嵌合抗原受体T细胞治疗儿童复发、难治急性B淋巴细胞白血病48例的长期疗效分析

Chimeric antigen receptors T cells for treatment of 48 relapsed or refractory acute lymphoblastic leukemia children: long term follow-up outcomes

目的评价嵌合抗原受体(CAR)T细胞技术治疗复发、难治儿童急性B淋巴细胞白血病(B-ALL)的疗效,探讨影响预后的因素。方法2014年9月至2017年8月应用第四代CD19特异性CAR-T细胞治疗复发、难治CD19阳性B-ALL/B淋巴母细胞性淋巴瘤患儿48例,其中男29例,女19例,中位年龄8(3~17)岁。48例患儿共接受61次CAR-T细胞输注,观察输注后的不良反应,治疗前后应用流式细胞术或实时定量聚合酶链反应方法监测白血病微小残留病(MRD)水平。中位随访时间406(16~1 259)d。结果61例次CAR-T细胞输注过程中均无不良反应。CAR-T细胞输注后最常见的不良反应为细胞因子释放综合征(CRS)。仅2例患儿出现3级CRS表现,包括持续高热、惊厥、谵妄、浆膜腔积液、血压下降等,1例经对症治疗后好转,另1例应用妥珠单抗治疗后缓解。无一例患者发生CAR-T细胞治疗相关死亡。CAR-T细胞治疗反应率为77.1%,反应出现的时间为输注后第7~28天,CAR-T细胞输注前肿瘤负荷<5%组与≥5%组的反应率分别为87.1%和58.8%(χ^2=4.968,P=0.036)。对于有治疗反应的37例患儿,2年总生存率和年龄、疾病状态及CAR-T细胞输注前的肿瘤负荷相关(P<0.05);而CAR-T细胞输注前的肿瘤负荷≥5%[RR=3.433(95%CI 1.333~8.844),P=0.011]及未桥接造血干细胞移植(HSCT)[RR=4.996(95%CI 1.852~13.474),P=0.001]是影响患儿无事件生存的独立危险因素。结论抗CD19的CAR-T细胞技术治疗儿童复发、难治B-ALL安全有效。通过有效的预处理手段,尽可能降低CAR-T细胞输注前的肿瘤负荷有利于提高CAR-T细胞治疗的反应率。对于难治性白血病或仅分子水平复发的患儿进行CAR-T细胞治疗后桥接HSCT可能是更优的治疗策略。

Objective To evaluate the safety and efficacy of chimeric antigen receptors T cells (CAR-T) in childhood acute B lymphoblastic leukemia (B-ALL) to probe the prognosis-related factors. Methods Forty-eight children, 29 boys and 19 girls, aged 3-17years old (median age was 8 years old), with recurrent or refractory CD19 positive B-ALL, were treated by the CD19 specific CAR-T cells. A total of 48 cases received 61 infusions. Flow cytometry or real-time quantitative polymerase chain reaction method were used to monitor micro residual disease (MRD). The follow-up period was from 16 to 1 259 days with the median follow-up of 406 days. SPSS software was used to statistical analysis. Results No adverse reaction was observed during 61 infusions. The most common adverse reaction after CAR-T cell infusions was cytokine-release syndrome (CRS). Only 2 cases experienced level 3 CRS performance, including continuous high fever, convulsions, delirium, serous cavity effusion, and decreasing of blood pressure. Tocilizumab was given to release CRS performance. No treatment-related death occurred. Thirty-seven patients showed response during 7 to 28 days after infusions. The early response rate was 77.1%, with MRD before infusion less than 5% group higher than the MRD more than 5% group (87.1% vs 58.8%,χ^2=4.968, P=0.036). For the 37 patients who showed response to CAR-T cell infusions, univariate analysis identified that age, disease status at the time of treatment, MRD before infusion affected 2-year OS rate (P<0.05). Multivariate prognostic analysis for EFS disclosed that the MRD before infusion more than 5%(RR=3.433, 95% CI 1.333-8.844, P=0.011) and not bridge to HSCT (RR=4.996, 95% CI 1.852-13.474, P=0.001) were the independent risk factors. Conclusion The fourth generation CAR-T cells directed against CD19 could effectively and safely treat relapsed and refractory B-ALL, which implicated that CAR-T therapy as a novel therapeutic approach could be useful for patients with relapsed or refractory B-ALL who have failed all other treatment options. Reducing MRD as far as possible by effective pretreatment chemotherapy was in favor of increasing the response rate. Bridging HSCT after CAR-T cell treatment might be a better therapeutic strategy for the patient with refractory or molecular relapsed B-ALL.