Existing treatments for lower-risk myelodysplastic syndromes/neoplasms (LR-MDS) focus on symptom relief. Until recently, altering the disease course was rarely considered a therapeutic objective. The first-in-class, direct, competitive telomerase inhibitor, imetelstat, demonstrated significantly higher rates of red blood cell (RBC) transfusion independence (TI) versus placebo in patients with non-del(5q), RBC transfusion-dependent LR-MDS who were relapsed/refractory to or ineligible for erythropoiesis-stimulating agents in the Phase 3 IMerge study (NCT02598661). In this exploratory analysis of IMerge, patients treated with imetelstat had greater sustained reductions in variant allele frequency of multiple mutations versus placebo recipients, which was positively associated with RBC-TI duration. Subsequent analyses showed that 70% of patients with a cytogenetic response with imetelstat achieved ≥1-year RBC-TI. Additionally, higher rates of ≥1-year RBC-TI were observed in patients with maximum variant allele frequency reduction of ≥50% in SF3B1 (58% vs. 7%), TET2 (90% vs. 9%), DNMT3A (100% vs. 13%), or ASXL1 (50% vs. 0%) and patients with ≥50% bone marrow ring sideroblast reduction (46% vs. 0%) versus patients who did not. Lastly, 60% of patients with ≥1-year RBC-TI had ≥50% reduction in telomerase activity/human telomerase reverse transcriptase RNA. These results suggest that imetelstat targets clonal progenitor cells and may modify LR-MDS biology.

6573 Background: IME showed significantly longer median OS (mOS) in patients (pts) with Janus kinase inhibitor (JAKi) R/R intermediate-2–risk or high-risk MF in the IMbark trial (NCT02426086) vs closely matched RW pts treated with best available therapy (BAT) after ruxolitinib (RUX; HR, 0.35; P =.0019). The MF tx landscape changed considerably in recent years, potentially impacting OS. We present an updated OS analysis of IMbark pts vs a larger RW pt cohort after extended follow-up. Methods: The updated RW dataset included 126 pts who discontinued RUX and were subsequently treated with BAT at Moffitt Cancer Center between 2010 and 2025. To assess changes in RW tx patterns, baseline/disease characteristics and OS of pts diagnosed before/after 2016 and 2019 were compared. To update the IMbark vs RW OS analysis, a closely matched cohort was identified using IMbark eligibility criteria, including pts diagnosed before 2016 who received RUX but were R/R. The mOS was measured from time of JAKi discontinuation to death or censored at last follow-up. Propensity score approaches using average tx effect for overlap population (ATO) or stabilized inverse probability tx weighting (sIPTW) were implemented to adjust for baseline covariates/prognostic factors that may impact outcomes. Results: The RW tx pattern assessment included 96 pts. Time from diagnosis to start of RUX and duration of RUX tx were significantly shorter after 2016 vs before (Table). Similar changes were observed after 2019 vs before. The mOS in pts diagnosed after 2016 and 2019 was significantly longer vs before. The updated mOS analysis included 59 IMbark pts and 54 closely matched RW pts. With a median follow-up of 46.2 mo for IMbark pts and 48.2 mo for RW pts, mOS (95% CI) was 30.7 mo (25.5-36.9) with IME in IMbark vs 15.4 mo (13.1-30.5) with BAT in RW (HR, 0.512; P= .003) per the unweighted analysis. Propensity-weighted analyses (ATO, sIPTW) had similar results. Conclusions: This updated post hoc analysis confirms a significantly more favorable OS benefit with IME vs BAT in pts with R/R MF and poor prognosis consistent with the previous report (Kuykendall 2021). A significant improvement in OS in RW pts over the last decade was also demonstrated, potentially due to shorter time from diagnosis to start of RUX and earlier switch to next-line JAKi or clinical trial. Evolving tx patterns are key considerations for interpreting future clinical trial outcomes. Clinical trial information: NCT02426086 . Updated RW data by time of diagnosis. Before 2016(N=54) After 2016(N=42) Before 2019(N=69) After 2019(N=27) Time from diagnosis to RUX start (mean), mo 46.7 10.5 39.7 8.2 RUX duration (mean), mo 30.4 13.5 26.1 15.0 Transplant, n (%) 3 (5.6) 4 (9.5) 5 (7.2) 2 (7.4) mOS (95% CI), mo 15.4(13.1-30.5) 34.2(24.2-NA) 16.6(14.2-30.0) 39.8(34.2-NA) mOS, median overall survival; NA, not available; RUX, ruxolitinib; RW, real world.

