Phase 3 Findings Demonstrate Durable Benefit With Imetelstat For Patients With R/R MDS


Treatment with imetelstat elicited statistically significant and clinically meaningful improvements in transfusion independence among patients with lower-risk myelodysplastic syndrome.

Amer Zeidan, MBBS, MHS

Amer Zeidan, MBBS, MHS

Imetelstat, a first-in-class telomerase inhibitor, decreased transfusion dependence and increased hemoglobin counts for patients with heavily transfusion dependent, non-del(5q) lower-risk myelodysplastic syndrome (MDS) that is relapsed or refractory to erythropoiesis stimulating agents (ESAs), according to findings from the phase 3 IMerge trial (NCT02598661) presented during the 2023 ASCO Annual Meeting.1

Primary data from the trial showed that, as of October 2022, patients who received imetelstat (n = 118) achieved 8-week red blood cell transfusion independence at a rate of 39.8% (95% CI, 30.9%-49.3%) compared with 15.0% (95% CI, 7.1%-26.6%) among patients who received placebo (n = 59; P < .001). Moreover, 16-week transfusion independence was also improved, at 31.4% (95% CI, 23.1%-40.5%) vs 6.7% (95% CI, 1.9%-16.2%), respectively (P < .001), as was 24-week transfusion independence, at 28.0% (95% CI, 20.1%-37.0%) vs 3.3% (95% CI, 0.4%-11.5%), respectively (P < .001). At 1 year, patients experienced respective transfusion independence rates of 13.6% (95% CI, 8.0%-21.1%) and 1.7% (95% CI, 0.0%-8.9%; P = .012).

“The number of positive phase 3 trials in MDS in the last 25 years can be counted on 1 hand,” Amer Zeidan MBBS, MHS the medical director of Hematology Early Therapeutics Research, the leader of the Myeloid malignancies DART (Disease Aligned Research Team), and the director of Continuing Medical Education (CME) in the Division of Hematology at Yale Cancer Center in New Haven, Connecticut, said during the presentation. “To see [multiple] randomized, positive phase 3 trials in MDS is unique for us who have been in the field for a very long time, and it's really an indication of the progress we've been seeing in MDS.”

The double-blind IMerge trial enrolled patients from 77 clinical sites in 17 countries. Patients had to have IPSS low- or intermediate 1-risk MDS that was relapsed/refractory to an ESA or erythropoietin given at a dose of over 500 mU/mL if the patient was ineligible for an ESA. Patients also had to be transfusion dependent, defined as receiving at least 4 units of red blood cells per 8 weeks over a 16-week prestudy period, as well as not undergone prior treatment with lenalidomide (Revlimid) or hypomethylating agents.

Patients were randomly assigned 2:1 to treatment with intravenous imetelstat at a dose of 7.5 mg/kg or placebo every 4 weeks. Patients were subsequently stratified base on transfusion burden (4-6 units vs > 6 units) and IPSS risk category (low vs intermediate-1).

The primary end point was transfusion independence at 8 weeks. Secondary end points included 24-week transfusion independence, transfusion independence duration, hematologic improvement-erythroid, and safety. Investigators also explored changes in variant allele frequency and patient-reported outcomes.

Baseline patient characteristics were well-balanced between the 2 arms; the median age was 72 years (range, 44-87) compared with 73 years (range, 39-85) in the imetelstat and placebo arms, respectively. Most patients in both arms had prior ESA treatment (92% vs 87%), IPSS low-risk disease (68% vs 65%), were men (60% vs 67%), were classified by the World Health Organization as having ring sideroblasts (62% vs 62%), and had at least 4 but no more that 6 units of red blood cell transfusions per 8 weeks (53% vs 55%).

In the imetelstat arm, the median time since diagnosis was 3.5 years (range, 0.1-26.7) compared with 2.8 years (range, 0.2-25.7) in the placebo arm. Median pretreatment hemoglobin was 7.9 g/dL (range, 5.3-10.1) vs 7.8 g/dL (range, 6.1-9.2), respectively. The respective median prior red blood cell transfusion burdens were 6 units per 8 weeks (range, 4-33) and 6 units per 8 weeks (range, 4-13).

In the safety population, patients who received imetelstat experienced any-grade adverse effects (AEs) such as thrombocytopenia (75%), neutropenia (74%), anemia (20%), COVID-19 (19%), and asthenia (19%). These AEs occurred at grade 3 or 4 severity at a rate of 62%, 68%, 19%, 2%, and 0%, respectively.

In the placebo arm (n = 59), common any-grade AEs consisted of asthenia (14%), COVID-19 (14%), diarrhea (12%), pyrexia (12%), and constipation (12%). Grade 3 or 4 instances of these events were reported in 0%, 5%, 2%, 0%, and 0%, of patients, respectively.

