CD19 CAR-T细胞治疗B细胞淋巴瘤22例疗效及安全性

Efficacy and safety of CD19 chimeric antigen receptor T cells for the treatment of 22 patients with B-cell lymphoma

目的探讨CD19 CAR-T治疗B细胞淋巴瘤的疗效及安全性。方法评估2017年2月1日至2018年7月1日CD19 CAR-T治疗22例B细胞淋巴瘤患者的疗效及不良反应情况。结果22例患者输注CD19 CAR-T后,总体完全缓解(CR)率为45.5%,部分缓解(PR)率为31.8%,总有效率为77.3%。其中12例复发难治患者9例有效,2例达CR,7例PR;10例微小残留病(MRD)阳性患者,8例MRD转阴。全部患者外周血中均检测到CD19 CAR-T细胞在体内增殖,复发难治患者与MRD阳性患者T细胞增殖的达峰时间分别为治疗后第4.5(1~12)天和治疗后第12(5~19)天,外周血CAR-T细胞分别占总的T淋巴细胞的4.02%(2.23%~28.60%)和10.10%(3.55%~24.74%)。MRD转阴患者持续缓解,中位随访8(3~18)个月均未复发,且此组患者有3例联合PD-1抗体治疗,均达CR。复发难治患者中,7例CAR-T治疗后达PR患者疗效保持时间为1.5~6.0个月,PD-1表达率为25.7%~55.3%,5例CAR-T治疗无效患者PD-1均高表达;共有3例患者联合应用PD-1抗体,其中2例有效;2例CAR-T治疗后达CR患者中1例行异基因造血干细胞移植,另1例随访12个月仍持续缓解。22例患者输注CAR-T细胞后14例发生不同程度的细胞因子释放综合征(CRS),其中9例为1级CRS,4例为2级CRS,其中1例复发难治患者发生3级CRS,经糖皮质激素、IL-6抗体治疗后CRS得到控制。治疗有效的17例患者中14例发生CRS,治疗无效的5例患者均未发生CRS。难治复发患者发生CRS的严重程度高于MRD阳性患者。结论CD19 CAR-T在CD19^+ B细胞淋巴瘤中取得了疗效。CAR-T联合免疫检查点抑制剂的应用能够更好地提高疗效,CAR-T细胞治疗可作为复发难治患者的挽救治疗,清除B细胞淋巴瘤的MRD效果更好且不良反应小。

Objective To investigate the efficacy and safety of CD19 chimeric antigen receptor T (CAR-T) lymphocytes for the treatment of B cell lymphoma. Methods A total of 22 patients with B-cell lymphoma from February 1, 2017 to July 1, 2018 were reviewed to evaluate the efficacy and adverse reactions of CD19 CAR-T. Results Of 22 patients with B-cell lymphoma received CD19 CAR-T cells, the median dose of CAR-T cells was 7.2 (2.0-12.0)×10^6/kg. Nine of 12 cases of relapse refractory patients were overall response. Complete remission (CR) occurred in 2 of 12 patients, partial remission (PR) in 7 of 12 patients. The overall response in minor residual disease positive (MRD) group was 8 of 10 patients. CD19 CAR-T cells proliferated in vivo and were detectable in the blood of patients. The peak timepoints of CAR-T cells proliferated in the relapsed refractory and MRD positive groups were 12 (5-19) and 4.5 (1-12) days after treatment respectively, and among peripheral blood cells, CAR-T cells accounted for 10.10%(3.55%-24.74%) and 4.02%(2.23%-28.60%) of T lymphocytes respectively. The MRD positive patients achieved sustained remissions during a median follow-up of 8 months (rang 3-18 months). None of all the patients relapsed during a median follow-up time of 10 months (3-18 months). However, 7 PR responders of the relapsed refractory patients maintained a good condition for 1.5-6.0 months. One patient bridged to hematopoietic stem cell transplantation, another one sustained remission for 12 months. Cytokine-release syndrome (CRS) occurred in 14 patients with grade 1-2 CRS in MRD positive group and grade 3 CRS in relapsed refractory group. Conclusions CAR-T cell therapy not only played a role in the rescue treatment of relapsed and refractory patients, but also produced a surprising effect in the consolidation and maintenance of B-cell lymphoma. CD19 CAR-T cells might be more effective in the treatment of MRD positive B-cell lymphoma patients than in the refractory or relapsed cases. High response rate was observed with fewer adverse reactions.