Type: Oral
Session: 637. Myelodysplastic Syndromes – Clinical and Epidemiological II
Hematology Disease Topics & Pathways:
Research, Non-Biological therapies, Clinical Research, Therapies, Study Population, Human
Methods: IMerge (MDS3001; NCT02598661) is a global, phase 2/3 study of imetelstat in RBC TD, ESA-R/R LR-MDS. After an initial analysis, the phase 2 study was expanded to include patients with no prior HMA or lenalidomide and a non-del(5q) MDS subtype. Imetelstat was administered as a 2-hour intravenous infusion every 4 weeks at 7.5 mg/kg. The primary end point was 8-week TI rate. Secondary end points included safety, 24-week TI rate, MDS response, overall survival (OS), progression free survival (PFS), and time to progression (TTP) to acute myeloid leukemia (AML). The proportion of patients with 8-week, 24-week, and 1-year TI, and other binary end points, were summarized with percentage and 95% 2-sided exact Clopper-Pearson CI. The Kaplan-Meier (KM) method was used to estimate the distribution of duration of TI, OS, PFS, and TTP to AML.
Results: Of 57 patients enrolled and treated in the phase 2 study, 38 patients were in the non-del(5q) and lenalidomide/HMA-naive subset. Of these 38, 11 (29%) achieved >1-year sustained TI, representing 69% of the ≥8-week TI responders (n = 16) and 92% of the ≥24-week TI responders (n = 12). Furthermore, 27 of the 38 patients were MDS-RS, and of these, 10 (37%) achieved TI for >1 year. The prior RBC transfusion burden for the 11 patients who achieved >1 year of sustained TI was 6 units over 8 weeks, and additional baseline characteristics can be found in the table. These 11 patients were treated with imetelstat for a median of 126.1 weeks (range, 70.1-168.1) for a median of 27 cycles (range, 18-40). The median duration of TI was 92.4 weeks (95% CI, 69.6-140.9; Figure). After a median follow-up of 51.5 months, median PFS was 34.2 months (95% CI, 25.1-39.2), median OS was 57.0 months (95% CI, 29.4 to NE), and none of the 11 patients progressed to AML. Of the patients with TI duration >1 year, 9 had mutation data available; 8 (89%) demonstrated a reduction in SF3B1 variant allele frequency (VAF), and 5 (56%) achieved ≥50% VAF reduction. Reduction in VAF correlated with longer TI duration (median, >20 months) and shorter time to onset of TI (<10 weeks). Safety findings were consistent with those of the overall population; the most frequent adverse events were reversible thrombocytopenia and neutropenia.
Conclusions: Treatment with imetelstat achieved >1 year sustained, continuous TI in 29% of RBC TD, ESA-R/R LR-MDS patients who were non-del(5q) and lenalidomide/HMA-naïve and was safe and well tolerated. Of the overall population, attainment of 24-week TI was indicative of a likelihood to achieve TI >1 year. In this ESA-R/R population with a high transfusion burden prior to treatment, a decrease to zero RBC transfusions for a period >1 year represents relief from iron overload and other transfusion-associated complications, and decreased demand on health care resources. Furthermore, durable TI, meaningful reduction in mutational burden, and good survival post-ESA suggest imetelstat may have disease-modifying activity not expected with currently available therapies. Enrollment is complete for the phase 3 part of IMerge, a randomized (2:1) double-blind, placebo-controlled trial to compare efficacy of imetelstat versus placebo in TD, ESA-R/R, non-del(5q), lenalidomide/HMA-naive LR-MDS; results from the primary analysis are expected in early January 2023.
Disclosures: Platzbecker: Geron: Honoraria; Jazz: Honoraria; Abbvie: Honoraria; BMS/Celgene: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Silence Therapeutics: Honoraria; Janssen: Honoraria. Komrokji: PharmaEssentia: Honoraria, Other, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Geron: Honoraria, Membership on an entity's Board of Directors or advisory committees; CTI biopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servio: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Taiho: Honoraria, Membership on an entity's Board of Directors or advisory committees. Fenaux: AbbVie, BMS, Janssen, Jazz, Novartis: Consultancy, Honoraria, Research Funding. Sekeres: Takeda/Millenium: Membership on an entity's Board of Directors or advisory committees; Bristol Myers-Squibb: Membership on an entity's Board of Directors or advisory committees; Kurome: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Savona: Karyopharm: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Ryvu: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Other: serves on Data and Safety Monitoring Boards; TG Therapeutics: Research Funding; Incyte: Research Funding; Astex: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Taiho: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Geron: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Forma: Consultancy; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: serves on Data and Safety Monitoring Boards; ALX Oncology: Research Funding. Madanat: BluePrint Medicines, GERON, OncLiv: Consultancy, Honoraria; Sierra Oncology, Stemline Therapeutics, Morphosys, Taiho, and Novartis: Membership on an entity's Board of Directors or advisory committees. Raza: Taiho: Consultancy; Epizyme: Consultancy. Germing: Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria. Sherman: Geron Corporation: Current Employment, Current equity holder in publicly-traded company. Berry: Geron Corporation: Current Employment, Current equity holder in publicly-traded company. Dougherty: Geron Corporation: Current Employment, Current equity holder in publicly-traded company. Shah: Geron: Current Employment, Current equity holder in publicly-traded company. Sun: Geron Corporation: Current Employment, Current equity holder in publicly-traded company. Wan: Geron Corporation: Current Employment, Current equity holder in publicly-traded company. Huang: Geron Corporation: Current Employment, Current equity holder in publicly-traded company. Ikin: Geron: Current Employment, Current equity holder in publicly-traded company. Feller: Geron Corporation: Current Employment, Current equity holder in publicly-traded company. Zeidan: BMS, AbbVie, Takeda, Novartis, Aprea, Amgen, Otsuka, Gilead, Kura, Loxo Oncology, Geron, Mendus, Tyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Santini: Takeda: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Otsuka: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees; Geron: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees.
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