Efficacy and safety of thalidomide (1 vs 2 mg/kg/d) in transfusion-dependent thalassemia: A Non-Inferiority Trial

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Thalidomide has emerged as a fetal hemoglobin-inducer with potential to reduce transfusion burden in transfusion-dependent thalassemia (TDT). However, optimal dosing remains undefined A prospective, randomized, open-label, multicentric clinical trial was conducted at four centres in India to compare efficacy and safety of thalidomide at 1 mg/kg/day (Group 1) versus 2 mg/kg/day (Group 2) in patients with TDT aged ≥12 years. The primary endpoint was reduction in transfusion requirement at week 24, categorized as good (>50%), moderate (25-50%), or no (<25%) response. Responders underwent stepwise dose tapering during weeks 25-72 to evaluate response sustainability. Safety assessments were performed every 4 weeks. Of 188 enrolled patients (94 per group), 82.4% completed the week-24 evaluation. The overall response rate (ORR) was 58.5%, significantly higher in Group 1 than Group 2 (67.1% vs 50.0%, p=0.012). Good, moderate, and no response were observed in 20.5%, 37.8%, and 41.6% of patients, respectively, with transfusion independence in 9 patients (5.6%). Clinical benefit was observed within 12 weeks in 71.8% of good responders and 100% moderate responders. Sustained response at week 72 was seen in 49% and 57.5% of initial responders in Groups 1 and 2, respectively. Adverse effects were mostly grade 1; drug discontinuation due to toxicity was required in 10.6 % participants. These findings suggest that Thalidomide at 1 mg/kg/day was non-inferior to 2 mg/kg/day in reducing transfusion burden in patients with TDT, with an acceptable safety profile. Low-dose thalidomide appears to be a feasible treatment option in resource-limited settings. ICMR trial registry (Trial no. CTRI/2022/05/042781).