Luspatercept Improves Fatigue-Related Quality of Life through 5 Years of Treatment in Non-Transfusion Dependent Beta-Thalassemia

Introduction: Luspatercept has been shown to increase hemoglobin levels and improve health-related quality of life (HRQoL) in patients with non-transfusion-dependent beta-thalassemia (NTDT) participating in the phase 2, double-blind randomized controlled trial, BEYOND (NCT03342404). After completing the BEYOND study, patients could rollover to a phase 3B open-label single-arm follow-up study (the long-term follow-up [LTFU] study [NCT04064060]) where they are followed for safety, HRQoL, and overall survival. The objective of this study was to evaluate the long-term effects of luspatercept on HRQoL as assessed by the Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) questionnaire.

Methods: In the BEYOND study, 145 patients with NTDT were randomized 2:1 to luspatercept (Q3W) + best supportive care (BSC) (n = 96) or placebo + BSC (n = 49). Patients completed the FACIT-F at screening, Dose 1 Day 1, and Day 1 of every other dose (i.e., Q6W). In the LTFU study, the FACIT-F was assessed every fourth cycle (i.e., Q12W). To assess the long-term impact of luspatercept, FACIT-F scores were analyzed for those patients randomized to luspatercept who continued to receive it through to the LTFU study. Data from the final datacut of BEYOND and an interim datacut of the LTFU study were used. As patients' timing of rollover to the LTFU study varied, assessment visits were realigned using 6-week windows from the nominal Week 0 (i.e., first dose of luspatercept). A longitudinal mixed model for repeated measures was used to estimate least-square (LS) mean changes from baseline (dependent variable) in FACIT-F domain scores at each post-baseline visit, with baseline domain score included as a covariate. Key domains of interest included the fatigue subscale (FS), trial outcome index (TOI; i.e., the sum of the FS and the general physical and functional well-being [PWB and FWB, respectively] scores), and total score (TS; i.e., the sum of the FS and the general PWB, FWB, social/family well-being [SWB] and emotional well-being [EWB] scores).

Results: 65 of the 96 patients randomized to luspatercept (67.7%) continued to receive it through to the LTFU study and were followed for a median (range) of 5.2 years (3.4 to 5.9). At baseline (N=58 patients with non-missing FACIT-F scores), scores for the general domains of the FACIT-F (PWB, SWB, EWB, and FWB) were similar to those of the general population (Brucker PS, et al. Eval Health Prof. 2005;28(2):192-211); however, the FS score was clinically meaningfully lower than the general population (mean FS score: 35.8 vs 43.6), indicating greater fatigue symptoms (Cella D, et al. Cancer. 2002;94(2):528-38). Over approximately 5 years of treatment, the overall LS mean change from baseline (95% confidence interval [CI]; p-value) in FS was 3.6 (2.0, 5.1; <0.001), exceeding the prespecified meaningful improvement threshold of 3 points (Webster K, et al. Health Qual Life Outcomes. 2003:1:79). At 1, 2, 3, 4, and 5 years after initiating luspatercept, LS mean changes from baseline in the FS were: 3.7 (1.6, 5.8; 0.001; n=42); 3.5 (1.5, 5.5; 0.001; n=47); 2.6 (0.6, 4.6; 0.012; n=37); 2.2 (0.1, 4.3; 0.037; n=28); and 3.3 (0.6, 6.1; 0.018; n=12), respectively, demonstrating that patients maintained this improvement in fatigue symptoms over the follow-up period. The overall LS mean changes from baseline for the TOI and TS over five years of treatment were 4.6 (2.4, 6.7; <0.001) and 5.1 (2.3, 7.8; <0.001), respectively, also showing significant improvement. LS mean changes from baseline indicated that scores for general domains of the FACIT-F were maintained at a level comparable to the general population over the follow-up period.

Conclusions: Patients with NTDT generally experienced fatigue-related symptoms at baseline. Treatment with luspatercept meaningfully improved fatigue-related symptoms up to at least five years of treatment, while other domains were maintained.

Musallam:Novartis: Consultancy; Celgene Corp (Bristol Myers Squibb): Consultancy; Agios Pharmaceuticals: Consultancy, Research Funding; CRISPR Therapeutics: Consultancy; Vifor Pharma: Consultancy; Pharmacosmos: Consultancy, Research Funding; Novo Nordisk: Consultancy. Taher:Vifor: Consultancy, Research Funding; Pharmacosmos: Consultancy, Research Funding; Novo Nordisk: Consultancy; Bristol Myers Squibb (Celgene): Consultancy, Research Funding; Agios Pharmaceuticals, Inc.: Consultancy, Research Funding. Hnoosh:Bristol Myers Squibb: Current Employment, Divested equity in a private or publicly-traded company in the past 24 months. Eliason:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Pelligra:Evidera Inc., a part of Thermo Fisher Scientific.: Current Employment, Other: Evidera received funding from BMS. Guo:Bristol Myers Squibb: Research Funding; Evidera Inc., a part of Thermo Fisher Scientific.: Current Employment, Other: Evidera, a consulting company, received fees for consultancy from BMS to carry out this work.. Mu:Evidera, part of Thermo Fisher Scientific: Current Employment. Cappellini:Vifor: Membership on an entity's Board of Directors or advisory committees; Silence: Membership on an entity's Board of Directors or advisory committees; Sanofi-Genzyme: Membership on an entity's Board of Directors or advisory committees; Pharmacosmos: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb (Celgene): Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Vertex Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.