Introduction: Limited treatment options are available for patients with red blood cell (RBC) transfusion-dependent (TD) lower-risk myelodysplastic syndromes (LR-MDS). Imetelstat (IME), a first-in-class, direct, and competitive inhibitor of telomerase activity, was approved by the United States Food and Drug Administration in June 2024 for the treatment of RBC-TD LR-MDS in patients who were relapsed or refractory to or ineligible for erythropoiesis-stimulating agents (ESA) based on the results of the pivotal IMerge trial (NCT02598661). IMerge demonstrated significant and durable efficacy of IME (n=118) versus placebo (n=60) for ≥8-week, ≥24-week, and ≥1-year RBC-transfusion independence (TI), with a generally manageable safety profile in this patient population (Platzbecker U, Santini V, et al. Lancet. 2024). This analysis pooled data from the 3 parts of the IMerge trial (phase 2, phase 3 and QTc study) to investigate the effect of prior therapies on the clinical activity of IME. Methods: IMerge was a phase 2/3 trial with a clinical QTc study that enrolled patients with heavily RBC-TD LR-MDS who were ESA-ineligible or relapsed/ refractory. IME was administered intravenously every 4 weeks at 7.1 mg/kg (equivalent to 7.5 mg/kg IME sodium). Prior lenalidomide (LEN) and prior hypomethylating agent (HMA) use were exclusion criteria in phase 3 only. In this analysis, IME-treated patients (N=226) were pooled from phase 2, phase 3, and the QTc study of IMerge and analyzed on the basis of prior treatment as follows: ± ESA, luspatercept (LUSP), LEN, and HMA. Prior treatment was not exclusive; patients may have received >1 prior therapy. Outcomes included ≥8-week and ≥24-week RBC-TI, rates of hematologic improvement-erythroid (HI-E) based on the revised International Working Group (IWG) 2018 criteria, transfusion reduction of ≥4 U/8 weeks, and a hemoglobin (Hb) rise of ≥1.5 g/dL for ≥8 weeks. Results: As previously presented, data from the IMerge phase 3 pivotal analysis demonstrated that patients treated with IME (n=118) had ≥8-week and ≥24-week RBC-TI rates of 40% and 28%, respectively, 42% met HI-E (IWG 2018) criteria, 60% had transfusion reductions of ≥4 U/8 weeks, and 34% had a Hb rise of ≥1.5 g/dL for ≥8 weeks (Platzbecker U, Santini V, et al. Lancet. 2024). In the current analysis of all IME-treated patients pooled in IMerge (N=226), 204 had prior treatment with an ESA and 22 were ineligible for ESAs; 35 had prior LUSP, 26 had prior LEN, and 22 had prior HMA treatment. Of IME-treated patients with prior ESA therapy, 40% and 28% achieved ≥8-week and ≥24-week RBC-TI, respectively, 43% met HI-E, 64% had a transfusion reduction of ≥4 U/8 weeks, and 33% had a Hb rise of ≥1.5 g/dL for ≥8 weeks. In IME-treated patients ineligible for ESA therapy, 36% and 14% achieved ≥8-week and ≥24-week RBC-TI, respectively, 41% met HI-E, 64% had a transfusion reduction of ≥4 U/8 weeks, and 2% had a Hb rise of ≥1.5 g/dL for ≥8 weeks. Of IME-treated patients who had prior treatment with LUSP, 29% and 20% achieved ≥8-week and ≥24-week RBC-TI, respectively, 26% met HI-E, 69% had a transfusion reduction of ≥4 U/8 weeks, and 29% had a Hb rise ≥1.5 g/dL for ≥8 weeks. Of IME-treated patients with prior LEN treatment, 23% and 12% achieved ≥8-week and ≥24-week RBC-TI, respectively, 31% met HI-E, 54% had a transfusion reduction of ≥4 U/8 weeks, and 19% had a Hb rise of ≥1.5 g/dL for ≥8 weeks. Of the 22 IME-treated patients who had prior treatment with HMA, 14% and 9% achieved ≥8-week and ≥24-week RBC-TI, respectively, 18% met HI-E, 50% had a transfusion reduction of ≥4 U/8 weeks, and 14% had a Hb rise of ≥1.5 g/dL for ≥8 weeks. Conclusions: Patients who were ESA-ineligible or who had prior treatment with LUSP, LEN, or HMA in IMerge experienced clinical benefit from IME treatment, though the number of patients was small. Given the evolving therapeutic landscape for LR-MDS and the limited data available on outcomes in later lines of treatment, these results have important clinical implications, suggesting that IME demonstrates clinical activity regardless of prior therapies.

