IMerge (NCT02598661) is a phase 2/3 global study of imetelstat, a first-in-class telomerase inhibitor, for patients with RBC transfusion-dependent non-del(5q) LR-MDS R/R to or ineligible for ESAs, a population with unmet needs. Phase 3 results showed that the rate of ≥8-week, ≥24-week and 1-year RBC-TI was higher with imetelstat than placebo (Zeidan et al. ASCO 2023. Abstr 7004; Platzbecker et al. EHA 2023. Abstr S165).

Toevaluate clinical efficacy of imetelstat across different International Prognostic Scoring System (IPSS), revised IPSS (IPSS-R), IPSS-R cytogenetic, or IPSS-molecular (IPSS-M) risk categories,cytogenetic analysis was performed centrally on bone marrow aspirates by karyotyping, and mutation profile was analyzed using peripheral blood samples by next-generation sequencing on a panel of 36 genes commonly mutated in MDS. Baseline IPSS, IPSS-R, IPSS-R cytogenetic, or IPSS-M risk categories were derived for patients in the phase 3 portion of IMerge based on specific classification criteria, and rates of RBC-TI ≥8-week, ≥24-week, ≥1-year were assessed for each risk subgroup.

In 105 IPSS-low patients, 95 (90.5%) remained IPSS-M very low/low/moderate low, and 10 patients (9.5%) upstaged to IPSS-M moderate high and high. In 50 IPSS-intermediate-1 patients, 39 (78%) remained IPSS-M very low/low/moderate low, and 11 patients (22%) upstaged to IPSS-M moderate high/high. Among 129 IPSS-R low/very low patients, 118 (91.5%) remained IPSS-M very low/low/moderate low, and 11 (8.5%) patients upstaged to IPSS-moderate high/high. In 25 IPSS-R-intermediate patients, 16 (64%) remained IPSS-M low/moderate low, and 9 patients (36%) upstaged to IPSS-M moderate high/high/very high. One IPSS-R high-risk patient remained IPSS-M high.

Overall, significantly higher rates of ≥8-week, ≥24-week, and ≥1-year RBC-TI were achieved in patients receiving imetelstat (39.8%, 28%, and 13.6%) vs those receiving placebo (15%, 3.3%, and 1.7%). Further subgroup analysis demonstrated that imetelstat consistently had higher TI response rates than placebo across different risk subgroups, irrespective of classification system.

For IPSS risk groups, the TI rates of ≥8-week, ≥24-week, and ≥1-year with imetelstat vs placebo were 40.0% vs 20.5% ( P = 0.034), 28.8% vs 5.1% ( P = 0.003), and 12.5% vs 2.6% ( P = 0.082), respectively, in patients with low risk and 39.5% vs 4.8% ( P = 0.004), 26.3% vs 0% ( P = 0.009), and 15.8% vs 0% ( P = 0.048), respectively, in patients with intermediate-1 risk.

For IPSS-R risk groups, the TI rates of ≥8-week, ≥24-week, and ≥1-year with imetelstat vs placebo were 42.5% vs 19.6%, 29.9% vs 4.3%, and 11.5% vs 2.2%, respectively, in the low-risk subgroup. The TI rates of ≥8-week, ≥24-week, ≥1-year TI with imetelstat were 35%, 25%, and 20%, respectively, in the intermediate-risk subgroup, whereas placebo treatment had no response. The number of patients was too low in both arms of the very low or high IPSS-R subgroups to assess difference in TI response.

For IPSS-R cytogenetic risk groups, the TI rates of ≥8-week, ≥24-week, and ≥1-year with imetelstat vs placebo were 37.1% vs 17.0%, 24.7% vs 4.3%, and 10.1% vs 2.1%, respectively, in very good/good risk groups and 54.5% vs 11.1%, 40.9% vs 0%, and 22.7% vs 0%, respectively, in the intermediate-risk group.

For IPSS-M risk groups, the TI rates of ≥8-week, ≥24-week, and ≥1-year with imetelstat vs placebo were 47.8% vs 21.2%, 34.8% vs 3%, and 14.5% vs 0%, respectively, in patients with very low/low risk and 20.7% vs 6.3%, 10.3% vs 0%, and 6.9% vs 0%, respectively, in patients with moderate low/moderate high risk. In patients with high/very high risk, ≥8-week TI rates were 40% vs 0% with imetelstat vs placebo, with no ≥24-week or ≥1-year TI observed in either arm. All results are summarized in the Table.

