Post Hoc Analysis Shows Imetelstat Drives Benefit in RS-Negative, Lower-Risk MDS

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Imetelstat (Rytelo) demonstrated clinical benefit in patients with ring sideroblast (RS)–negative lower-risk myelodysplastic syndromes (MDS) who were relapsed/refractory to or ineligible for erythropoiesis-stimulating agents (ESAs), according to data from a post hoc analysis from pooled populations from the phase 2/3 IMerge trial (NCT02598661).1

The data, which were presented at the 2025 EHA Congress, revealed that among 78 patients with RS-negative disease treated with imetelstat, 33%, 21%, and 13% of patients had red blood cell transfusion independence (RBC-TI) at 8 or more weeks, 24 or more weeks, and at least 1 year, respectively. Additionally, 56% of patients demonstrated high improvement–erythroid (HI-E) per the International Working Group (IWG) 2006 at any point; 55% of patients experienced transfusion reductions of 4 or more units per 8 weeks, and 24% saw a rise in hemoglobin by at least 1.5 g/dL per 8 weeks. Additionally, in the overall population, 40% of patients experienced HI-E per the IWG 2018. Of note, this rate was 36% in patients with low transfusion burden (n = 11) and 40% in patients with high transfusion burden (n = 67).

“A rise in hemoglobin was observed in [patients with] RS-negative MDS who achieved RBC-TI with imetelstat,” lead study author Valeria Santini, MD, and colleagues wrote in a poster presentation of the data. “This analysis was limited by differing methodologies of the phase 2/3 and QT correction [QTc] substudy parts of [the] IMerge [study] and by the small number of patients in some subgroups.”

Santini is an associate professor of hematology at the University of Florence in Italy.

Background and the Post Hoc Analysis Methodology

In June 2024, the FDA approved imetelstat for the treatment of adult patients with low- to intermediate-1–risk MDS and transfusion-dependent anemia, requiring 4 or more RBC units over 8 weeks, who were relapsed/refractory to or ineligible for ESAs.2 The regulatory decision was supported by data from the phase 3 IMerge study, which evaluated intravenous infusion of imetelstat at 7.5 mg/kg compared with placebo in 28-day treatment cycles until disease progression or unacceptable toxicity.1,2

The post hoc analysis included pooled patient populations from 3 parts of the IMerge study, including the phase 2 portion (single-arm, open-label), the phase 3 portion (double-blind, randomized 2:1), and the QTc substudy of the phase 3 portion (double-blind, randomized 2:1).

Specifically, the phase 2 portion included all patients treated with imetelstat (n = 57); these patients had International Prognostic Scoring System (IPSS) low- or intermediate-1–risk MDS, were relapsed/refractory to ESA or erythropoietin (EPO) at 500 mU/mL or greater, were transfusion dependent (≥4 RBC units/8 weeks over 16-week prestudy period), and were allowed to have 5q deletions and prior lenalidomide (Revlimid) and a hypomethylating agent (HMA). Furthermore, the intention-to-treat population (ITT; n = 118) from the phase 3 portion of the IMerge study included patients with IPSS low- or intermediate-1–risk MDS who were relapsed/refractory to ESAs or EPO at 500 mU/mL or greater, transfusion dependent (≥4 RBC U/8 weeks over 16-week prestudy period), and without 5q deletions and no prior lenalidomide and HMA use. The QTc substudy (n = 35) differed from that of the phase 3 portion of the study, in which patients with 5q deletions were included, prior lenalidomide and HMA use was permitted, and patients had the option to cross over from placebo to imetelstat (n = 16) after 2 cycles at investigator discretion.

The efficacy end points of the post hoc analysis included 8-week or greater and 24-week or greater RBC-TI rates, and HI-E per IWG 2006 and 2018. Of note, patient-reported outcomes (PROs) were assessed with the validated Functional Assessment of Chronic Illness Therapy (FACIT)–Fatigue. The PROs regarding FACIT-Fatigue were an exploratory outcome that was analyzed during the phase 3 portion of the IMerge study; thus, the data were not available in the phase 2 or QTc substudy sections.

Baseline Patient Characteristics

Among 78 patients with RS-negative MDS from the pooled population of the 3 studies, the median age was 71.0 years (range, 44-86), and the majority were male (63%). The median time since diagnosis was 2.8 years (range, 0.1-12.9). Moreover, the IPSS risk category included low (60%) and intermediate-1 (40%). The median pretreatment hemoglobin level was 77 g/dL (range, 51-101), and the median prior RBC transfusion burden was 6.5 RBC units per 8 weeks (range, 4-33). Prior RBC transfusion burden included 6 units per 8 weeks or less (50%) and greater than 6 units per 8 weeks (50%). Furthermore, the median serum EPO level was 422 mU/mL (range, 16-5424), of which serum EPO levels included 500 mU/mL or less (51%), 500 mU/mL or greater (46%), and missing (3%). Prior treatments received included ESAs (79%), luspatercept-aamt (Reblozyl; 6%), lenalidomide (10%), and HMA (9%). Mutation status at baseline included at least 1 (63%), at least 2 (29%), and missing (12%); mutated genes included SF3B1 (42%), TET2 (29%), ASXL1 (19%), DNMT3A (17%), and SRSF2 (15%).

Additional Efficacy and PROs Data

Notably, the median length of the RBC-TI period for 8-weeks-or-greater responders, 24-weeks-or-greater responders, and 1-year-or-greater responders indicated durable TI beyond the outcome threshold. Specifically, the duration of response in patients who achieved RBC-TI with imetelstat was 44 weeks at 8 weeks or greater (n = 26), 123 weeks at 24 weeks or greater (n = 16), and 141 weeks at 1 year or greater (n = 10). Additionally, the median changes in hemoglobin in the longest RBC-TI interval in these respective groups were 4.3 g/dL, 5.2 g/dL, and 5.3 g/dL.

Regarding the PROs, of 118 and 57 evaluable patients treated with imetelstat and placebo, 44 and 20 had RS-negative status, respectively. Fatigue improvement was observed in 43% and 30% of patients treated in the respective arms.

“In this post hoc analysis of the 3 parts of IMerge, patients with RS-negative low-risk MDS who were relapsed or refractory to or ineligible for ESAs appeared to experience clinical benefit with imetelstat treatment,” the study authors concluded in the poster.

References

1. Santini V, Platzbecker U, Zeidan AM, et al. Outcomes of imetelstat therapy in patients with ring sideroblast–negative lower-risk myelodysplastic syndromes from the pooled IMerge study populations. Presented at: 2025 European Hematology Association Congress; June 12-15, 2025; Milan, Italy. Abstract PS1622.
2. FDA approves imetelstat for low-to intermediate-1 risk myelodysplastic syndromes with transfusion-dependent anemia. FDA. June 6, 2025. Accessed June 17, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-imetelstat-low-intermediate-1-risk-myelodysplastic-syndromes-transfusion-dependent