Introduction: IME is a first-in-class, direct, and competitive telomerase inhibitor approved for the treatment (tx) of certain adult pts with LR-MDS with red blood cell (RBC) transfusion-dependent anemia who are relapsed or refractory to/ineligible for erythropoiesis-stimulating agents. In the pivotal Phase 3 IMerge trial (NCT02598661), a significantly higher proportion of pts on IME vs placebo achieved ≥8-wk (40% vs 15%; P<.001) and ≥24-wk (28% vs 3%; P<.001) RBC transfusion independence (TI). The most common grade 3/4 tx-emergent adverse events with IME were neutropenia (68%) and thrombocytopenia (62%), typically occurring within the first 3 tx cycles and generally manageable and reversible. This post hoc analysis explored the possible association between IME-related cytopenias and Hb increase, a measure linked to RBC-TI achievement. Methods: Pooled pts from the 3 parts of IMerge (Phase 2/3 and QTc substudy) who received 7.1 mg/kg IME active dose (equivalent to 7.5 mg/kg IME sodium) were included. The relationship between percent reduction in platelet (PLT)/neutrophil (NEUT) counts occurring within the first 2 cycles of IME tx and subsequent outcomes was analyzed, including maximum (max) Hb increase from baseline (pre-tx Hb), hematologic improvement-erythroid (HI-E) per IWG 2006 criteria (defined as Hb rise ≥1.5 g/dL lasting 8 wk), and rates of ≥8-wk and ≥24-wk RBC-TI. Cytopenia levels were dichotomized at ≥50% reduction for PLTs and ≥75% reduction for NEUTs to assess categorical correlations with HI-E and RBC-TI responses (yes/no) using Fisher exact test and t test for group differences in Hb increase. Univariate linear regression was conducted to evaluate the association between continuous percent reduction in PLT/NEUT counts and max Hb increase. Multivariate analyses were conducted via stepwise linear regression (for max Hb increase) or logistic regression (for HI-E/TI response) with dichotomized percent reduction in PLT/NEUT counts in the presence of other baseline prognostic factors. An unadjusted nominal P value from each test was reported. Results: Data cutoff dates were 10/13/2023 (Phase 2/3) and 10/13/2024 (QTc substudy); 226 pts were included. Median values at baseline were 71 y of age, pre-tx Hb 7.8 g/dL, and PLT and NEUT counts 236×109/L and 2.6×109/L, respectively. Median IME tx duration was 34 wk. Pts with ≥50% max PLT reduction within the first 2 cycles of IME tx had a significantly greater mean max Hb increase from pre-tx (2.07 g/dL [n=169] vs 1.17 g/dL [n=39]; P=.003), HI-E rate (34.2% vs 11.9%; P=.005) and ≥24-wk RBC-TI rates (32.6% vs 7.1%; P<.001), and numerically greater ≥8-wk RBC-TI rates (42.4% vs 26.2%; P=.056) vs pts with <50% PLT reduction. As a continuous variable, PLT reduction remained significantly associated with Hb increase (P=.0095; linear regression). Similarly, pts with ≥75% max NEUT reduction within the first 2 cycles of IME tx had a significantly greater mean max Hb increase from pre-tx (2.53 g/dL [n=70] vs 1.58 g/dL [n=138]; P=.011), numerically greater HI-E rate (34.6% vs 27.7%), and comparable ≥8-wk (41.0% vs 38.5%) and ≥24-wk RBC-TI rates (30.8% vs 26.4%) vs pts with <75% NEUT reduction. As a continuous variable, NEUT reduction was also significantly associated with max Hb increase (P=.012). Multivariate analyses showed that the likelihood of achieving ≥8-wk and ≥24-wk RBC-TI was significantly correlated with the max Hb increase from pre-tx, g/dL (odds ratio [OR; 95% CI], 6.47 [3.73-11.24; P<.001] and 3.87 [2.66-5.64; P<.001], respectively). Multivariate analyses further confirmed that max Hb increase, g/dL, significantly correlated with ≥75% NEUT reduction (coefficient estimate [95% CI], 0.94 [0.32-1.57; P=.003]), and the likelihood of achieving HI-E significantly correlated with ≥50% PLT reduction (OR [95% CI], 4.16 [1.54-11.23; P=.005]). Conclusions: In this post hoc analysis, pts with ≥75% NEUT or ≥50% PLT reductions in the first 2 cycles of IME tx were more likely to have greater Hb increases from pre-tx or to achieve an HI-E response. The greater Hb increase from pre-tx emerged as a main driver for achieving ≥8-wk and ≥24-wk RBC-TI responses. Collectively, these data suggest that tx-emergent cytopenias with IME may be associated with potential for clinical benefit, similar to lenalidomide in del5q MDS. Further research is needed to confirm this on-target effect of IME resulting from its activity on clonal progenitor cells and subsequent recovery in blood cell production.

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.