In the imetelstat and placebo arms, bleeding events (2.5% vs 1.7%), infections (11.0% vs 13.6%), and febrile neutropenia (0.8% vs 0%) occurred at a severity of grade 3 or higher. The median duration of thrombocytopenia was 1.4 weeks (range, 0.1-12.6) vs 2.0 weeks (range, 0.3-11.6), respectively, and 86.3% vs 44.4% of instances, respectively, resolved within 4 weeks. The median duration of neutropenia was 1.9 weeks (range, 0.0-15.9) vs 2.2 weeks (range, 1.0-4.6), respectively, and 81.0% vs 50.0% of instances, respectively, resolved within 4 weeks.

In general, nonhematologic events were low grade with imetelstat treatment. Approximately 75% of patients who received the agent experienced dose modification due to AEs, however less that 15% of patients discontinued treatment due to treatment-emergent AEs. No instances of Hy’s Law or drug-induced liver injury were observed.

The median treatment duration with imetelstat was 33.9 weeks compared with 28.3 weeks in the placebo arm. Most patients in both arms discontinued treatment (77.1% vs 76.3%). Reasons for discontinuation included lack of efficacy (23.7% vs 42.4%), AEs (16.1% vs 0%), disease relapse following response (14.4% vs 1.7%), disease progression (5.9% vs 8.5%), death (0.8% vs 3.4%), or other (16.1% vs 20.3%). Two patients in the investigational arm progressed to acute myeloid leukemia, as did 1 patient in the placebo arm.

Additional findings from the study revealed that patients who responded to imetelstat treatment had a significantly longer duration of transfusion independence compared with those who received placebo. The median duration of red blood cell transfusion independence was 51.6 weeks (95% CI, 26.9-83.9) compared with 13.3 weeks (95% CI, 8.0-24.9), respectively (HR, 0.23; 95% CI, 0.09-0.57; P < .001).

Red blood cell transfusion independence at 8 weeks also favored imetelstat over placebo across several key lower-risk MDS subgroups. This trend was observed in patients without ring sideroblasts (P = .038), those who previously received over 6 units of red blood cell transfusions per 8 weeks (P = .023), and those with IPSS risk intermediate-1 disease (P = .004), among other subgroups.

There was also a significant and sustained increase in hemoglobin levels in patients who received imetelstat. Among the 8-week transfusion independence responders, the median hemoglobin rise was 3.6 g/dL (range, -0.1 to 13.8) vs 0.8 g/dL (range, -0.2 to 1.7) in the imetelstat and placebo groups, respectively. Additionally, median peak hemoglobin levels were 11.3 g/dL (range, 8.0-21.9) vs 8.9 g/dL (range, 7.9-9.7), respectively.

“This was 1 of the most impressive findings of this study,” Zeidan said. “I remind you that the baseline hemoglobin level for patients in the study was around 8 grams [per dL]. The median hemoglobin rise for those patients on imetelstat was 3.6 grams [per dL] and they went to a peak level of 11 [g/dL]. This is a huge rise that is not common to see.”

Additionally, a significant improvement in hematologic improvement-erythroid was reported with imetelstat treatment compared with placebo. The rate of hematologic improvement-erythroid was 42.4% (95% CI, 33.3%-51.8%) vs 13.3% (95% CI, 5.9%-24.6%), respectively (P < .001). Among those with low transfusion burden, the rate of hematologic improvement-erythroid response, defined as 16-weeks of red blood cell transfusion independence, was 33.3% (95% CI, 14.6%-57.0%) vs 22.2% (95% CI, 6.4%-47.6%) in the imetelstat (n = 21) and placebo (n = 18) arms, respectively (P = .562). Notably, patients who received imetelstat who had a high transfusion burden (n = 97) experienced 16-week red blood cell transfusion independence at a rate of 30.0% (95% CI, 21.9%-41.1%) compared with 0% (95% CI, 0.0%-8.4%) in the placebo arm (n = 42; P < .001).

Finally, treatment with imetelstat also resulted in greater reductions in variant allele frequency of genes frequently mutated in MDS compared with placebo. This included reductions in SF3B1 (P < .001), TET2 (P = .032), DNMT3A (P = .019), and ASXL1 (P = .146).

“Beyond the improvement in anemia, we are seeing signs of modification of the disease, which is really what we need to aim for [in] lower-risk MDS now that we have very good drugs,” Zeidan said. “We could see a significant reduction [in] the variable allele frequency in the 4 most commonly abnormal genes [in MDS]. Importantly, the reduction in SF3B1 was also associated with higher hemoglobin levels, as well as prolonged duration of transfusion independence.”


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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