Health-Related Quality of Life of Luspatercept Versus Epoetin Alfa in Red Blood Cell Transfusion-Dependent Lower-Risk Myelodysplastic Syndromes: Results from the Final Datacut of the Phase 3 COMMANDS Study

Introduction: Treatment goals in lower-risk myelodysplastic syndromes (LR-MDS) include reduction of red blood cell (RBC) transfusion burden, improvement of cytopenias, and maintenance of, or improvement in, health-related quality of life (HRQoL). COMMANDS (NCT03682536) is a global, randomized, phase 3 study comparing the efficacy and safety of luspatercept vs epoetin alfa for the treatment of anemia due to LR-MDS, defined by the Revised International Prognostic Scoring System, in erythropoiesis-stimulating agent-naive patients requiring regular RBC transfusions. The study met its primary endpoint of RBC transfusion independence for at least 12 weeks with a concurrent mean hemoglobin increase of at least 1.5 g/dL. This analysis aimed to investigate the impact of luspatercept on HRQoL using the final COMMANDS datacut (September 22, 2023). Methods: Patients were randomized to receive luspatercept Q3W or epoetin alfa (QW). The European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire - Core 30 (EORTC QLQ-C30) (15 domains) and the Functional Assessment of Cancer Therapy-Anemia (FACT-An) (9 subscales and 1 total score) were administered on Day 1 prior to the first dose (baseline). The EORTC QLQ-C30 was subsequently administered Q6W, while the FACT-An was administered weekly for the first 3 weeks and Q3W thereafter. Time to confirmed improvement and time to confirmed deterioration from baseline by a clinically important difference (CID) threshold prespecified for each HRQoL domain, or RBC transfusion through Day 1 of Week 49 were analyzed using a stratified Cox proportional hazards regression. Time to confirmed improvement (or deterioration) were defined as time from randomization to onset of confirmed improvement (or deterioration) through Week 49. The event for confirmed improvement was defined as an improvement from baseline in a given HRQoL domain meeting or exceeding the CID threshold followed by at least one subsequent improvement ≥42 days after the onset of improvement, without experiencing treatment discontinuation or RBC transfusions thereafter up to Week 49. For confirmed deterioration or RBC transfusion, the event was defined as either the onset of a confirmed deterioration (i.e., a deterioration from baseline ≥CID following by a subsequent one ≥42 days later), treatment discontinuation due to treatment toxicity, or an RBC transfusion, whichever occurred first. Analyses were conducted on the respective HRQoL-evaluable populations, including patients who had a baseline and at least one post-baseline assessment, and were at risk of improvement/deterioration at baseline (i.e., excluding patients with a baseline score too good to have any further improvement or too poor to have any further deterioration based on the prespecified CID thresholds). Results: The EORTC QLQ-C30-evaluable population included 168 patients of the 178 randomized to luspatercept and 160 of the 178 randomized to epoetin alfa, while the FACT-An-evaluable population included 170 and 169 patients, respectively. Hazard ratios (HRs; luspatercept vs. epoetin alfa) for time to confirmed improvement were statistically significantly (p <0.05) in favor of luspatercept in 5 of the 15 domains of the QLQ-C30 and 6 of the 10 subscales/total score of the FACT-An, among patients who had a baseline score that allowed the possibility to improve ≥CID. HRs (95% CIs, p-value from log-rank test) for the key anemia- and fatigue-related domains (subscales) were 1.58 (1.00, 2.49; 0.048) for the QLQ-C30 fatigue domain, 1.76 (1.10, 2.83; 0.016) for the FACT-An anemia subscale (AnS), and 1.60 (1.01, 2.56; 0.042) for the fatigue subscale (FS). Among patients who were at risk of deterioration at baseline, time to confirmed deterioration or RBC transfusion was statistically significantly in favor of luspatercept for all domains of the QLQ-C30 and FACT-An. HRs were 0.66 (0.50, 0.87; 0.003) for the QLQ-C30 fatigue domain, 0.68 (0.52, 0.87; 0.003) for the FACT-An AnS, and 0.70 (0.54, 0.90; 0.006) for the FS. Conclusions: The analyses indicate superior treatment effects of luspatercept over epoetin alfa on shortening time to achieving a meaningful HRQoL improvement or delaying time to experiencing a meaningful HRQoL deterioration or RBC transfusion. These findings provide further evidence to support the use of luspatercept as a front-line treatment for patients with RBC transfusion-dependent LR-MDS.