Efficacy and safety of imetelstat in transfusion-dependent lower-risk myelodysplastic syndromes: A systematic review and meta-analysis.

Abstract

e18579 Background: Myelodysplastic syndromes (MDS) are a diverse group of clonal hematopoietic stem cell disorders characterized by blood cytopenia, ineffective hematopoiesis, and an increased risk of acute myeloid leukemia. Managing lower-risk MDS (LR-MDS) remains challenging due to limited therapeutic options. Erythropoiesis-stimulating agents (ESAs) have been the first-line treatment to improve anemia and reduce transfusion needs, but about 40% of patients do not respond. Imetelstat, a first-in-class telomerase inhibitor, has shown promise in early trials for hematological malignancies, including MDS. This study evaluates the efficacy and safety of imetelstat in red blood cell transfusion-dependent LR-MDS patients unresponsive or ineligible for ESAs. Methods: This systematic review and meta-analysis adhered to PRISMA guidelines and the Cochrane Handbook. A comprehensive literature search was performed in PubMed, Scopus, Web of Science, and Cochrane Library databases through August 2024, using terms related to myelodysplastic syndrome, imetelstat, and clinical trials. Risk of bias was assessed using the ROBINS-I tool. Primary outcomes included 8-week and 24-week RBC-TI and HI-E rates. Secondary outcomes were grade 3–4 neutropenia, grade 3–4 thrombocytopenia, major/minor HI-E responses, RBC-TI duration, and cytogenetic/molecular responses. Meta-analyses were conducted in R 4.1.0 using a random-effects model. Pooled proportions with 95% CIs were calculated using Freeman-Tukey transformation, with heterogeneity assessed via the I² statistic (I² > 50% denoting substantial heterogeneity). Statistical significance was set at P < 0.05. Results: Our systematic search identified 609 records, of which four met the inclusion criteria after screening and full-text review. The risk of bias assessment revealed high methodological quality for randomized trials using ROBINS-I tool. Our meta-analysis found a pooled 8-week RBC-TI rate of 0.52 (95% CI: 0.45, 0.58), while the pooled 24-week RBC-TI rate was lower at 0.26 (95% CI: 0.20, 0.33). The pooled HI-E rate based on IWG 2006 criteria was 0.64 (95% CI: 0.57, 0.71). Further analysis showed a pooled major HI-E response rate of 0.30 (95% CI: 0.23, 0.38) and a minor HI-E response rate of 0.46 (95% CI: 0.38, 0.54). Our findings showed that the pooled incidence of grade 3-4 neutropenia was 0.67 (95% CI: 0.60, 0.73) and grade 3-4 thrombocytopenia was 0.59 (95% CI: 0.53, 0.66). Interestingly, no significant heterogeneity was detected across studies. Moreover, the safety profile across studies consistently showed that cytopenia was the most common adverse event. Conclusions: This meta-analysis provides evidence for the efficacy of imetelstat in achieving transfusion independence in heavily transfused patients with LR-MDS and limited treatment options. Further studies are needed to confirm its efficacy and safety.