Cytopenias following anti-CD19 chimeric antigen receptor (CAR) T cell therapy: a systematic analysis for contributing factors

Cytopenia is one of the most common adverse events following the CAR-T cell infusion, affecting the quality of life and potentially leading to life-threatening bleeding and infection. This study aimed to systematically review the cytopenias following anti-CD19 CAR-T therapy and further analyse the contributing factors. Databases including PubMed, MEDLINE, Embase and Cochrane were systematically searched on 8 May 2022. A random-effect meta-analysis was used to estimate the incidence of cytopenia, and subgroup analyses were applied to explore heterogeneity. A total of 68 studies involving 2950 patients were included in this study. The overall incidence of all grade anaemia, thrombocytopenia, neutropenia, leukopoenia, lymphocytopenia and febrile neutropenia was 65%, 55%, 78%, 62%, 70% and 27%, respectively, and the corresponding cytopenias of grade 3 or worse were 33%, 31%, 61%, 45%, 46%, and 21%, respectively. Subgroup analysis showed increased incidence of cytopenias in subgroups with lower median age, proportion of males (<65%) and proportion of bridging therapy (<80%) and in the subgroup with a median line of prior therapy ≥3. In terms of disease and therapeutic target, cytopenias were more frequent in ALL patients and in dual-target CAR-T therapies (targeting CD19 in combination with other targets). Furthermore, CAR-T products manufactured by lentiviral vectors and those with the costimulatory domain of CD28 were more likely to cause haematological toxicity. No significant differences were observed in cytopenia between patients treated with CAR-T products with murine and humanized scFv. In conclusion, neutropenia is the most frequent cytopenia after CAR-T therapy, both in all grades or grade ≥3. The incidence of cytopenias following CAR-T therapy is influenced by the age, sex, disease and number of prior therapy lines of the patients, as well as the target and costimulatory domain of CAR-T cells, and viral vectors used for manufacturing.KEY MESSAGESNeutropenia is the most frequent cytopenia after CAR-T therapy.The clinical characteristics of the patients, the design of CAR-T cells and the protocol of CAR-T treatment can influence the occurrence of cytopenias following the CAR-T therapy. Neutropenia is the most frequent cytopenia after CAR-T therapy. The clinical characteristics of the patients, the design of CAR-T cells and the protocol of CAR-T treatment can influence the occurrence of cytopenias following the CAR-T therapy.

血细胞减少症（Cytopenia）是嵌合抗原受体T细胞（CAR-T）输注后最常见的不良事件之一，可影响患者生活质量，甚至引发危及生命的出血与感染。本研究旨在系统回顾抗CD19 CAR-T治疗后出现的血细胞减少症，并进一步分析其相关影响因素。
研究于2022年5月8日系统检索了PubMed、MEDLINE、Embase及Cochrane等数据库。采用随机效应Meta分析估算血细胞减少症的发生率，并通过亚组分析探讨异质性。本研究共纳入68项研究，涉及2950例患者。
所有级别贫血、血小板减少症、中性粒细胞减少症、白细胞减少症、淋巴细胞减少症及发热性中性粒细胞减少症的总体发生率分别为65%、55%、78%、62%、70%和27%；其中3级及以上的上述血细胞减少症发生率分别为33%、31%、61%、45%、46%和21%。
亚组分析显示，在中位年龄更低、男性占比（<65%）及桥接治疗占比（<80%）更低的亚组，以及既往治疗线数中位数≥3的亚组中，血细胞减少症的发生率更高。就疾病类型与治疗靶点而言，急性淋巴细胞白血病（ALL）患者及双靶点CAR-T治疗（联合CD19与其他靶点）人群的血细胞减少症发生率更高。此外，采用慢病毒载体制备的CAR-T产品以及携带CD28共刺激结构域的CAR-T细胞，更易引发血液学毒性。而使用鼠源及人源化单链可变区片段（scFv）的CAR-T产品治疗的患者，在血细胞减少症的发生上无显著差异。
综上，无论在所有级别还是≥3级的血细胞减少症中，中性粒细胞减少症都是CAR-T治疗后最常见的血细胞减少类型。CAR-T治疗后血细胞减少症的发生率受患者年龄、性别、疾病状态、既往治疗线数，以及CAR-T细胞的靶点、共刺激结构域和制备所用病毒载体等因素影响。

核心要点
中性粒细胞减少症是CAR-T治疗后最常见的血细胞减少症。
患者的临床特征、CAR-T细胞的设计以及CAR-T治疗方案，均可影响CAR-T治疗后血细胞减少症的发生。中性粒细胞减少症是CAR-T治疗后最常见的血细胞减少症。患者的临床特征、CAR-T细胞的设计以及CAR-T治疗方案，均可影响CAR-T治疗后血细胞减少症的发生。