Introduction: Imetelstat, a direct and competitive inhibitor of telomerase enzymatic activity, was approved by the United States Food and Drug Administration (FDA) in June 2024 for adult patients (pts) with red blood cell (RBC) transfusion-dependent (TD) lower-risk myelodysplastic syndromes (LR-MDS) who are relapsed or refractory to or ineligible for erythropoiesis-stimulating agents (ESA) based on the results of the pivotal phase 3 IMerge trial (NCT02598661). IMerge demonstrated a clinically meaningful and statistically significant RBC-transfusion independence (TI) rate for imetelstat versus placebo for the primary endpoint (≥8-wk RBC-TI: 40% vs 15%, respectively; P<.001) and a generally manageable safety profile (Platzbecker U, Santini V, et al. Lancet. 2024). A ventricular repolarization substudy of IMerge was conducted as per FDA guidance. Here, we report the first efficacy and safety results from this substudy. Methods: Adult pts were randomized to receive imetelstat (7.1 mg/kg, equivalent to 7.5 mg/kg imetelstat sodium) or placebo, every 4 wk in 28-d cycles. Placebo recipients could cross over to imetelstat after completing 2 cycles. Efficacy endpoints included ≥8-wk and ≥24-wk RBC-TI rates, hematologic improvement-erythroid (HI-E) by International Working Group (IWG) 2018 criteria, and transfusion reduction and hemoglobin (Hb) changes by IWG 2006 criteria. The proportion of pts with RBC-TI and other binary endpoints were summarized with percentages and 95% 2-sided exact Clopper-Pearson CI. Kaplan-Meier methodology estimated the distribution of duration of RBC-TI. The primary objective of the substudy was to evaluate the concentration-QT relationship by the primary electrocardiogram (ECG) endpoint (change from baseline QTcF using a linear mixed-effects modeling approach). Triplicate ECGs were collected on cycle 1, day 1 (−1, −0.5, and 0 h predose, and at 0.5, 1, 2, 4, 6, and 8 h after the start of infusions). This substudy differed from the IMerge phase 3 trial in its crossover design and by allowing prior lenalidomide and hypomethylating agent (HMA) therapy besides ESAs. Results: The mean age of the QTc substudy population (N=53 [35 imetelstat, 18 placebo]) was 69 y (range, 43-84); 81% were male, 87% had prior ESA use, 98% were non-del(5q), and 43% had prior luspatercept use. At baseline, 55% were receiving >6 U RBC/8 wk and median Hb was 7.6 g/dL. No clinically meaningful effects of imetelstat on cardiac repolarization or other ECG parameters were observed. As of the data cutoff (05/10/2024), 16 placebo recipients crossed over to receive imetelstat. With a median treatment duration of 29.3 wk in the 51 total imetelstat-treated pts (including 35 randomized and 16 crossover pts), 41% (21/51) achieved ≥8-wk RBC-TI; the median (95% CI) duration of RBC-TI among responders was 52.6 wk (40.9-not estimable). Subgroup analyses demonstrated ≥8-wk RBC-TI rates of 30% (7/23) and 50% (14/28) in pts with and without prior luspatercept, 38% (5/13) and 42% (16/38) in pts with and without prior lenalidomide, and 21% (3/14) and 49% (18/37) in pts with and without prior azacitidine or decitabine use, respectively. In the 51 imetelstat-treated pts, ≥24-wk RBC-TI was achieved by 25% (13/51) of pts, HI-E per IWG 2018 response was achieved by 41% (21/51) of pts, 35% (18/51) experienced a Hb increase of ≥1.5 g/dL lasting ≥8 wk per IWG 2006, and 75% (38/51) of pts had a reduction in transfusions by ≥4 U/8 wk per IWG 2006. No new safety signals emerged and in the total imetelstat-treated population, grade 3/4 neutropenia and thrombocytopenia by laboratory evaluation occurred in 65% (33/51) and 49% (25/51) of pts, respectively, of which most cases resolved to grade ≤2 within 4 wk; incidence was similar to the overall phase 3 imetelstat-treated population. As of the data cutoff, progression to acute myeloid leukemia occurred in none of the imetelstat-treated pts versus 1 placebo recipient (before crossover). Conclusions: In this QTc substudy, imetelstat was associated with an absence of proarrhythmic risk, durable RBC-TI, transfusion reduction, clinically meaningful increases in Hb, and safety comparable to the overall population of the pivotal IMerge phase 3 trial. Of note, responses to imetelstat were seen in pts receiving prior treatments including luspatercept, lenalidomide, and HMA. Overall, the results of this IMerge QTc substudy support the use of imetelstat in pts with relapsed/refractory LR-MDS.

