Chimeric antigen receptors T cells as second line therapy for acute leukemia relapsed after allogeneic hematopoietic stem cell transplantation: high remission rate without causing graft versus host disease

目的 探讨表达嵌合抗原受体的T淋巴细胞(CAR-T细胞)治疗急性B淋巴细胞白血病(B-ALL)行异基因造血干细胞移植(allo-HSCT)后复发,且经供者淋巴细胞输注(DLI)无效者的疗效及安全性.方法 10例B-ALL患者,allo-HSCT后原发病复发,在化疗联合DLI治疗无效后接受供者来源的CAR-T细胞治疗.10例患者共接受25例次CAR-T细胞治疗,输注针对CD19抗原的CAR-T细胞22例次,针对CD123抗原的CAR-T细胞2例次,针对CD22抗原的CAR-T细胞1例次.首次输注指征为血液学复发(7例)或微小残留病变阳性(3例),首次输注时间为allo-HSCT后6～66个月,中位数为24个月,回输CAR-T细胞(4.4～55)×10Vkg,中位数为2.53 × 106/kg.结果 10例患者均在第1次CAR-T细胞治疗后获得最佳疗效,其中5例完全缓解,3例部分缓解,总有效率为80％(8/10).起效时间为CAR-T细胞治疗后第14～37天,中位数为第24天,疗效维持时间1.3～6.3个月,中位数为4.75个月.血液学复发的患者CAR-T细胞治疗效果与治疗前骨髓幼稚细胞中位数相关(P=0.010),而与输注的CAR-T细胞数无关(P=0.538).22例次可评估不良反应的CAR-T细胞治疗中,输注后出现发热13例次,出现发热的中位时间为CAR-T细胞输注后第6天(第0～8天),其中12例次发热考虑由细胞因子释放综合征(CRS)所致;1例次出现少许皮疹,诊断为Ⅰ度移植物抗宿主病(GVHD).至随访结束(CAR-T细胞治疗后0.9～17个月),10例中,死于复发者3例,复发后失访1例,复发状态下存活3例,MRD阳性状态下存活2例,CR 1例,总体存活率为49.4％.结论 CAR-T细胞用于B-ALL行allo-HSCT治疗后原发病复发且DLI无效的患者有一定效果,疗效与骨髓幼稚细胞水平相关;治疗相关的不良反应主要为轻、中度CRS,还未发现其可诱发严重的GVHD.Objective To analyze the efficiency and safety of chimeric antigen receptors T cells for acute B lymphoblastic leukemia (B-ALL) patients who relapsed after allogeneic hematopoietic stem cell transplantation (allo HSCT) andshowednoresponseforchemotherapy followed by donor lymphocyte infusion (DLI).Methods We conducted a clinical trial of allogeneic T cells engineered to express a chimericantigen receptor (CAR) for patients with B-ALL that had progressed after allo HSCT and DLI.Chemotherapies were administered for most cases.The T cells were obtained from each recipient 's allo-HSCT donor.The clinical data of 10 patients between 2015.1.1 and 2016.3.31 were collected and analyzed.Results Ten patients have been treated to date.Morphology relapses occurred in 7.cases,and 3 patients had minimal residual disease.The median age was 35 years (8-52 years).They received the first course of CAT-T cells at a median of 24 months (range 6.0-66 months) after the allo-HSCT,and the median dose of CAR-T cells was 2.53 × 106/kg [(0.44-5.5) × 106/kg].Eightout of 10 treated patients obtained remission,including complete remissions (CR) in 5 casesand partial remissions (PR) in 3 cases.The overall response rate was 80％.All the responded patients achieved the best effect after the first course.The median days to reach the best response in patients with morphology relapses were 24 days (14-37days) and the maintaining time of the curative effect was 1.3 to 6.3 months (mean 4.75 months after CAR-T cells infusion.The response was associated with the blast cells in bone marrow (response group vs.non-response group,28.5％ vs.90.0％,P =0.010),and not with the dose of CAR-T cells (13.1 × 106/kg vs.20.0 × 106/kg,p =0.538).The side effects of treatment could be evaluated in 22 courses.Fever occurred in 13 courses,and the median time for the onset of fever was 6 days (range 0-8 days) after infusion.Twelve of them were clinically diagnosed with cytokine release syndrome (CSR),including 1 moderate case and the others were mild.Only 1 case had rash and diagnosed with grade Ⅰ graft-versus-host disease (GVHD),and the rash regressed spontaneously.To the end of 2016.3.31,the overall survival of all patients was 49.4％ at 15th month after CAR-T cells therapy.Conclusion Our study demonstrates that immunotherapy with CAR-T cells is feasible in patients with B-ALL relapsed and heavily treated by DLI after allo HSCT without causing GVHD.The response rate is related to the percentage of morphological blasts.国家自然科学基金重点项目; 北京市卫生科技成果和适宜技术推广项目; 首都卫生发展科研专项(首发2016-1-4082)The Key Program of National Natural Science Foundation of China; project TG-2015-003 supported by Health Science Promotion Project of Beijing; Scientific Research Foundation for Capital Medicine Development中国科技核心期刊(ISTIC)中国科学引文数据库(CSCD)7421-4263