化疗联合供者淋巴细胞输注对异基因造血干细胞移植后微小残留病阳性患者慢性移植物抗宿主病及预后的影响

Effects of chemotherapy combined with donor lymphocyte infusion on chronic graft-versus-host disease and prognosis in minimal residual disease positive patients after allogeneic hematopoietic stem cell transplantation

目的 探讨异基因造血干细胞移植(allo-HSCT)后微小残留病(MRD)阳性患者接受化疗联合供者淋巴细胞输注(Chemo-DLI)后慢性移植物抗宿主病(cGVHD)的临床特点以及其严重程度对患者预后的影响.方法 纳入接受allo-HSCT后出现MRD阳性的急性白血病患者,给予Chemo-DLI治疗,采用美国国立卫生研究院(NIH)标准评估cGVHD的特点及严重程度,并分析其对预后的影响.结果 共有54例(59.3%)患者在Chemo-DLI后出现cGVHD,中位发生时间为DLI后70(13~504)d.分别有6例(6.6%)、21例(23.1%)、27例(29.7%)患者发生轻度、中度、重度cGVHD.未发生cGVHD、轻中度cGVHD、重度cGVHD患者Chemo-DLI后5年复发率分别为61.9%(95%CI 45.3%~78.5%)、15.1%(95%CI 1.1%~29.1%)、26.6%(95%CI 9.2%~44.0%)(χ^2=18.901,P<0.001).未发生cGVHD、经典型cGVHD、重叠综合征患者Chemo-DLI后5年复发率分别为61.9%(95%CI 45.3%~78.5%)、19.9%(95%CI 8.1%~31.7%)、28.6%(95%CI 0.0%~65.0%)(χ^2=18.307,P<0.001).cGVHD与治疗后的非复发死亡无关.未发生cGVHD、轻中度cGVHD、重度cGVHD患者Chemo-DLI后5年无白血病生存(LFS)率分别为24.0%(95%CI 9.1%~38.9%)、77.2%(95%CI 60.8%~93.6%)、64.9%(95%CI 45.7%~84.1%)(χ^2=24.447,P<0.001).未发生cGVHD、经典型cGVHD、重叠综合征患者Chemo-DLI后5年LFS率分别为24.0%(95%CI 9.1%~38.9%)、75.5%(95%CI 62.7%~88.3%)、42.9%(95%CI 1.8%~84.0%)(χ^2=25.665,P<0.001).未发生cGVHD、轻中度cGVHD、重度cGVHD患者Chemo-DLI后5年总生存(OS)率分别为50.0%(95%CI 31.1%~68.9%)、87.9%(95%CI 74.7%~100.0%)、71.0%(95%CI 52.0%~90.0%)(χ^2=9.517,P=0.009).未发生cGVHD、经典型cGVHD、重叠综合征患者Chemo-DLI后5年OS率分别为50.0%(95%CI 31.1%~68.9%)、83.9%(95%CI 72.8%~95.0%)、51.4%(95%CI 6.2%~96.6%)(χ^2=10.673,P=0.005).多因素分析显示,移植前处于第1次完全缓解期、经典型cGVHD与Chemo-DLI后较低的复发风险和较好的生存相关.结论 在allo-HSCT后MRD阳性患者中,Chemo-DLI干预后的cGVHD可以降低急性白血病患者的复发风险并改善生存;表现为重叠综合征的患者,需要积极控制cGVHD以改善预后.

Objective To explore clinical features and severity of chronic graft-versus-host disease(cGVHD)after chemotherapy plus donor lymphocyte infusion(Chemo-DLI)in a consecutive cohort of acute leukemia patients who were minimal residual disease(MRD)positive after allogeneic hematopoietic stem cell transplantation(allo-HSCT).Methods The global scoring system proposed by National Institutes of Health(NIH)Consensus Conference was used to identify the characteristics and severity of cGVHD in patients who MRD positive after Chemo-DLI.Results 54(59.3%)patients were diagnosed with cGVHD after Chemo-DLI,with the median time of onset of 70(13-504)days.There were 6 cases(6.6%)of mild cGVHD,21 cases(23.1%)of moderate cGVHD and 27 cases(29.7%)of severe cGVHD.The 5-year cumulative incidence of relapse after Chemo-DLI was 61.9%(95%CI 45.3%-78.5%),15.1%(95%CI 1.1%-29.1%),and 26.6%(95%CI 9.2%-44.0%)(χ^2=18.901,P<0.001)in non-cGVHD,mild to moderate cGVHD,and severe cGVHD groups,respectively.The 5-year cumulative incidence of relapse after Chemo-DLI was 61.9%(95%CI 45.3%-78.5%),19.9%(95%CI 8.1%-31.7%),and 28.6%(95%CI 0.0%-65.0%)(χ^2=18.307,P<0.001)in non-cGVHD,classical cGVHD,and overlap syndrome groups,respectively.cGVHD was not associated with non-relapse morality after Chemo-DLI.Probabilities of 5-year leukemia-free survival(LFS)after Chemo-DLI were 24.0%(95%CI 9.1%-38.9%),77.2%(95%CI 60.8%-93.6%),and 64.9%(95%CI 45.7%-84.1%)(χ^2=24.447,P<0.001)in non-cGVHD,mild to moderate cGVHD,and severe cGVHD groups,respectively.Probabilities of 5-year LFS after Chemo-DLI were 24.0%(95%CI 9.1%-38.9%),75.5%(95%CI 62.7%-88.3%),and 42.9%(95%CI 1.8%-84.0%)(χ^2=25.665,P<0.001)in non-cGVHD,classical cGVHD,and overlap syndrome groups,respectively.Probabilities of 5-year overall survival(OS)after Chemo-DLI were 50.0%(95%CI 31.1%-68.9%),87.9%(95%CI 74.7%-100.0%),and 71.0%(95%CI 52.0%-90.0%)(χ^2=9.517,P=0.009)in non-cGVHD,mild to moderate cGVHD,and severe cGVHD groups,respectively.Probabilities of 5-year OS after Chemo-DLI were 50.0%(95%CI 31.1%-68.9%),83.9%(95%CI 72.8%-95.0%),and 51.4%(95%CI 6.2%-96.6%)(χ^2=10.673,P=0.005)in non-cGVHD,classical cGVHD,and overlap syndrome groups,respectively.In multivariate analysis,patients receiving allo-HSCT in first complete remission stage and classical cGVHD after Chemo-DLI were associated with lower relapse risk and better survival.Conclusions These findings highlight the close relation between cGVHD and the graft-versus-leukemia effect in patients who were MRD positive and received Chemo-DLI after allo-HSCT.However,overlap syndrome could not improve the clinical outcomes of these patients.