Abstract
Introduction: In the phase 3 randomized, double blind, placebo-controlled BELIEVE trial (NCT02604433) in transfusion-dependent β-thalassemia, 21.4% of patients (pts) treated with luspatercept vs 4.5% with placebo achieved an erythroid response, defined as ≥33% red blood cell (RBC) transfusion burden (TB) reduction from baseline (BL) plus reduction of ≥2 units in wk 13–24. While this definition ensured objective evaluation of efficacy in the trial, it may not capture all clinically meaningful responses. Subsequent analyses have shown that luspatercept treatment can result in benefits outside of the response definition used in BELIEVE, including TB reductions <33% or later response. To better assess luspatercept benefit in routine clinical practice, a revised framework for response evaluation was proposed based on real-world experience (Musallam KM, et al. Ther Adv Hematol 2023;14:20406207231195594). Retrospective application of this framework to a large cohort highlighted its utility in evaluating luspatercept's real-world benefit (Origa R, et al. Am J Hematol 2025;0:1–5). Here, we use a modified version of this framework to recategorize primary erythroid response in the BELIEVE trial to better understand the spectrum of benefit in these pts.
Methods: This post hoc study reanalyzed erythroid response data from the BELIEVE trial (cutoff date: Jan 5, 2021). Modified response categories using changes from BL in RBC TB and pretransfusion hemoglobin (Hb) over rolling 12-wk periods during wk 1–24 were defined as: excellent (≥50% TB reduction, reduction of ≥2 RBC units, and same or better Hb over the same period; or ≥2 g/dL increase in Hb, and same or lower TB over the same period; or achievement of RBC transfusion independence (TI) for ≥12 wk); good (≥33% TB reduction, reduction of ≥2 RBC units, and same or better Hb over the same period; or ≥1 g/dL increase in Hb, and same or lower TB over the same period); satisfactory (any TB reduction with same or better Hb over the same period); no response (remaining pts). Pts could meet >1 criterion per response category. BL TB was the total RBC units transfused in the 12 wk prior to or on dose 1 day 1 of BELIEVE; BL pretransfusion Hb was the mean of a pt's values in the 24 wk prior to dose 1 day 1. Odds ratios, P values, and 95% confidence intervals (CIs) were estimated using unstratified Cochran Mantel–Haenszel test.
Results: This analysis included pts randomized to luspatercept (n=224) or placebo (n=112) in BELIEVE. Median (range) BL TB (6.12 RBC units/12 wk [3.0–14.0] vs 6.27 RBC units/12 wk [3.0–12.0]) and pretransfusion Hb (9.31 g/dL [4.5–11.4] vs 9.15 g/dL [5.8–11.7]) were similar between luspatercept and placebo. By wk 24, only 55/223 (24.7%) pts treated with luspatercept had received the maximum dose (1.25 mg/kg). When recategorized based on modified response criteria, the number of pts who achieved an erythroid response was: excellent (48 [21.4%] luspatercept vs 3 [2.7%] placebo), good (67 [29.9%] vs 15 [13.4%]), satisfactory (38 [17.0%] vs 20 [17.9%]). No response was seen in 71 (31.7%) pts treated with luspatercept vs 74 (66.1%) with placebo. For pts with excellent response with luspatercept, 44 (19.6%) achieved ≥50% TB reduction with reduction of ≥2 RBC units at same or better Hb, 4 (1.8%) achieved ≥2 g/dL increase in Hb at same or lower TB, and 6 (2.7%) achieved RBC-TI for ≥12 wk. For pts with good response with luspatercept, 46 (20.5%) achieved ≥33% TB reduction with reduction of ≥2 RBC units at same or better Hb, and 39 (17.4%) achieved ≥1 g/dL increase in Hb at same or lower TB. The odds of achieving excellent or good response with luspatercept were 5.5 times higher than with placebo (51.3% vs 16.1%; 95% CI, 3.1–9.7; P<0.0001). The odds of achieving only excellent response were 9.9 times higher with luspatercept (21.4% vs 2.7%; 95% CI, 3.0–32.6; P<0.0001).
Conclusions: Recategorization of BELIEVE erythroid responses based on real-world criteria showed higher response rates for pts treated with luspatercept vs placebo, consistent with the original trial. As some pts in BELIEVE had delayed response, possibly due to suboptimal dosing or mandated dose delays, evaluation beyond 24 wk may be needed. This framework provides a practical approach for evaluating luspatercept treatment in routine clinical practice, especially in regions where pretransfusion Hb levels are suboptimal, which could better reflect the spectrum of response and increase understanding of pt benefit.
