-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

459 Imetelstat Achieved Prolonged, Continuous Transfusion Independence (TI) in Patients with Heavily Transfused Non-Del(5q) Lower-Risk Myelodysplastic Syndrome (LR-MDS) Relapsed/Refractory (R/R) to Erythropoiesis Stimulating Agents (ESAs) within the IMerge Phase 2 Study

Program: Oral and Poster Abstracts
Type: Oral
Session: 637. Myelodysplastic Syndromes – Clinical and Epidemiological II
Hematology Disease Topics & Pathways:
Research, Non-Biological therapies, Clinical Research, Therapies, Study Population, Human
Sunday, December 11, 2022: 5:00 PM

Uwe Platzbecker, MD1, Rami S. Komrokji, MD2, Pierre Fenaux3, Mikkael A. Sekeres, MD4, Michael Robert Savona5*, Yazan F. Madanat, MD6, Koen Van Eygen, MD7*, Azra Raza, MD8,9, Ulrich Germing10*, Laurie Sherman, BSN11, Tymara Berry, MD12*, Souria Dougherty, BS, MBA12*, Sheetal Shah12*, Libo Sun, PhD12*, Ying Wan, PhD11*, Fei Huang, PhD12*, Annat Ikin12*, Faye Feller, MD11, Amer M. Zeidan, MD13 and Valeria Santini, MD14

1University Hospital Leipzig, Leipzig, Germany
2Moffitt Cancer Center, Tampa, FL
3Hôpital St Louis/Paris 7 University, PARIS, FRA
4Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL
5Vanderbilt University Medical Center, Nashville, TN
6Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX
7UT Southwestern Medical Center, Dallas
8Columbia Presbyterian, New York, NY
9Myelodysplastic Syndrome Center, Columbia University Medical Center, New York, NY
10University Hospital of Düsseldorf, Düsseldorf, Germany
11Geron Corporation, Parsippany, NJ
12Geron Corporation, Parsippany
13Yale University School of Medicine, New Haven, CT
14DMSC, MDS Unit, AOU Careggi, University of Florence, Firenze, Italy

Background: Novel treatments that are both efficacious and safe are needed for patients with LR-MDS who are red blood cell (RBC) transfusion dependent (TD) and R/R to ESAs, especially for those with MDS with ring sideroblasts (RS), as primary resistance to ESAs is more frequent. Imetelstat is a first-in-class telomerase inhibitor that targets cells with high telomerase activity and human telomerase reverse transcriptase expression, both of which have been reported in MDS. In the phase 2 part of the IMerge study in patients with RBC TD, ESA-R/R LR-MDS, imetelstat led to a prolonged, durable TI rate (median TI duration, 65 weeks) across a broad range of heavily transfused patients; longer TI duration (median, 86 weeks) was seen in patients with non-del(5q) and lenalidomide/hypomethylating agent (HMA)-naive disease (Steensma. J Clin Oncol. 2021). Here, we describe the characteristics and clinical benefit for patients who were non-del(5q) and lenalidomide/HMA naive and had continued TI for >1 year while on imetelstat.

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.

*signifies non-member of ASH