6566 Background: In the IMerge trial (NCT02598661) of RBC transfusion-dependent (TD) patients (pts) with lower-risk myelodysplastic syndromes (LR-MDS) relapsed/refractory to or ineligible for erythropoiesis stimulating agents, imetelstat showed significant efficacy vs placebo (PBO) for 8-wk, 24-wk, and 1-y TI endpoints, with neutropenia and thrombocytopenia as the most common adverse events (Platzbecker. Lancet 2024). Supportive care was given to all pts as needed, per investigator discretion. Here we report RBC-TI rates in the absence of platelet transfusions or myeloid growth factor use. Separately, RBC-TI with mean central hemoglobin (Hb) rise of ≥1.5 g/d was assessed in all pts. Methods: Pts were randomized 2:1 to receive imetelstat (n=118) 7.5 mg/kg or PBO (n=60) Q4W IV until disease progression. Primary endpoint was 8-wk RBC-TI; 24-wk RBC-TI was a key secondary endpoint. Primary analysis cutoff was Oct 2022, with Oct 2023 cutoff for 1-y RBC-TI analyses. Results: Overall, 21/118 (18%) pts in the imetelstat group and 1/60 (2%) pts in the PBO group needed platelet transfusions; 41/118 (35%) and 2/60 (3%) pts received myeloid growth factors, respectively. Significantly higher percentages of pts achieved 8-wk, 24-wk, and 1-y RBC-TI with imetelstat vs PBO in the absence of either platelet transfusions or growth factor support (Table). In a separate analysis, 8-wk, 24-wk, and 1-y RBC-TI and concurrent Hb rise of ≥1.5 g/dL with imetelstat vs PBO occurred in 28% vs 2%, 23% vs 0%, and 17% vs 0% of pts, respectively (Table). Among responders, imetelstat increased median central Hb levels compared with PBO: 3.6 g/dL vs 0.8 g/dL for 8-wk, 4.2 g/dL vs 1.1 g/dL for 24-wk, and 5.2 g/dL vs 1.7 g/dL for 1-y RBC-TI. Conclusions: Results from this subanalysis confirm that pts who achieve RBC-TI with imetelstat do so without developing severe neutropenia and thrombocytopenia (functionally defined as needing myeloid growth factors or platelet transfusions, respectively), therefore not negating the clinical benefit of the drug. Imetelstat also led to significant rise in Hb levels in RBC-TI responders, particularly long-term responders. These data further support the efficacy of imetelstat in TD pts with LR-MDS. Clinical trial information: NCT02598661 . [Table: see text]

Context In IMerge (NCT02598661), imetelstat resulted in significantly higher ≥8-week, ≥24-week, and ≥1-year RBC-TI rates than placebo in patients with non-del(5q) LR-MDS who were RBC-TD, relapsed/refractory (R/R) to or ineligible for erythropoiesis-stimulating agents (ESA), and lenalidomide/hypomethylating agent-naive. Objective Assess OS and clinical benefit of durable RBC-TI with imetelstat. Design Randomized (2:1), double-blind, placebo-controlled, phase 3 trial. Setting Total of 118 global sites; 2019-2022. Patients Consenting patients with non-del(5q) LR-MDS, were RBC-TD, R/R/ineligible for ESAs, and lenalidomide/hypomethylating agent-naive. Interventions Intravenous imetelstat 7.5 mg/kg or placebo q4wk until disease progression, unacceptable toxicity, or withdrawal of consent. Main Outcome Measures RBC-TI duration and OS calculated by Kaplan-Meier method and compared by stratified log-rank test. Cutoff dates: 10/2022 (primary analysis), 10/2023 (≥1-year RBC-TI), and 1/2024 (OS). Results Among imetelstat-treated ≥8-week RBC-TI responders, median RBC-TI duration was 52 weeks (47/118 patients) versus 13 weeks with placebo (9/60 patients; P<.001); median increase from baseline in central hemoglobin was 3.6 g/dL versus 0.8 g/dL. Of imetelstat-treated ≥8-week responders, 70% remained RBC-TI for ≥24 weeks; 64% of these ≥24-week responders remained RBC-TI for ≥1 year. Among ≥24-week RBC-TI responders, median RBC-TI duration was 80 weeks with imetelstat (n=33) versus not estimable (NE) with placebo (n=2; P<.001); median hemoglobin increase was 4.2 g/dL versus 1.1 g/dL. In ≥1-year RBC-TI responders, median RBC-TI duration was 132 weeks with imetelstat (n=21) versus 131 weeks with placebo (n=1); median hemoglobin increase was 5.2 g/dL versus 1.7 g/dL. Assessed separately, ≥8-week, ≥24-week, and ≥1-year RBC-TI with concurrent hemoglobin rise of ≥1.5 g/dL occurred in 28% versus 2%, 23% versus 0%, and 17% versus 0% of patients receiving imetelstat and placebo, respectively (all P<.001). As of January 2024, median follow-up was 32 and 28 months for imetelstat (n=55/118) and placebo (n=26/60), with median OS of 40.4 months and NE, respectively (hazard ratio, 0.98; 95% CI, 0.526-1.823). For imetelstat, the 2-year OS rate was 78% overall and 81% in ≥8-week RBC-TI responders; for placebo, it was 74%. Conclusions Updated analyses confirm RBC-TI achievement with imetelstat is durable and associated with improved hemoglobin level. Preliminary OS analysis suggests no detriment with imetelstat versus placebo. Funding Geron Corporation.

