单倍型造血干细胞移植中抗胸腺细胞球蛋白的最适剂量:一项多中心、随机对照研究的长期随访

Optimizing antithymocyte globulin dosing in haploidentical hematopoietic cell transplantation:long-term follow-up of a multicenter,randomized controlled trial

探索抗胸腺细胞球蛋白(ATG)最佳剂量是优化"北京方案"单倍型造血干细胞移植(haplo-HCT)疗效的重要步骤.本研究弥补了探索ATG剂量的前瞻性、多中心、随机对照试验尤其是长期随访资料的匮乏.纳入408例白血病患者,年龄为14~65岁,采用"北京方案"行haplo-HCT,依据所用ATG剂量被1:1随机分为7.5 mg/kg(n=203,ATG-7.5)组和10mg/kg(n=205,ATG-10.0)组.中位随访时间为1968(1300~2710)天.两组的5年中重度慢性GVHD发生率、非复发死亡率、复发率、无病生存率、无GVHD/无复发生存率均无显著差异.5年晚发合并症两组间无显著差异.但ATG-10.0组的CMV/EBV相关死亡率显著高于ATG-7.5组(9.8%vs.1.5%;P=0.003).由此可见,相对于10 mg/kg ATG,行haplo-HCT的患者更能获益于7.5mg/kgATG带来的GVHD和感染之间的平衡.因此,本研究不仅有助于优化"北京方案"中ATG的使用,更有意义的是秉持持续探索的科学态度提高临床研究的意识、水平,为通过系列临床研究回答亟需解决的临床问题提供了示范.

Given that randomized studies testing the long-term impact of antithymocyte globulin(ATG)dosing are scarce,we report the results of an extended follow-up from the original trial.In our prospective,multicenter,randomized trial,408 leukemia patients 14–65 years of age who underwent haploidentical hematopoietic cell transplantation(haplo-HCT)under our original“Beijing Protocol”were randomly assigned one-to-one to ATG doses of 7.5 mg/kg(n=203,ATG-7.5)or 10 mg/kg(n=205,ATG-10.0)at four sites.Extended follow-up(median 1968 d(range:1300–2710 d)indicated comparable 5-year probabilities of moderate-to-severe chronic graft-versus-host disease(GVHD)(hazard ratio(HR):1.384,95%confidence interval(CI):0.876–2.189,P=0.164),nonrelapse mortality(HR:0.814,95%CI:0.526–1.261,P=0.357),relapse(HR:1.521,95%CI:0.919–2.518,P=0.103),disease-free survival(HR:1.074,95%CI:0.783–1.473,P=0.658),and GVHD-free/relapse-free survival(HR:1.186,95%CI:0.904–1.555,P=0.219)between groups(ATG-7.5 vs.ATG-10.0).The 5-year rate of late effects did not differ significantly.However,the cytomegalovirus/Epstein-Barr virus-related death rate was much higher in the ATG-10.0 cohort than in the ATG-7.5 cohort(9.8%vs.1.5%;P=0.003).In summary,patients undergoing haplo-HCT benefit from 7.5 mg/kg ATG compared to 10.0 mg/kg ATG based on a balance between GVHD and infection control.ATG(7.5 mg/kg)is potentially regarded as the standard regimen in the platform.These results support the optimization of ATG use in the“Beijing Protocol”,especially considering the potential economic advantage in developing countries.