KEY TAKEAWAYS
- The IMerge phase II/III trial aimed to assess cytogenetic response, VAF changes, and their clinical correlates in the IMerge study.
- The study showed promise in fixing ineffective RBC production and rewiring LRMDS, offering a deeper therapeutic approach.
Myelodysplastic syndromes(MDS) present with low blood cell counts, often requiring frequent transfusions. The IMerge phase 3 trial tested imetelstat, a drug targeting telomerase, an enzyme crucial for blood cell production.
Researchers aimed to assess cytogenetic response, variant allele frequency(VAF) changes, and their clinical correlates in the IMerge study.
The study was conducted at 118 global clinical sites from 2019 to 2022 and focused on heavily RBC transfusion-dependent (TD) non-del(5q) lower-risk myelodysplastic syndrome (LR-MDS) patients who were relapsed/refractory/ineligible for erythropoiesis-stimulating agents (ESA) and naïve to lenalidomide and hypomethylating agents. The interventions involved 2-hour infusions of imetelstat 7.5 mg/kg or placebo every 4 weeks until disease progression or unacceptable toxicity.
The primary outcome measure included the assessment of cytogenetic response through bone marrow (BM) aspirates collected every 24 weeks post-treatment in patients with baseline cytogenic abnormalities. Additionally, post-treatment, VAF changes were evaluated using blood and BM samples collected every 12 weeks in patients with ≥5% VAF at baseline and ≥1 postbaseline assessment.
Among 178 patients, baseline cytogenetic abnormalities were present in 22% of each group. Cytogenetic response rates were (34.6%, 95% CI: 17.2-55.7) and (15.4%,95% CI: 1.9-45.5) for imetelstat and placebo, respectively.
The imetelstat group exhibited higher rates of ≥50% VAF decreases in SF3B1, TET2, DNMT3A, and ASXL1 mutations compared to placebo. Patients in the imetelstat group achieving ≥8-week, ≥24-week, and ≥1-year transfusion independence were enriched with reductions in SF3B1 and TET2 VAF compared to the placebo group.
Imetelstat responders at 8 and 24 weeks demonstrated significantly greater reductions in SF3B1 VAF compared to non-responders (both P<.001). Reductions in SF3B1 VAF with imetelstat correlated significantly with increased hemoglobin (r, −0.626; P<.001) and longer transfusion independence duration (r, −0.549; P<.001).
The imetelstat group had a higher percentage of patients achieving ≥50% reduction in BM ring sideroblasts from baseline compared to placebo.
The study showed promise in fixing ineffective RBC production and rewiring LRMDS, offering a deeper therapeutic approach.
Source: https://clml-soho2023.elsevierdigitaledition.com/374/index.html
Clinical Trial: https://clinicaltrials.gov/study/NCT02598661
Santini V, Platzbecker U, Fenaux P, Sekeres M, Savona M, Madanat Y, Díez-Campelo M, Valcárcel-Ferreiras D, Illmer T, JonáŠová A, Bělohlávková P, Sherman L, Berry T, Dougherty S, Shah S, Xia Q, Peng L, Sun L, Wan Y, Huang F, Ikin A, Navada S, Feller F, Zeidan A, Komrokji R. Disease Modifying Activity of Imetelstat in Patients With Heavily Transfused Non-Del(5q) Lower-Risk Myelodysplastic Syndromes Relapsed/Refractory/Ineligible for Erythropoiesis-Stimulating Agents in IMerge Phase 3.
