective analysis, presented by Rami S. Komrokji, MD, Moffitt Cancer Center, Tampa, Florida, was designed to unravel the characteristics, treatment responses, and survival outcomes of patients with MDS-SF3B1^del5q.^1,2

The multicenter, international, retrospective study included 77 participants with  lower-risk MDS and SF3B1^del5 mutations, less than 5% myeloblasts, and no complex karyotype who received at least one line of therapy. Overall survival and hematologic improvement, defined as a hemoglobin concentration increase of 1.5 g/dL, a larger number of non–transfusion-dependent participants, or more red blood cell transfusion independence among the transfusion-dependent participants, were monitored.

Of all participants, 61% had received lenalidomide; 23%, erythroid stimulating agents (ESA); 5%, luspatercept; and 8%, hypomethylating agents (HMAs) as first-line therapy. Hematologic improvement was achieved by 53% of all participants. Lenalidomide yielded the highest hematologic improvement response rate (64%), followed by ESA (42%) and HMA (20%). Notably, no responses were observed with luspatercept as first-line therapy. Of the 47 participants who had received second-line therapy, 26% received lenalidomide; 9%, luspatercept; 47%, HMA; and 1% received ESA and other treatments. Hematologic improvement rates were 46%, 47%, and 50% for lenalidomide, luspatercept, and HMA, respectively.

Participants treated with lenalidomide at any time demonstrated a 59% hematologic improvement rate, independent of TP53 mutation status. The median overall survival for the SF3B1^del5q cohort was 66 months and thus shorter than the overall survival of participants from comparison cohorts with isolated SF3B1 (103 months) or del5q (82 months) mutations. Dr. Komrokji highlighted, “Yet, an overall survival of 66 months is longer than the previously reported data from the Molecular International Prognostic Scoring System for Myelodysplastic Syndromes (IPSS-M) for this MDS-SF3B1^del5q subgroup of patients.”³

Acute myeloid leukemia transformation rates were higher in the SF3B1^del5q group (20%) compared with SF3B1 (5%) or del5q (12%) alone, potentially linked to the higher prevalence of TP53 mutations (26% vs 18% and 2%, respectively). Despite this, the study found no significant survival difference between participants with TP53 wild-type and mutant MDS.

Overall, this study reports a median overall survival of 66 months for participants with SF3B1^del5q mutations, which is better than reported earlier, yet still inferior to outcomes of participants with isolated SF3B1 or del5q mutations. Based on the treatment outcomes in the study, Dr. Komrokji concluded, “Our data suggest that lenalidomide should be first-line therapy for patients with concomitant SF3B1^del5q MDS, followed by luspatercept and HMA.”

REFERENCES

1. Komrokji RS, Schwabkey ZI, Al Ali NH, et al. Myelodysplastic syndromes with concomitant SF3B1 mutation and deletion of the long arm of chromosome 5 (SF3B1^del5q): outcomes and response to treatment. Abstract #1845. Presented at the ASH Annual Meeting December 7-10, 2024; San Diego, California.
2. Komrokji R, Schwabkey Z, Ali N, et al. Myelodysplastic syndromes with concomitant SF3B1 mutation and deletion of the long arm of chromosome 5 (SF3B1del5q): Outcomes and response to treatment. Blood. 2024;144(Suppl1):1845. doi: 10.1182/blood-2024-207474
3. Bernard E, Tuechler H, Greenberg PL, et al. Molecular International Prognostic Scoring System for Myelodysplastic Syndromes. NEJM Evid. 2022;1(7):EVIDoa2200008. doi: 10.1056/EVIDoa2200008