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This article summarizes key data from three presentations on novel treatments in myelodysplastic syndromes (MDS) from the 64th American Society of Hematology (ASH) Annual Meeting and Exposition. Amer Zeidan1 presented results from the STIMULUS-MDS1 phase II study of sabatolimab, Uwe Platzbecker2 presented phase II study results of imetelstat in low-risk MDS, and Guillermo Garcia-Manero3 presented the outcomes from the phase I/II trial of canakinumab in low-risk MDS.
STIMULUS-MDS1 (NCT03946670) is an ongoing phase II study of sabatolimab that enrolled 127 adult treatment-naïve patients with intermediate-, high-, or very high-risk MDS (as defined by the revised International Prognostic Scoring System). All patients received hypomethylating agents (HMAs) and were randomized 1:1 to also receive either sabatolimab or placebo. The HMA given (azacitidine or decitabine) was decided at the investigator’s discretion, with 89% of patients receiving azacitidine. The primary endpoint of this study was the rate of complete remission (CR) and progression-free survival (PFS). And secondary endpoints included response rates, overall survival (OS), duration of response, and safety.
The median follow-up of the study was 24 months.
The rates of the most common hematologic Grade ≥3 adverse events (AEs) are summarized in Figure 1. The most common non-hematologic all-grade AEs were constipation and diarrhea.
Figure 1. Most common Grade ≥3 adverse events*
HMA, hypomethylating agent.
*Adapted from Zeidan.1
Treatment discontinuation was 78.5% and 82.3% in the sabatolimab + HMA and placebo + HMA groups, respectively.
The overall response rates are shown in Figure 2. The mean duration of CR was 18 months and 9.2 months in the sabatolimab + HMA and placebo + HMA groups, respectively.
Figure 2. Overall response rate*
CR, complete remission; HI, hematologic improvement; HMA, hypomethylating agent; mCR, marrow CR; ORR, overall response rate; SD, stable disease.
*Adapted from Zeidan.1
The median overall survival was 19 months and 18 months in the sabatolimab + HMA and placebo + HMA groups, respectively.
In exploratory subgroups of PFS, survival was higher in the sabatolimab + HMA group compared with the placebo + HMA group for patients with a lower Molecular International Scoring System score (23.7 months vs 8.77 months, respectively) and also in patients with <10% blasts (11.3 months vs 8.3 months, respectively).
This study shows that sabatolimab + HMA can be used safely in patients with high-risk MDS. Although significant improvements in CR were not seen, exploratory analyses suggest sabatolimab may be more effective in patients with a lower disease burden. There is currently an ongoing phase III trial (STIMULUS-MDS2) which will provide further data on the safety and efficacy of sabatolimab.
IMerge is an ongoing phase II/III study (NCT02598661) of imetelstat that enrolled 57 patients with lower-risk MDS. The primary endpoint of this study was ≥8-week red blood cell transfusion independence (TI). Secondary endpoints included safety, 24-week TI rate, MDS response, OS, PFS, and time to progression to acute myeloid leukemia.
Figure 3. Survival outcomes*
OS, overall survival; PFS, progression-free survival; TI, transfusion independence.
*Adapted from Platzbecker.2
The safety profile of imetelstat in this study was similar to previous reports, in addition to providing a durable TI especially in non-del(5q) lenalidomide/HMA-naïve patients. Enrolment in the phase III part of this study is complete, with top-line results expected in January 2023. The phase III study will compare the efficacy of imetelstat with the placebo.
This is an ongoing phase II study (NCT04239157) of canakinumab, a monoclonal antibody targeting interleukin-1 beta, in patients with low-risk MDS. The primary objective of this study was the safety and clinical activity of canakinumab, as defined by the International Working Group 2006 response criteria.
This study has shown that canakinumab can be used safely in patients with lower-risk MDS. Further studies in patients with earlier-stage MDS and clonal cytopenias with unknown significance will provide further data on the efficacy and safety of canakinumab.
These results demonstrate that these novel therapies have acceptable safety and efficacy for use in patients with MDS. Sabatolimab was found to have a favorable safety profile and was well tolerated, with similar rates of adverse events to placebo-treated patients. Further data are to be provided by the ongoing STIMULUS-MDS2 trial. Imetelstat provided the best efficacy in patients who were lenalidomide/HMA-naïve with a non-del(5q) mutation. Results from the phase III study will provide further efficacy data. The study of canakinumab showed it can be safely used in patients with lower-risk MDS, although single-cell RNA sequencing suggests it may have greater efficacy in patients with certain mutations and in patients with fewer total mutations.
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