Correlation of Patient-Reported Outcomes with Red Blood Cell Transfusion Reduction and Rise in Hemoglobin in Patients with Lower-Risk Myelodysplastic Syndromes in the IMerge Trial

Introduction: Quality of life (QOL) in patients with lower-risk myelodysplastic syndromes (LR-MDS) often declines as anemia and associated symptoms (such as fatigue) worsen, and progressive dependence on red blood cell (RBC) transfusions affects daily life. Imetelstat, a first-in-class, competitive inhibitor of telomerase activity, was recently approved by the United States Food and Drug Administration for patients with heavily RBC-transfusion dependent (TD) LR-MDS who are relapsed or refractory to or ineligible for erythropoiesis-stimulating agents (ESA), based on results of the randomized, double-blind, placebo-controlled, phase 3 IMerge trial (NCT02598661). As previously reported in IMerge, treatment with imetelstat resulted in clinically meaningful and statistically significant increases in ≥8-week and ≥24-week RBC transfusion independence (TI), with 50% of imetelstat-treated patients and 40% of placebo recipients who experienced a sustained, meaningful improvement in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue (Platzbecker U, Santini V, et al. Lancet. 2024). Here, we further explore treatment effects and improvement in patient-reported outcomes (PRO) across subgroups in IMerge. Methods: Adults with RBC-TD LR-MDS who were relapsed or refractory to or ineligible for ESAs and lenalidomide- and hypomethylating agent-naive were randomized to imetelstat (7.1 mg/kg active dose, equivalent to 7.5 mg/kg imetelstat sodium) or placebo administered as 2-hour intravenous infusions every 4 weeks. PROs were assessed with validated FACIT-Fatigue, Functional Assessment of Cancer Therapy-Anemia (FACT-An), and the Quality of Life in Myelodysplasia Scale (QUALMS) questionnaires. FACIT-Fatigue assessed fatigue for all patients and across subgroups (ring sideroblast-positive [RS+] vs RS-negative [RS−]; baseline transfusion burden [4-6 U/8weeks vs >6 U/8 weeks]). Sustained meaningful improvement in fatigue was defined as a ≥3-point increase in FACIT-Fatigue score for ≥2 consecutive assessments. Results: A total of 175 patients (118 imetelstat, 57 placebo) comprised the PRO population. In these post-hoc analyses in RS+ and RS− groups, respectively, sustained, meaningful improvement in fatigue was achieved by 55% and 43% of imetelstat-treated patients; differences (95% CI) versus placebo appeared to favor imetelstat (9% [−12, 29] for RS+ and 13% [−15, 36] for RS−). Similarly, in patients with prior transfusion burdens of 4-6 U/8 weeks or >6 U/8 weeks, respectively, sustained improvement in fatigue was achieved by 44% and 57% of imetelstat-treated patients; differences (95% CI) versus placebo appeared to favor imetelstat (8% [−15, 29] for 4-6 U/8 weeks and 11% [−13, 34] for >6 U/8 weeks). Similar to the RBC-TI response and improvement in fatigue association, for imetelstat-treated patients with versus in those without a ≥1.5-g/dL increase in hemoglobin (Hb) lasting ≥8 weeks, improvements in fatigue were seen in 70% (28/40) versus 40% of patients, respectively (31/78; P=.003); in those with versus in those without transfusion reduction of ≥4 U/8 weeks, improvements were seen in 69% (49/71) versus 21% of patients (10/47; P<.001). The QUALMS and FACT-An analyses suggested that imetelstat maintained QOL and anemia symptoms, while placebo recipients experienced worsening QOL and anemia symptoms. For imetelstat versus placebo, respectively, least squares mean changes from baseline to cycle 30 scores were as follows: QUALMS total (−0.55 vs −5.21; P=.016), QUALMS physical burden (−0.41 vs −6.75; P=.007), FACT-An total (−1.60 vs −9.72; P=.005), and FACT-An physical well-being (−0.43 vs −1.16; P=.197). Conclusions: Among imetelstat-treated patients enrolled in the IMerge trial, improvement in fatigue was associated with a rise in Hb and reductions in transfusion burden. In addition, more imetelstat-treated patients experienced maintenance of QOL and anemia symptoms compared with worsening with placebo. Imetelstat appears to offer the advantage of sustained RBC-TI while maintaining QOL in patients with RBC-TD LR-MDS.