CONCLUSIONS MDS are serious life-threatening hematologic malignancies in which a heterogeneous group of clonal disorders results in ineffective hematopoiesis. An unmet need remains for new therapies for patients (pts) with LR-MDS who are red blood cell transfusion dependent (RBC-TD) and R/R to or ineligible for ESAs. Imetelstat, an oligonucleotide, is a first-in-class telomerase inhibitor that targets cells with high telomerase activity by direct binding to the RNA template of telomerase. In the IMerge phase 3 trial, imetelstat produced higher rates of TI for ≥8 weeks, ≥24 weeks, and ≥1 year (39.8%, 28.0%, and 17.8%) than placebo (15.0%, 3.3%, and 1.7%) in pts with non-del(5q) LR-MDS that was RBC-TD, R/R to/ineligible for ESAs, and naïve to lenalidomide or hypomethylating agents (HMAs; Platzbecker et al. EHA 2023. Abstr S165). We report characteristics and clinical benefit for pts with sustained TI for ≥1 year from this trial. IMerge (MDS3001, NCT02598661) is a global, double-blind, randomized, placebo-controlled, phase 3 trial of imetelstat in RBC-TD, ESA-R/R, non-del 5(q) lenalidomide/HMA-naïve LR-MDS. The primary end point was 8-week TI rate; secondary end points included safety, 24-week TI, duration of response, hematologic improvement, and MDS response. Exploratory end points included assessment of cytogenetic response and mutational status with clinical response. The proportion of pts with>1-year TI and other binary end points, were summarized with percentage and 95% 2-sided exact Clopper-Pearson CI. The Kaplan-Meier method was used to estimate the distribution of TI. Of 118 pts receiving imetelstat, 21 (17.8%; 95% CI, 11.4-25.9) achieved ≥1-year sustained TI, representing 45% of ≥8-week TI (21 of 47 pts) and 64% of ≥24-week TI (21 of 33 pts); of 60 pts receiving placebo plus supportive care, 1 (1.7%; 95% CI, 0-8.9) achieved ≥1-year TI. Of the ≥1-year TI imetelstat responders, 15/21 (71.4%) had ring sideroblasts, as did the 1 placebo pt. The median prior RBC transfusion burden was 6 U over 8 weeks (range, 4-9 U) for the imetelstat group and 5 U for the placebo pt. Additional baseline characteristics are in the table. Pts received imetelstat for a median of 101.1 weeks (range, 75.1-163.9 weeks) and a median of 24 cycles (range, 18-41 cycles). The median duration of TI for imetelstat ≥1-year TI responders was 123 weeks (95% CI, 80.4 to not evaluable); the median increase in hemoglobin during the longest TI interval was 5.18 g/dL (range, 2.67-13.76 g/dL) for the imetelstat group vs 1.67 g/dL for the placebo pt. After a median follow-up of 125 weeks, none of the patients with ≥1 year TI on either arm progressed to acute myeloid leukemia (AML). Of the pts receiving imetelstat, 7 had an abnormal karyotype at baseline, of which 6 had reduction in the cytogenetic abnormal clones (4 with cytogenetic complete response and 2 with cytogenetic partial response by independent review committee). Mutation data were available for 18 pts receiving imetelstat, all with SF3B1 mutations present at baseline, and multiple of these pts concurrently had TET2, DNMT3A, ASXL1, or JAK2 mutations. The maximal reduction ranged from −6% to −100% in SF3B1 variant allele frequency (VAF) in these pts, and 13 of 18 (72.2%) achieved ≥50% VAF reduction, including 7 with complete elimination of the VAF. Reduction in other concurrent mutations was also observed in these pts. Safety was consistent with that previously reported; most frequent adverse events were reversible grade 3 or 4 thrombocytopenia and neutropenia. At the time of data cutoff (May 10, 2023), 13 pts receiving imetelstat and the pt receiving placebo were ongoing (Figure); of the 8 who discontinued treatment, 7 had loss of response, and 1 was due to adverse event. Analyses for progression-free and overall survival were not evaluable as of this cutoff date (insufficient follow-up). Treatment with imetelstat resulted in ≥1-year sustained, continuous TI in 17.8% of pts in the IMerge phase 3 trial. In this ESA-R/R/ineligible population with a high prior transfusion burden, a reduction to 0 RBC transfusions for ≥1 year represents an opportunity to achieve relief from iron overload and other transfusion associated complications, and decreased demand on already limited blood product supply. Furthermore, durable TI and meaningful reductions in mutational burden suggest imetelstat may have disease-modifying activity.