Improvement in RBC-TI rates was observed in patients treated with imetelstat vs placebo across different risk subgroups as defined by IPSS, IPSS-R, IPSS-R cytogenetic, or IPSS-M risk profiles. Notably, placebo had not achieved durable (≥24-week and ≥1-year) TI response in the higher-risk groups irrespective of the risk classification assessment model used, while TI response rates with imetelstat in higher-risk subgroups with poor prognosis were similar to TI response rates in lower-risk subgroups of heavily transfused R/R ESA LR-MDS, indicating that clinical efficacy of imetelstat is independent of risk categories.

Komrokji:AbbVie, CTI biopharma, Jazz, Pharma Essentia, Servio: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Geron: Consultancy; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Rigel, Taiho, DSI: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Santini:Syros: Other: Advisory boards; Janssen: Other: travel grant; CTI: Other: Advisory boards; Geron: Other: Advisory boards; Gilead: Other: Advisory boards; BMS/Celgene: Other: Advisory boards; Novartis: Other: Advisory boards; Otsuka: Other: Advisory boards; Servier: Other: Advisory boards; AbbVie: Other: Advisory boards. Fenaux:Janssen: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; French MDS Group: Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Savona:Incyte: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding; AbbVie: Consultancy; BMS/Celgene: Consultancy; Forma: Consultancy; Geron: Consultancy; Karyopharm: Consultancy, Current equity holder in publicly-traded company; Novartis: Consultancy; Ryvu: Consultancy, Current equity holder in publicly-traded company; Sierra Oncology: Consultancy; Taiho: Consultancy; Takeda: Consultancy; TG Therapeutics: Consultancy; Astex: Research Funding; ALX Oncology: Research Funding. Madanat:Blueprint Medicines: Consultancy, Honoraria, Other: travel reimbursement; MD Education: Honoraria; OncLive: Honoraria; Novartis: Honoraria; Taiho oncology: Honoraria; Stemline therapeutics: Honoraria; Morphosys: Honoraria, Other: travel reimbursement; Sierra Oncology: Honoraria; GERON: Consultancy; Rigel Pharmaceuticals: Honoraria. Berry:Geron: Current Employment, Current equity holder in publicly-traded company. Sherman:Geron: Current Employment, Current equity holder in publicly-traded company. Navada:Geron Corporation: Current Employment, Current equity holder in publicly-traded company. Feller:Geron: Current Employment, Current equity holder in publicly-traded company. Sun:Geron: Current Employment, Current equity holder in publicly-traded company. Xia:Geron: Current Employment, Current equity holder in publicly-traded company. Wan:Geron: Current Employment, Current equity holder in publicly-traded company. Huang:Geron: Current Employment, Current equity holder in publicly-traded company. Zeidan:Otsuka: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Taiho: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Schrödinger: Consultancy, Honoraria; Ionis: Consultancy, Honoraria; ALX Oncology: Consultancy, Honoraria; Chiesi: Consultancy, Honoraria; Kura: Consultancy, Honoraria; BioCryst: Consultancy, Honoraria; Zentalis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; BeyondSpring: Consultancy, Honoraria; Celgene/BMS: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Geron: Consultancy, Honoraria; Notable: Consultancy, Honoraria; Lox Oncology: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Orum: Consultancy, Honoraria; Syros: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Boehringer-Ingelheim: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Foran: Consultancy, Research Funding; Astex: Research Funding; Shattuck Labs: Research Funding; Regeneron: Consultancy, Honoraria; Tyme: Consultancy, Honoraria; Mendus: Consultancy, Honoraria; Syndax: Consultancy, Honoraria. Platzbecker:AbbVie: Consultancy; Janssen Biotech: Consultancy, Research Funding; Merck: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; MDS Foundation: Membership on an entity's Board of Directors or advisory committees; Curis: Consultancy, Research Funding; Servier: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Fibrogen: Research Funding; Syros: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria, Research Funding; Roche: Research Funding; Silence Therapeutics: Consultancy, Honoraria, Research Funding; Celgene: Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; medical writing support, Research Funding; Amgen: Consultancy, Research Funding; Geron: Consultancy, Research Funding; BeiGene: Research Funding; BMS: Research Funding.

Imetelstat to treat lower-risk myelodysplastic syndromes relapsed/refractory to or ineligible for erythropoiesis-stimulating agents

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2023
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