Impact of long-term luspatercept treatment on iron parameters in patients with transfusion-dependent and non-transfusion-dependent β-thalassemia: Results from the phase 3b long-term follow-up study

Abstract

Abstract Introduction: Iron overload is a common complication of chronic anemia and ineffective erythropoiesis in β-thalassemia. Initial analyses of extended treatment with luspatercept have shown significant and durable erythroid responses and improvement or stabilization of iron parameters in patients with transfusion-dependent β-thalassemia (TDT) and non-transfusion-dependent β-thalassemia (NTDT) from the BELIEVE and BEYOND trials, respectively. In both patient populations, data from long-term treatment are important to inform robust characterization of iron outcomes. Here we report observations of iron parameters up to a total of 384 wk of treatment for patients with TDT and NTDT who received luspatercept in the BELIEVE and BEYOND trials, respectively, and continued treatment in the long-term follow-up (LTFU) study (NCT04064060). Methods: This phase 3b, open-label, single-arm rollover study includes patients ≥18 y of age who participated in other luspatercept trials. In this analysis, iron parameters were evaluated for patients with TDT from BELIEVE (data cutoff January 28, 2025) or patients with NTDT from BEYOND (data cutoff November 8, 2024) who continued to experience clinical benefit in the absence of unacceptable toxicity in the LTFU study. Treatment timing was defined from initiation of luspatercept treatment in the parent trial (baseline). Patients received the same luspatercept dose and schedule in the LTFU study as at the end of the parent trial. Iron parameters evaluated herein were liver iron concentration (LIC; derived from T2*, R2*, or R2 MRI), serum ferritin (SF; mean per 24 wk), and myocardial iron (by T2* MRI). Baseline values for SF were calculated as mean per 12 wk (BELIEVE) or 24 wk (BEYOND) prior to first dose, and for LIC and cardiac T2* at the last assessment on/before first dose. Results: In the BELIEVE trial, 127/224 patients with TDT from the luspatercept group transitioned to the LTFU study to continue treatment. At baseline, median (range) transfusion burden was 28.0 red blood cell (RBC) units (12.0–48.0; n=224) per 48 wk. Patients experienced a mean change in RBC transfusion burden of −6.3 RBC units/48 wk (−21.7%; n=81) at wk 336 and −4.2 units/48 wk (−14.7%; n=64) at wk 384. Concomitant iron chelation therapy (ICT) was received by >98% of patients in BELIEVE. Median (range) baseline LIC was 5.7 mg/g dry weight (dw; 0.8–42.0; n=187); mean change in LIC from baseline was –3.2 mg/g dw (n=53) at wk 336 and −4.4 mg/g dw (n=50) at wk 384. SF also decreased: baseline median (range) SF was 1446.5 μg/L (88.0–6400.0; n=207), and mean changes in SF of −393.0 μg/L (n=86) and −378.5 μg/L (n=73) were observed at wk 336 and 384, respectively. At baseline, 85.6% (166/194) of patients had cardiac T2* levels >20 ms (median [range], 35.0 ms [3.0–205.9]). Most patients had cardiac T2* levels remain >20 ms with luspatercept treatment (44/47 [93.6%] patients at wk 336; 38/44 [86.4%] at wk 384). Shifts from ≤20 ms at baseline to >20 ms at wk 336 and 384 were experienced by 8 and 7 patients, respectively. In the BEYOND trial, 65/96 patients with NTDT from the luspatercept group transitioned to the LTFU study and continued treatment. Of these, 31 received ICT (during the whole study) and 34 did not receive ICT. Median (range) LIC at baseline was 6.4 mg/g dw (2.1–39.9; n=30) for patients who received ICT and 2.5 mg/g dw (1.0–7.8; n=34) for those who did not; the least-squares (LS) mean change in LIC from baseline (95% CI) at wk 288 was −4.6 mg/g dw (−6.4 to −2.8; n=19) and −0.2 mg/g dw (−1.8 to 1.4; n=23), respectively. Median (range) SF at baseline was 626.5 μg/L (184.5–3528.0; n=31) and 276.3 μg/L (30.0–777.5; n=34) for patients who did and did not receive ICT, respectively; LS mean change from baseline in SF (95% CI) at wk 336 was 150.5 μg/L (−108.7 to 409.6; n=13) for patients who received ICT and 44.8 μg/L (−204.9 to 294.5; n=14) for those who did not. Conclusions: These data from the phase 3b LTFU study of luspatercept indicate that long-term treatment of patients with TDT led to durable reductions in RBC transfusion burden, LIC, and SF levels, while cardiac iron markers remained stable. LIC also decreased in patients with NTDT who received luspatercept with ICT and remained stable in patients without ICT, whereas SF remained stable with luspatercept regardless of ICT status. Overall, these data suggest long-term luspatercept treatment of patients with TDT and NTDT is associated with durable benefit.