CONCLUSIONS Imetelstat, a first-in-class telomerase inhibitor, showed higher rates of red blood cell (RBC) transfusion independence (TI) for ≥8 weeks, ≥24 weeks, and ≥1 year (39.8%, 28.0%, and 17.8%) than placebo (15.0%, 3.3%, and 1.7%) in the IMerge (NCT02598661) phase 3 study of patients with RBC transfusion-dependent non-del(5q) lower-risk myelodysplastic syndromes (LR-MDS) relapsed/refractory to erythropoiesis-stimulating agents (Platzbecker et al. EHA 2023. Abstr S165). To evaluate the impact of MDS-associated mutations on clinical efficacy of imetelstat, we performed next-generation sequencing of a panel of 36 genes, recurrently mutated in MDS, using DNA samples from peripheral blood collected at study entry. Further analysis of TI responses to imetelstat was performed across different mutation subgroups, defined based on genes involved in different biological functions, including the splicing process, epigenetic modifiers, transcription regulation, and receptors/kinases. Baseline mutation data were available in 165 of 178 patients (imetelstat, n = 110; placebo, n = 55; 93.2% and 91.7% of total in each group, respectively). Of patients with mutation data, 161 (97.6%) had ≥1 mutation detected, among whom, 75 (70.1%), 33 (30.8%), and 9 (8.4%) patients in the imetelstat group and 38 (70.4%), 15 (27.8%), and 7 (13%) patients in the placebo group had >1, >2, and >3 mutations, respectively. The ≥8-week TI rates in the imetelstat vs placebo groups were 42.7% vs 15.8% ( P = .006) for patients with >1 mutation, 45.5% vs 6.7% ( P = .012) for patients with >2 mutations, and 55.6% vs 14.3% ( P = .089) for patients with >3 mutations, respectively. The ≥24-week TI rates were 26.7% vs 2.6% ( P = .003), 33.3% vs 0% ( P = .014), and 33.3% vs 0% ( P = .117), respectively. In patients with mutations associated with poor prognosis ( TP53, ETV6, RUNX1, ASXL1 or EZH2), 31.8% and 9.1% of patients in the imetelstat group achieved ≥8-week and ≥24-week TI vs 0 of those in the placebo group. TP53 mutations were detected in 2 patients in each group; both patients in the imetelstat group and none in the placebo group had ≥8-week TI. Among patients with ASXL1 mutations, 5 of 18 patients (27.8%) in the imetelstat and 0 of 6 (0) in placebo group had ≥8-week TI. Among patients with ETV6 mutations, 1 of 2 (50%) in the imetelstat group and 0 of 1 patients in the placebo group had ≥8-week TI. Two patients in each group had RUNX1 mutations; none achieved TI. Imetelstat ≥8-week TI rates were 43.8%, 37.7%, 40.0%, and 80.0% for patients harboring mutated genes in the RNA spliceosome, epigenetic modifiers, transcription regulation, and receptors/kinases, respectively; ≥24-week TI was 30.2%, 27.5%, 20.0%, and 80.0%, respectively. The most frequently mutated gene was SF3B1 (125 of 165; 75.8%), the ≥8-week and ≥24-week TI rates were 48.8% vs 16.3% ( P = .001) and 35.4% vs 2.3% ( P < .001) with imetelstat vs placebo. In the imetelstat group, ≥8-week TI was achieved in patients with different spectrum of SF3B1 hot-spot mutations: 2 of 8 patients (25.0%) with E622D, 4 of 7 (57.1%) with R625C/L/G, 7 of 12 (58.3%) with H662Q/N/D/Y, 2 of 2 (100%) with T663P, 2 of 6 (33.3%) with K666R/T/Q/N, 18 of 41 (43.9%) with K700E, 2 of 2 (100%) with A744P, and 1 of 2 patients (50.0%) with E783K. Durable ≥24-week TI was also observed in patients with these hot-spot mutations. Other genes with mutation frequency >10% were TET2 (32.7%), DNMT3A (17.0%), ASXL1 (14.5%), and CUX1 (12.7%). The ≥8-week TI rates in the imetelstat group vs placebo group were 50% vs 21.4% for TET2 mutations; 31.6% vs 22.2% for DNMT3A mutations; 27.8% vs 0 for ASXL1 mutations; 35.7% vs 14.3% for CUX1 mutations (Figure). The ≥24-week TI rates were 40% vs 0, 26.3% vs 11.1%, 11.1% vs 0, and 14.3% vs 0, respectively, for those mutations (Figure). Higher RBC-TI rates were observed in patients with various baseline mutational profiles treated with imetelstat compared with placebo in IMerge. While the sample size for specific mutations was small, consistent with the observation that patients with LR-MDS have a low number of specific mutations, TI responses in patients receiving imetelstat occurred regardless of the presence of mutations associated with poor prognosis or the number of mutations. Imetelstat showed comparable TI rates across different molecularly defined subgroups, suggesting that clinical benefit of imetelstat in patients with LR-MDS is independent of the underlying molecular pattern.

