FDA Approves Imetelstat for Low- to Intermediate-1–Risk MDS With Transfusion-Dependent Anemia


Key Takeaways

  • Imetelstat significantly improved RBC transfusion independence rates in MDS patients compared to placebo in the phase 3 IMERGE study.
  • The 8-week RBC transfusion independence rate was 39.8% with imetelstat vs 15% with placebo.


The FDA has approved imetelstat (Rytelo) for adults with low- to intermediate-1–risk myelodysplastic syndrome (MDS) and transfusion-dependent anemia requiring four or more red blood cell (RBC) units over 8 weeks who have not responded to or have lost response to or are not eligible for erythropoiesis-stimulating agents (ESAs).1-3

The decision was supported by findings from the phase 3 IMerge study (NCT02598661), which showed that patients who received imetelstat (n = 118) experienced an 8-week RBC transfusion independence (RBC-TI) rate of 39.8% (95% CI, 30.9%-49.3%) vs 15% (95% CI, 7.1%-26.6%) for those who received placebo (n = 59; P <.001).

About IMerge: Eligibility, Treatment, Objectives

The randomized, double-blind, phase 3 trial enrolled patients with International Prognostic Scoring System (IPSS) low- or intermediate 1–risk MDS that was relapsed/refractory to an ESA or erythropoietin of more than 500 mU/mL if they were ineligible for an ESA.2 Patients also needed to be transfusion dependent, requiring at least 4 units of RBCs per 8 weeks over a 16-week pre-study. Patients could not have 5q deletions or have previously received lenalidomide (Revlimid) or hypomethylating agents.

Participants were randomly assigned 2:1 to receive 7.1 mg/kg of intravenous imetelstat in 28-day treatment cycles or matching placebo. Stratification factors included transfusion burden (4 to 6 units vs >6 units) and IPSS risk category (low vs intermediate 1). All participants received supportive care, which included RBC transfusions.

The trial’s primary end point was rate of 8-week RBC-TI. Secondary end points included 24-week RBC-TI, duration of TI, hematologic improvement–erythroid (HI-E), and safety.

Efficacy was established after a median follow-up time of 19.5 months (range, 1.4-36.2) in the imetelstat arm and 17.5 months (range, 0.7-34.3) in the placebo arn based upon the proportion of patients who achieved 8-week or longer and 24-week or longer RBC TI.1

Additional Data

The 16-, 24-, and 52-week RBC-TI rates with imetelstat were 31.4% (95% CI, 23.1%-40.5%), 28.0% (95% CI, 20.1%-37.0%), and 13.6% (95% CI, 8.0%-21.1%), respectively, vs 6.7% (95% CI, 1.9%-16.2%), 3.3% (95% CI, 0.4%-11.5%), and 1.7% (95% CI, 0%-8.9%) with placebo, respectively.

The median duration of RBC-TI was 51.6 weeks (95% CI, 26.9-83.9) with imetelstat vs 13.3 (95% CI, 8.0-24.9) with placebo (HR, 0.23; 95% CI, 0.09-0.57; P < .001). In the entire study population, the median duration of the longest RBC-TI interval was 5.0 weeks (95% CI, 4.0-7.7) with imetelstat vs 3.9 weeks (95% CI, 3.6-4.0) with placebo.

Among evaluable 8-week RBC-TI responders, those who in the imetelstat arm (n = 47) experienced a median hemoglobin rise of 3.6 g/dL (range, –0.1 to 13.8) vs 0.8 g/dL (range, –0.2 to 1.7) for those in the placebo arm (n = 9). The median hemoglobin peak was 11.3 g/dL (range, 8.0-21.9) vs 8.9 g/dL (range, 7.9-9.7), respectively.

The rate of HI-E was 64% with imetelstat vs 52% with placebo, failing to show a significant difference between arms (P < .112). Additionally, neither complete or partial response occurred with either imetelstat or placebo. Stable disease was achieved by 69% of patients given imetelstat vs 68% of those who received placebo. Disease progression occurred in 6% and 3% of patients, respectively. Twenty-four percent and 28% of patients were not evaluable, largely owing to absent post-baseline bone marrow assessment.

At the time of the primary analysis, the hazard ratio for OS was 1.07 (95% CI, 0.46-2.48). At the time of the updated analysis with over 2 years of follow-up, the hazard ratio for OS was 0.98 (95% CI, 0.53-1.82). Specifically, the median OS was 40.4 months (95% CI, 37.1-not estimable [NE]) with imetelstat and NE (95% CI, 32.2-NE) with placebo.

PRO analysis revealed no difference in the deterioration in FACIT fatigue, at 43% and 46% with imetelstat and placebo, respectively. However, PROs were evaluated infrequently, according to the FDA, with available data dropping to below 50% after cycle 8 of treatment. Fifty percent or higher reductions in variant allele frequency in SF3B1 (29.5% vs 2.6%), TET2 (34.3% vs 8.3%), DNMT3A (11.1% vs 0.0%), and ASXL1 (40.0% vs 16.7%) occurred in higher percentages of those in the imetelstat arm vs those in the placebo arm, respectively.

Safety Insights

Grade 3/4 adverse effects (AEs) were experienced by 91% of patients on imetelstat vs 48% of those on placebo. Serious AEs occurred in 32% and 22% of patients, respectively. Fourteen of patients experienced AEs that resulted in discontinuation of imetelstat. AE-related dose reduction or delay were required in 70% of those in the imetelstat arm vs 24% of those on the placebo arm.

Grade 3/4 cytopenia was significantly more common with imetelstat vs placebo, with decreased rates of neutrophil counts, leukocyte counts, and platelet counts of 71%, 53%, and 65%, vs 7%, 1.7%, and 8%, respectively. This led to a greater need for myeloid growth factor (35% vs 3%) and platelet transfusion (18% vs 2%) for those on imetelstat vs placebo. Despite these interventions, the rates of grade 3/4 infections and hemorrhage were 11% (all grade, 42%) and 2.5% (all grade, 21%) with imetelstat.

The most common toxicities experienced by 10% or more of patients, including laboratory abnormalities, comprised decreased platelet counts, decreased white blood cells, decreased neutrophil counts, increased aspartate aminotransferase, increased alkaline phosphatase, increased alanine aminotransferase, fatigue, prolonged partial thromboplastin time, arthralgia/myalgia, COVID-19 infections, and headache.

The Road to Approval

In March 2024, The FDA’s Oncologic Drugs Advisory Committee voted 12 to 2 that the benefits of imetelstat outweigh its risks for the treatment of transfusion-dependent anemia in adult patients with IPSS low- to intermediate-1–risk MDS who have not responded to, have lost response to, or are ineligible for ESAs.2


  1. FDA approves imetelstat for low- to intermediate-1 risk myelodysplastic syndromes with transfusion-dependent anemia. FDA. June 6, 2024. Accessed June 6, 2024.
  2. March 14, 2024, Meeting of the Oncologic Drugs Advisory Committee (ODAC). FDA.
  3. Zeidan AM, Platzbecker U, Santini V, et al. IMerge: results from a phase 3, randomized, double-blind, placebo-controlled study of imetelstat in patients (pts) with heavily transfusion dependent (TD) non-del(5q) lower-risk myelodysplastic syndromes (LR-MDS) relapsed/refractory (R/R) to erythropoiesis stimulating agents (ESA). J Clin Oncol. 2023;41(suppl 16):7004. doi:10.1200/JCO.2023.41.16_suppl.7004
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