In the primary analysis of the phase III randomized, double-blind, placebo-controlled IMerge trial, in those achieving the primary endpoint of 8-week transfusion independence, treatment with imetelstat significantly reduced transfusion dependence—for a median duration of 1 year—and improved a variety of other outcomes in patients with lower-risk myelodysplastic syndrome (MDS) dependent on red blood cell transfusions. The study of 178 patients met its primary and numerous secondary endpoints, reported Amer Methqal Zeidan, MBBS, MHS, Associate Professor of Internal Medicine at Yale School of Medicine and Yale Cancer Center, New Haven, Connecticut, at the 2023 ASCO Annual Meeting.¹

Amer Methqal Zeidan, MBBS, MHS

“Imetelstat demonstrated highly statistically significant and clinically meaningful benefit compared with placebo in this heavily transfusion-dependent, lower-risk myelodysplastic syndrome population in need of novel therapy,” Dr. Zeidan commented. “The majority of 8-week transfusion-independent responders [83%] experienced durable continuous red blood cell transfusion–independent episodes.”

Transfusion independence of at least 8 weeks was achieved by 39.8% of the imetelstat arm vs 15.0% of the placebo arm (P < .001), and transfusion independence for at least 24 weeks by 28.0% and 3.3%, respectively (P < .001). In responders, the median duration of transfusion independence was 51.6 weeks with imetelstat vs 13.3 weeks with placebo (hazard ratio [HR] = 0.23; P < .001), he reported.

Dr. Zeidan emphasized the refractoriness of the study population and the patients’ need for novel therapies. “These patients were getting almost one unit of red blood cells per week. This is how heavily transfused they were,” he noted.

Imetelstat is a first-in-class direct and competitive inhibitor of telomerase activity. It specifically targets malignant clones with abnormally high telomerase activity, enabling recovery of effective hematopoiesis. The phase II/III IMerge study is evaluating imetelstat in patients deemed at low- or intermediate-1 risk by the International Prognostic Scoring System; patients who lack deletion(5q) mutations, are heavily dependent on red blood cell transfusions (≥ 4 units per 8 weeks in the 16 weeks before entering the trial [or prior to study entry]), are relapsed or refractory to or ineligible for erythropoiesis-stimulating agents (ESAs); and are naive to lenalidomide and hypomethylating agents.

In the phase II portion, treatment induced durable and continuous transfusion independence; specifically, the primary endpoint—8-week transfusion independence—was achieved by 42% of patients, with a median duration of 86 weeks.² The current analysis constitutes the primary phase III results from IMerge in the same patient population.

Other Outcomes With Imetelstat

Patients responding to imetelstat achieved significantly higher hemoglobin levels (P < .001), reaching a median hemoglobin level of 11.3 g/dL, which reflected a median rise of 3.6 g/dL. With placebo, the median level achieved among responders was 8.9 g/dL, and the median increase was 0.8 g/dL (P < .001). Significant hematologic improvement was also observed with imetelstat vs placebo.

Dr. Zeidan called the drug’s effect on hemoglobin “one of the most impressive findings of this study…, as these patients are going from 8 g/dL to 11 g/dL. This is a huge rise that is not commonly seen,” he pointed out.

Noting that the benefit was seen across key subgroups, Dr. Zeidan highlighted two groups in particular: patients without ring sideroblasts, “who currently don’t have an indicated drug after ESA failure,” and those requiring at least six units of blood per 8 weeks. Approximately one-third of patients in each of these subgroups responded to imetelstat (vs less than 10% who responded to placebo), which represented absolute differences of 23% (P = .038) and 26% (P = .023), respectively, he noted.

Disease Modification Suggested

“What I also think is quite interesting with this drug, beyond the improvement in anemia, is that we are seeing signs of disease modification,” Dr. Zeidan stated. “Now that we have very good drugs, I think this is what we need to aim for in lower-risk disease.”

He referred to the reduction seen in the variant allele frequency of several genes commonly mutated in MDS. With placebo, minimal changes in these mutations were observed over baseline. However, patients receiving imetelstat experienced significant reductions in SF3B1 (P < .001), TET2 (P = .032), and DNMT3A (P = .019) as well as a nonsignificant reduction in AXSL1,” Dr. Zeidan noted.

The reduction in the SF3B1 variant allele frequency correlated with maximum increases in hemoglobin and longer duration of transfusion independence (P < .001). Changes in TET2, DNMT3A, and ASXL1 also correlated with a reduced need for transfusion.

No new safety signals were identified in this phase III analysis. The most common grade 3 or 4 adverse events were thrombocytopenia and neutropenia. According to the investigators, most of these events were manageable, of short duration (< 2 weeks), and reversible by treatment interruption. There was no increase in grade ≥ 3 bleeding or infection over placebo. Fewer than 15% discontinued treatment because of treatment-emergent adverse events, commented Dr. Zeidan.

More About the IMerge Population

For the 178 enrolled patients in the IMerge trial, the median patient age was 72; the median time since diagnosis was 3 years; 62% had ring sideroblasts; and 66% were considered low risk, and 34% were classified as intermediate-1 risk. The median pretreatment hemoglobin level was 7.8 g/dL; approximately 67% had a serum epoetin alfa level up to 500 mU/mL; approximately 90% had prior treatment with an ESA; and the median prior red blood cell transfusion burden was 6 units per 8 weeks.

The median treatment duration was 34 weeks with imetelstat and 28 weeks with placebo; 24% and 42% of the arms, respectively, discontinued treatment because of a lack of efficacy. Disease relapse after a response on study was documented for 14% and 2%, respectively; 6% and 9%, respectively, had disease progression; and 1.7% of each arm experienced progression to acute myeloid leukemia. 

DISCLOSURE: Dr. Zeidan reported financial relationships with AbbVie, Acceleron Pharma, Agios, Astellas Pharma, BeyondSpring Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb/Celgene, Daiichi Sankyo, Epizyme, Geron, Ionis Pharmaceuticals, Jazz Pharmaceuticals, Novartis, Otsuka, Pfizer, Seagen, Taiho Pharmaceutical, Takeda, Trovagene, and Incyte.

REFERENCES

1. Zeidan AM, Platzbecker U, Santini V, et al: IMerge: Results from a phase 3, randomized, double-blind, placebo-controlled study of imetelstat in patients with heavily transfusion dependent non-del(5q) lower-risk myelodysplastic syndrome relapsed/refractory to erythropoiesis-stimulating agents. 2023 ASCO Annual Meeting. Abstract 7004. Presented June 2, 2023.

2. Steensma DP, Fenaux P, Van Eygen K, et al: Imetelstat achieves meaningful and durable transfusion independence in high transfusion-burden patients with lower-risk myelodysplastic syndromes in a phase II study. J Clin Oncol 39:48-56, 2021.