Low- to moderate-dose thalidomide combination rescue after luspatercept failure in transfusion-dependent β-thalassemia: a real-world cohort study.

BACKGROUND

A proportion of transfusion-dependent β-thalassemia (TDT) patients show suboptimal or heterogeneous response to luspatercept. We explored a structured rescue approach by adding low- to moderate-dose thalidomide after predefined luspatercept failure in real-world practice.

METHODS

This study was a single-center retrospective cohort study. Adults with TDT on luspatercept who met predefined criteria for suboptimal response (failure to achieve ≥ 33% reduction in RBC units over a 12-week window versus each patient's baseline 12-week window, or failure to increase Hb by ≥ 1.0 g/dL under an unchanged transfusion trigger) received thalidomide 25-50 mg once daily while continuing luspatercept. Primary endpoint was 12-week transfusion independence (TI), defined as no transfusion for 12 consecutive weeks and Hb ≥ 9.0 g/dL. Secondary endpoints included ≥ 33%/≥50% reductions in RBC units over matched 12-week windows, longitudinal Hb change, and safety graded by CTCAE v5.0 and reported as exposure-adjusted incidence rates.

RESULTS

Eleven patients were included (median age 23 years; female 45.5%; β⁰/β⁰ 18.2%; prior splenectomy 63.6%). Twelve-week transfusion independence (TI) was achieved in 4/11 patients (36.4%; 95% CI 15.2-64.6). Proportions with ≥ 33% and ≥ 50% reductions in RBC units over matched 12-week windows were 45.5% (95% CI 21.3-72.0) and 45.5% (95% CI 21.3-72.0), respectively. Hemoglobin increased by 4.0 g/dL (Hodges-Lehmann, 95% CI 2.9-5.0; LMM p < 0.001). Total exposure was 112 patient-months; EAIR for any-grade treatment-emergent adverse events was 8.0 per 100 patient-months. No ≥Grade 2 neurotoxicity or thrombosis occurred.

CONCLUSIONS

In TDT patients with predefined luspatercept failure, adding low- to moderate-dose thalidomide was associated with improvements in hemoglobin levels and reductions in transfusion burden with favorable tolerability. These findings warrant prospective validation of this structured rescue approach.