沙利度胺治疗非输血依赖型β地中海贫血患者血液学反应的预测因素

Predictors of Hematologic Responses in Patients with Non-Transfusion-Dependent β-Thalassemia Receiving Thalidomide Therapy

目的:探讨非输血依赖型β地中海贫血患者对沙利度胺血液学反应的预测因素。方法:对2016年5月至2019年6月于中国人民解放军联勤保障部队第923医院使用沙利度胺治疗的33例非输血依赖型β地中海贫血患者的基本资料、血液学指标、治疗反应程度及遗传背景进行分析。结果:主要反应者(MaR)的基线胎儿血红蛋白(HbF)水平明显高于次要反应者(MiR)和无反应者(NR)(P=0.001)。HbF基线水平与治疗后血红蛋白增量呈正相关(r=0.601)。遗传背景研究发现:MaR组中HBG2rs7482144的基因型CT(P=0.031), HBS1L-MYB rs9399137的基因型CC/CT(P=0.030)、次要等位基因C(P=0.015),HBS1L-MYBrs4895440的基因型TT/AT(P=0.030)、次要等位基因T(P=0.028),以及HBS1L-MYBrs4895441的基因型GG/AG(P=0.030)、次要等位基因G(P=0.028)的检出率显著高于MiR和NR组。比较上述指标预测治疗后主要反应的ROC曲线下面积(AUC),结果显示HbF基线值对主要反应的预测价值显著优于rs7482144(0.91vs0.72, P=0.003)、rs9399137(0.91vs0.74,P=0.022)、rs4895440(0.91vs0.74, P=0.023)和rs4895441(0.91vs0.74, P=0.023)单独预测的价值,而与4个单核苷酸多态性(SNP)联合(0.91vs0.88, P=0.658)或者HbF基线值联合SNP(0.91vs0.97, P=0.132)的预测价值相比无显著差异。HbF基线值预测沙利度胺治疗疗效为主要反应的AUC值为0.91,截断值为27.4%,敏感度为100%,特异度为58.3%(P=0.001)。结论:非输血依赖型β地中海贫血对沙利度胺的血液学反应是可变且复杂的。相较于遗传背景,HbF基线水平或许可以作为更简单有效的疗效反应预测指标。

Objective:To explore the predictors of hematologic responses of non-transfusion-dependentβ-thalassemia(NTDT)to thalidomide. Methods: 33patients with NTDT who treated with thalidomide in the923rd Hospital of the Joint Logistics Support Force of the People′s Liberation Army from May2016to June2019were included in the study.The basic data,hematological indexes,degree of treatment response and genetic background of the patients were analyzed. Results:The baseline fetal hemoglobin(HbF)level of main responders(MaR)was significantly higher than that of minor responders(MiR)and no responders(NR)(P= 0.001). And the baseline HbF level was positively correlated with hemoglobin increment after treatment(r= 0.601). Genetic background analysis showed that the frequencies of the genotype CT of HBG2 rs7482144(P= 0.031),the genotypes CT/CC(P= 0.030)and the minor allele C(P= 0.015)of HBS1L-MYB rs9399137,the genotypes AT/TT(P= 0.030)and the minor allele T(P=0. 028)of HBS1L-MYB rs4895440,the genotypes AG/GG(P= 0.030)and the minor allele G(P= 0.028)of HBS1LMYB rs4895441(P= 0.030)in MaR group were significantly higher than those in MiR and NR groups. Comparing the area under the ROC curve(AUC)of the above indicators to predict the main response,the results demonstrated that the predictive value of baseline HbF level was significantly better than rs7482144(0.91vs0.72,P= 0.003),rs9399137(0.91vs0.74,P= 0.022),rs4895440(0.91vs0.74,P= 0.023)and rs4895441(0.91vs0.74,P=0. 023),but there was no significant difference in the predictive value between combined single nucleotide polymorphisms(SNPs)(0.91vs0.88,P= 0.658)and baseline HbF combined SNPs(0.91vs0.97,P= 0.132). The AUC value of baseline HbF predicting the efficacy of thalidomide as the main response was0.91,the cut-off value was27.4%,the sensitivity was100%,and the specificity was58.3%(P= 0.001). Conclusion:The hematologic response of NTDT to thalidomide is variable and complex. Compared to genetic background,baseline HbF may be a simpler and more efficient tool to predict efficacy response.