芦可替尼联合激素一线治疗急性移植物抗宿主病后外周血MDSC动力学研究

Kinetics of MDSC in Patients Treated Steroids-Ruxolitinib as the First Line Therapy for aGVHD

目的:分析关于芦可替尼联合激素一线治疗初诊中高危急性移植物抗宿主病(a GVHD)疗效(NCT04061876)的单臂、开放性临床试验患者,一线治疗前后外周血中淋巴亚群尤其是髓系来源抑制细胞(MDSC)的动力学特征。方法:前瞻性观察本院23例采用芦可替尼联合激素一线治疗的中高危a GVHD患者的疗效,同时监测其淋巴细胞亚群和MDSC的变化特征,并与20例allo-HSCT后无a GVHD及23例采用激素一线治疗的a GVHD患者进行比较。结果:23例中高危a GVHD患者采用芦可替尼联合激素一线治疗后28 d的CR率为78.26%(18/23)。治疗28 d后,患者外周血中CD4^(+)CD29^(+)T细胞(P=0.08)含量低于治疗前,而研究中监测的其他淋巴细胞亚群的含量均高于治疗前;与难治性a GVHD患者相比,CR患者外周血中CD4^(+)CD29^(+)T细胞呈下降趋势。治疗28 d后,a GVHD患者外周血中CD8^(+)CD28^(-)T细胞(P=0.03)及CD8^(+)CD28^(-)T/CD8^(+)CD28^(+)T细胞的比值(P=0.03)明显高于allo-HSCT后无a GVHD患者。alloHSCT后,a GVHD患者外周血中粒系MDSC(G-MDSC)含量均低于无a GVHD患者,allo-HSCT后14 d差异最为显著(P=0.04)。按一线治疗疗效分层,CR患者治疗后3、7 d外周血中单核系MDSC(M-MDSC)的含量较治疗前增高(P_(3)=0.01,P_(7)=0.03),治疗后28 d患者外周血中e-MDSC的含量较治疗前增高(P=0.01);难治性a GVHD患者治疗后3 d外周血中M-MDSC的含量较CR患者低(P=0.01),治疗后28 d患者外周血中e-MDSC的含量较CR患者低(P=0.01);按照治疗方案进行对比分析,结果显示芦可替尼组MDSC各亚群的含量较激素组高,以M-MDSC差异最为显著(P_(3)=0.0351;P_(7)=0.0142;P_(14)=0.0369)。结论:芦可替尼联合激素一线治疗a GVHD患者在获得较高的CR率的同时对allo-HSCT后患者的免疫重建的影响较小。a GVHD患者采用芦可替尼联合激素一线治疗后,外周血MDSC含量的增高提示,a GVHD患者对该治疗方案具有良好的反应性,且M-MDSC变化早于e-MDSC、G-MDSC。

Objective:To analyze the kinetic characteristics of lymphocyte subsets and myeloid-derived suppressor cell(MDSC)in patients who newly diagnosed intermediate-to high-risk aGVHD and treated with steroids-ruxolitinib as the first line therapy from a single-arm,open clinical trial(NCT04061876).Methods:We prospectively observed the efficacy of 23 patients having intermediate-to high-risk aGVHD and treated with steroids-ruxolitinib as the first line therapy.The kinetic characteristics of lymphocyte subsets and MDSC were monitored,and then we compared them in steroids-ruxolitinib group(n=23),free-aGVHD group(n=20)and steroids group(n=23).Results:Of the 23 patients,the CR rate was 78.26%(18/23)on day 28 after first-line treatment with steroids-ruxolitinib.On day 28 after treatment,patients had lower level of CD4^(+)CD29^(+)T cells(P=0.08)than that of pre-treatment,whereas levels of other lymphocyte subsets in this study were higher than that of pre-treatment;CD4 CD29 T cells in CR patients decreased,compared with refractory aGVHD patients.On day 28 of treatment,CD8^(+)CD28^(-)T cells(P=0.03)significantly increased in patients with aGVHD than that in patients without aGVHD,so did CD8^(+)CD28^(-)T/CD8^(+)CD28^(+)T cell ratio(P=0.03).Compared with patients without aGVHD,patients with aGVHD had lower level of G-MDSC,especially on day 14 after allo-HSCT(P=0.04).Compared with pre-treatment,M-MDSC was higher in CR patients on day 3 and 7 post-treatment(P_(3)=0.01,P_(7)=0.03),e-MDSC was higher on day 28 post-treatment(P=0.01).Moreover,compared with CR patients,M-MDSC was lower in refractory aGVHD patients on day 3 post-treatment(P=0.01)and e-MDSC was lower on day 28 post-treatment(P=0.01).Compared with steroids group,MDSC in steroids-ruxolitinib group was higher,with the most significant difference in M-MDSC(P_(3)=0.0351;P_(7)=0.0142;P_(14)=0.0369).Conclusion:We found that patients newly diagnosed intermediate-to high-risk aGVHD receiving first-line therapy with steroids-ruxolitinib achieved high response rate.Moreover,the novel first-line therapy has a small impact on the immune reconstitution of patients after allo-HSCT.Elevated MDSC might predict a better response in aGVHD patients receiving this novel first-line therapy.M-MDSC responded earlier to steroids-ruxolitinib than e-MDSC,G-MDSC.