Abstract
Thalidomide induces γ-globin expression in erythroid progenitor cells, but its efficacy on patients with transfusion-dependent β-thalassemia (TDT) remains unclear. In this phase 2, multi-center, randomized, double-blind clinical trial, we aimed to determine the safety and efficacy of thalidomide in TDT patients. A hundred patients of 14 years or older were randomly assigned to receive placebo or thalidomide for 12 weeks, followed by an extension phase of at least 36 weeks. The primary endpoint was the change of hemoglobin (Hb) level in the patients. The secondary endpoints included the red blood cell (RBC) units transfused and adverse effects. In the placebo-controlled period, Hb concentrations in patients treated with thalidomide achieved a median elevation of 14.0 (range, 2.5 to 37.5) g/L, whereas Hb in patients treated with placebo did not significantly change. Within the 12 weeks, the mean RBC transfusion volume for patients treated with thalidomide and placebo was 5.4 ± 5.0 U and 10.3 ± 6.4 U, respectively (P < 0.001). Adverse events of drowsiness, dizziness, fatigue, pyrexia, sore throat, and rash were more common with thalidomide than placebo. In the extension phase, treatment with thalidomide for 24 weeks resulted in a sustainable increase in Hb concentrations which reached 104.9 ± 19.0 g/L, without blood transfusion. Significant increase in Hb concentration and reduction in RBC transfusions were associated with non β0/β0 and HBS1L-MYB (rs9399137 C/T, C/C; rs4895441 A/G, G/G) genotypes. These results demonstrated that thalidomide is effective in patients with TDT.
Highlights
Thalidomide induces γ-globin expression in erythroid progenitor cells, but its efficacy on patients with transfusion-dependent β-thalassemia (TDT) remains unclear
A total of 107 participants were assessed for eligibility at 6 centers in Southern China, and 100 of them were randomized to receive placebo (n = 50) or thalidomide (n = 50) treatment (Fig. 1)
We showed that thalidomide was able to increase Hb levels by an average of
Summary
Thalidomide induces γ-globin expression in erythroid progenitor cells, but its efficacy on patients with transfusion-dependent β-thalassemia (TDT) remains unclear. Though HSCT is curative for those under 14 years of age at transplantation, it is available for less than 30% patients and has a 5–10% treatment related mortality for the recipients.[1,4] Gene therapy represents a promising therapy, but its long-term efficacy remains to be determined.[5] effective and affordable remedies are urgently needed to save patients with TDT, especially for those who are 14 years of age and older These authors contributed : Jiang-Ming Chen, Wei-Jian Zhu, Jie Liu, Gui-Zhen Wang, Xiao-Qin Chen, Yun Tan. Inducing production of compensative fetal Hb (Hb F) is an emerging treatment option for BTM, whose efficacy is associated with single nucleotide polymorphisms (SNPs) in the Gγ globin gene HBG27 ( known as Xmn I polymorphism that shows a G > A transition at position −158 of the gene), BCL11A8 and HBS1LMYB intergenic region.[9] The old and multidimensional drug thalidomide has been shown to be an Hb F inducer[1] that can significantly increase Hb (mainly Hb F) concentration in TDT patients in several case reports.[10,11,12] Chen et al.[13] reported that in 9 patients treated with thalidomide, Hb concentration and Hb F ratio increased from 51.3 ± 21.5 g/L and 35.7 ± 26.8% before treatment to 103.8 ± 11.9 g/L and 75.7 ± 14.6% after treatment, respectively. We described a phase II, multicenter, randomized, double-blinded, placebo-controlled clinical trial, followed by an extension phase, to evaluate the efficacy and safety of thalidomide in the treatment of patients with TDT
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