Background: Unmet need remains for novel therapies after failure of erythropoiesis stimulating agents (ESAs) in red blood cell (RBC) transfusion dependent (TD) lower-risk myelodysplastic syndromes (LR-MDS). In IMerge Phase 2 (NCT02598661), treatment with imetelstat, a telomerase inhibitor, resulted in prolonged, durable transfusion independence (TI) across a broad range of heavily RBC TD ESA relapsed/refractory non-del(5q) LR-MDS patients (pts) naive to lenalidomide and hypomethylating agents (len/HMA). Aims: Evaluate the efficacy and safety of imetelstat vs placebo in this pt population in IMerge Phase 3. Methods: Heavily RBC TD ESA relapsed/refractory/ineligible (R/R) non-del(5q) LR-MDS pts naive to len/HMA were randomized 2:1 to receive imetelstat 7.5 mg/kg (N=118) or placebo (N=60) every 4 wks. The primary endpoint was 8-wk TI rate; subgroup analyses included IPSS risk, prior transfusion burden, and ring sideroblasts (RS) status. Secondary endpoints included 24-wk TI rate, TI duration, and hematologic improvement-erythroid (HI-E) rate. Change in mutation burden (variant allele frequency [VAF]) was exploratory. The primary analysis cutoff was Oct 2022; cutoff for ≥1-yr TI was Jan 2023. The primary and key secondary endpoints were compared using a Cochran-Mantel-Haenszel test stratified by prior transfusion burden and IPSS category. TI duration was calculated by Kaplan-Meier method and compared by stratified log-rank test. Results: The primary endpoint was met; 47 pts (39.8%) vs 9 pts (15.0%) receiving imetelstat vs placebo achieved 8-wk TI, P < 0.001. The rate of 8-wk TI was also significantly higher with imetelstat vs placebo across subgroups, including in RS negative pts. Median TI duration (95% CI) was 51.6 (26.9–83.9) wks with imetelstat vs 13.3 (8.0–24.9) wks with placebo, P < 0.001. Twenty-four-wk TI was achieved in 33 pts (28.0%) vs 2 pts (3.3%) receiving imetelstat vs placebo, P < 0.001. With 3 months’ additional follow-up, 21 pts (17.8%) on imetelstat vs 1 pt (1.7%) on placebo achieved ≥1-yr TI, P = 0.002, representing 63.6% of ≥24-wk TI imetelstat responders (Figure). HI-E rates (2018 IWG, emphasizing >16-wk response) were 42.4% with imetelstat vs 13.3% with placebo, P < 0.001. Pts receiving imetelstat had significantly higher mean hemoglobin (P < 0.001) and fewer transfusions (P = 0.042) over time than those on placebo. VAF reduction in 3 genes frequently mutated in MDS was significantly greater in pts treated with imetelstat than placebo: SF3B1 (P < 0.001), TET2 (P = 0.032), DNMT3A (P = 0.019) and ASXL1 (P = NS). SF3B1 VAF reduction correlated with longer TI duration in imetelstat-treated pts, P < 0.001. No new safety signals were identified in IMerge P3. The most common Grade 3/4 AEs with imetelstat were thrombocytopenia and neutropenia; similar rates of Grade ≥3 bleeding and infections were observed on imetelstat and placebo. Cytopenias with imetelstat were of short duration, and >80% resolved to Grade ≤2 within 4 wks. Summary/Conclusion: Imetelstat demonstrated statistically significant and clinically meaningful efficacy with robust 8-wk, 24-wk, and 1-yr TI rates and durable continuous TI. For this LR-MDS patient population, almost one fifth of imetelstat-treated pts achieved continuous TI for ≥1 yr, representing substantial relief from transfusion-associated complications. VAF reduction and its correlation to clinical endpoints, including durable TI, support imetelstat’s disease-modifying potential. Safety results were consistent with prior reports. Imetelstat treatment provides significant clinical benefit to a heavily TD LR MDS pt population in need of novel therapy.Keywords: Therapy, Clinical trial, Myelodysplastic syndrome, Telomerase activity