| Objective: This study focused on the efficacy and safety of thalidomide for patients with β-thalassemia in a multicenter trial and the effect of HBG2,BCL11 A and HBS1L-MYB single nucleotide polymorphisms(SNPs)on thalidomide response.Methods: Patients with β-thalassemia,who were unable to pursue conventional therapy with transfusion and chelation,were recruited over3 years in three centers in southern China.We evaluated the efficacy and safety of thalidomide in the short-term(three months)and long-term follow-up(12 and 24 months).The efficacy of β-thalassemia patients with thalidomide treatmet in our research center was retrospectively analyzed.Eight SNPs in three major quantitative trait loci(QTLs)(HBG2,rs7482144;BCL11A,rs11886868,rs4671393,rs766432 and rs1427407;and HBS1L-MYB intergenic region,rs9399137,rs4895440 and rs4895441)were investigated by PCR and DNA sequencing,and their roles in thalidomide response in Chinese with β-thalassemia were assessed.Results: The overall response rate(ORR)was 93.5%,with main responders(Ma R)and minor responders(Mi R)rates accounting for62.9% and 30.6% in short-term follow-up.For patients with non-transfusion-dependent thalassemia(NTDT),the Hb level increased from a baseline mean of 6.8±1.1 g/dl to 9.7±1.9 g/dl(P<0.001).Elevated Hb was mainly attributable to increased fetal hemoglobin(Hb F)levels.Among patients with transfusion-dependent thalassemia(TDT),transfusions were terminated in 43.5%(10/23)of the patients and decreased by more than 50% in 52.2%(12/23)of the patients.This was accompanied by an increase in the average hemoglobin concentration.There was a significant drop in yearly transfusions from 20.7±7.7 to5.8±6.8 blood units per year(P<0.001).The response of patients in both categories was sustained even after an average follow up of 14.6±9.6months(3-37 months).Minimal side-effects were documented throughout,except peripheral neurotoxicity in one patient.Logistic regression analysis identified the ratio of Hb F at baseline(P=0.038,OR=1.111,95%CI: 1.006-1.226)as an independent risk factor for main response to thalidomide.Results demonstrated that there were significantly higher minor allele frequencies of rs4895441(P=0.015)in HBG2 and rs9399137(P=0.029),rs4895440(P=0.040)and rs4895441(P=0.040)in HBS1L-MYB in Ma R than that in Mi R and no responders(NR).And thefrequencies of the minor alleles of these 4 SNPs in the high Hb group were significantly higher than that in the low Hb group(P=0.001,0.027,0.045,and 0.045,respectively).Among patients with NTDT,with the minor allele of rs7482144(P=0.011),rs9399137(P=0.013),rs4895440(P=0.011)and rs4895441(P=0.011)increasing,the increased Hb after treatment was significantly increased.The cumulative effect of these four contributing variants on thalidomide response was observed in our study population.The cumulative effects of contributing minor alleles of these loci for patients carrying any combination of 1 or 3 contributing minor alleles had a gradually increased risk of main response compared to those without the contributing minor alleles(P=0.040-0.018,OR=8.556-11.000).Furthermore,Hb increments after treatment correlated with cumulative numbers of minor alleles in the four significant SNPs among patients with NTDT(P = 0.001).Conclusion: Thalidomide had significant therapeutic effects on patients with β-thalassemia with a sustained response.Peripheral neuropathy is one of the most feared complications.While these preliminary results support the potential long-term efficacy of thalidomide as a therapeutic agent for β-thalassemia,several issues need to be addressed before its application in the clinic.It was demonstrated that SNPs in HBG2 and HBS1L-MYB contribute significantly to thalidomide response in patients with β-thalassemia in southern Chinaand that the cumulative number of minor alleles at significant SNPs may serve as a better predictor of response in this population. |
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