Long-term outcomes from the randomized, double-blind, placebo (PBO)-controlled, phase 3 imerge trial of imetelstat (IME) for lower-risk myelodysplastic syndromes (LR-MDS)

Abstract Introduction: IME, a first-in-class telomerase inhibitor, was approved in the US and EU for the treatment (tx) of certain adult patients (pts) with LR-MDS and red blood cell (RBC) transfusion-dependent (TD) anemia who relapsed or are refractory (R/R) to, or are ineligible for erythropoiesis-stimulating agents (ESAs) based on the results of the Phase 3 IMerge trial (NCT02598661). In the primary analysis of IMerge (median follow-up, 18.5 mo) IME demonstrated statistically significant RBC transfusion independence (TI) vs PBO for ≥8-wk RBC-TI (primary endpoint; 40% IME vs 15% PBO; P<.001), ≥24-wk RBC-TI (key secondary endpoint; 28% IME vs 3% PBO; P<.001), and ≥1-y RBC-TI (post hoc endpoint; 18% vs 2%; P=.0023). At the time of the primary analysis, data were immature to assess overall survival (OS). Here, we report on secondary endpoints, including OS, progression-free survival (PFS), progression to acute myeloid leukemia (AML), safety, and long-term outcomes by subgroups of interest in IMerge, as well as ad hoc outcomes, including OS by response. Methods: In IMerge, pts with RBC-TD LR-MDS who were R/R to/ineligible for ESAs and lenalidomide- and hypomethylating agent–naive were randomized 2:1 to IME (7.1 mg/kg active dose, equivalent to 7.5 mg/kg IME sodium) or PBO. Kaplan-Meier and stratified Cox proportional hazard model were used; the study was not powered to detect statistical significance. Results: Of 178 pts enrolled in IMerge, 118 received IME and 60 received PBO (median age, 72 y; 62% of pts were male). At data cutoff (05/10/2025), median follow-up was 45 mo. In the intent-to-treat population, median (95% CI) OS was 47.8 mo (38.3-not estimable [NE]) for IME and 44.8 mo (37.4-NE) for PBO; pts treated with IME had 18% lower risk of death (hazard ratio [HR], 0.82 [95% CI, 0.48-1.38]). The landmark OS analysis (≥42 mo) showed a death rate of 11.4% (5/44) for IME and 31.6% (6/19]) for PBO (HR 0.33 [95% CI, 0.09, 1.20], P=.077). Median (95% CI) PFS in all pts was 47.6 mo (29.2-NE) for IME and 42.2 mo (16.7-NE) for PBO (HR, 0.82 [0.43-1.54], favoring IME). Progression to AML remained low in both tx arms (1.7% IME vs 3.3% PBO; HR, 0.45 [0.06-3.23], favoring IME). Among pts who achieved ≥8-wk RBC-TI with IME (n=47), median (95% CI) OS was 47.8 mo (35.3-NE) vs NE (30.7-NE) in nonresponders (n=71; HR, 0.93 [0.51-1.70]). Among pts who achieved ≥24-wk RBC-TI with IME (n=33), median (95% CI) OS was NE (40.4-NE) vs 45.7 mo (29.2-NE) in nonresponders (n=85; HR, 0.72 [0.37-1.38]). Among pts who achieved ≥1-y RBC-TI with IME (n=21), median (95% CI) OS was NE (39.1-NE) vs 47.8 mo (31.8-NE) in nonresponders (n=97; HR, 0.73 [0.35-1.53]). Among pts who achieved a 1.5-g/dL central hemoglobin (Hb) rise from pre-tx lasting ≥8 wk (International Working Group [IWG] 2006 hematologic improvement-erythroid criteria; n=40), median (95% CI) OS was NE (39.1-NE) vs 47.8 mo (29.2-NE) for nonresponders (n=78; HR, 0.74 [0.40-1.37]). Subgroup analyses of median OS generally favored IME over PBO. For pts with RS-positive disease, median OS was 47.6 mo for IME vs 47.2 mo for PBO (HR, 0.81 [95% CI, 0.43-1.52]). For pts with RS-negative disease, median OS was 47.8 mo for IME vs 44.8 mo for PBO (HR, 0.92 [95% CI, 0.34-2.50]). For pts with low-risk disease per International Prognostic Scoring System, median OS was NE for IME vs 47.2 mo for PBO (HR, 0.99 [95% CI, 0.53-1.86]). For pts with intermediate-1–risk disease, median OS was 45.7 mo for IME and 44.1 mo for PBO (HR, 0.52 [0.20-1.37]). For pts with serum erythropoietin (sEPO) ≤500 mU/mL, median OS was 47.6 mo for IME and 52.0 mo for PBO (HR, 0.97 [95% CI, 0.50-1.90]). For pts with sEPO >500 mU/mL, median OS was NE for IME vs 44.1 mo for PBO (HR, 0.54 [95% CI, 0.18-1.60]). For pts with high TB per IWG 2018 criteria, median OS was 44.2 mo for IME vs 44.1 mo for PBO (HR, 0.95 [95% CI, 0.52-1.71]). For pts with low TB, median OS was NE for IME vs 52.0 mo for PBO (HR, 0.23 [95% CI, 0.05-1.13]). Pts treated with IME with SF3B1-mutated disease had superior OS vs those without (HR 0.32 [95% CI, 0.16-0.64]; P<.001). No new safety signals emerged. Conclusions: IME resulted in a favorable trend in OS, PFS, and time to progression to AML vs PBO in the overall population; OS favored IME vs PBO in most subgroups. The OS results correlated with RBC-TI and Hb rise in IME-treated pts. Although not statistically powered to detect significance, these analyses support the clinical benefit of IME in pts with RBC-TD LR-MDS.