肿瘤细胞治疗研究
英文原题：Clonal Hematopoiesis is Associated With Severe Cytokine Release Syndrome in Patients Treated With Chimeric Antigen Receptor T-Cell (CART) Therapy.
本研究纳入 62 例 NHL 或 MM 患者，他们在 2017 年至 2022 年期间在 City of Hope 接受了 CD19 或 BCMA CAR T 治疗，并有可用的 CAR T 治疗前冷冻保存的外周血单个核细胞（PBMC）。
接受 CD19 或 B 细胞成熟抗原（BCMA）CAR T 细胞治疗的患者，CAR T 输注前后的炎症与细胞因子释放综合征（CRS）、免疫效应细胞相关神经毒性综合征（ICANS）等毒性的发生有关，也可能导致持续性血细胞减少。克隆性造血（CH）是携带体细胞突变的造血干细胞克隆性扩增，与炎性小体上调相关。本研究考察以既往未接受移植患者为主的非霍奇金淋巴瘤（NHL）或多发性骨髓瘤（MM）受者在 CAR T 治疗前 CH 的发生率，并评估 CH 突变与 CAR T 相关结局（包括 CRS、ICANS、持续性血细胞减少、无进展生存期[PFS]和总生存期[OS]）的关系。研究纳入 2017 至 2022 年间在 City of Hope 接受 CD19 或 BCMA CAR T 治疗、且有治疗前冻存外周血单个核细胞（PBMC）的 62 例 NHL 或 MM 患者。采用 QIAamp DNA Mini Kit（Qiagen）从 PBMC 样本提取 DNA（94% 样本在 CAR T 输注前 <30 天采集），并进行靶向外显子测序（预设 108 基因面板，测序深度 1000×），以确定 CH（变异等位基因频率[VAF]≥2%）。采用多变量逻辑回归分析 CH 与第 +30 天和 +60 天绝对中性粒细胞计数（ANC）恢复、CRS 和 ICANS 最高分级、<2 级与 2 级以上，以及 1 年 OS 和 PFS 的关系。纳入的协变量包括 CAR T 时年龄、基线 ANC、性别、种族、CAR-HEMATOTOX、LDH、是否接受桥接治疗及既往治疗线数。15 例患者（24%）至少有 1 个致病性 CH 突变；其中 2 例（13%）同时存在 2 个 CH 突变。DMT3A 突变最常见；29% 突变 VAF >10%。与无 CH 患者相比，CH 患者发生 2 级 CRS 的可能性显著更高（60% 对 28%，p=0.03；OR=3.9，95% CI 1.2–13.2；p=0.027）。考虑到基线 ANC（CH 组较高且与 ANC 恢复延迟相关，p=0.02）后，CH 患者与无 CH 患者的 ANC 延迟恢复率无显著差异（校正 OR 0.37，95% CI 0.09–1.5；p=0.17）。CH 与 ICANS、1 年 PFS 或 OS 均无关联。该 CAR T 受者队列中 CH 较常见（24%），且与 CAR T 后 2 级 CRS 风险增加相关。目前正在开展进一步验证研究，未来或可考虑将 CAR T 前 CH 作为风险分层生物标志物，以更主动地预防 CRS。转化研究可进一步验证 CH 突变髓系细胞与 CRS 之间是否存在直接关系。
Among patients receiving CD19 or B-cell maturation antigen (BCMA) CAR T therapy, inflammation pre- and post-CAR T infusion is implicated in the development of toxicities including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and likely contributes to prolonged cytopenias. Clonal hematopoiesis (CH), the clonal expansion of hematopoietic stem cells harboring somatic mutations, has been associated with inflammasome upregulation. Herein, we examined the prevalence of pre-CAR T CH in a predominantly transplant-na ve cohort of recipients with non-Hodgkin lymphoma (NHL) or multiple myeloma (MM), and assessed the relationship between the presence of CH mutations and CAR T-related outcomes including CRS, ICANS, prolonged cytopenia, progression-free survival (PFS), and overall survival (OS). This study included 62 patients with NHL or MM who underwent CD19 or BCMA CAR T therapy from 2017 to 2022 at City of Hope and had available pre-CAR T cryopreserved peripheral blood mononuclear cells (PBMCs). DNA was isolated with QIAamp DNA Mini Kit (Qiagen) from PBMC samples (94% collected <30d of CART infusion), on which we performed targeted exome sequencing (108 pre-defined gene panel with 1000x sequencing depth) to determine the presence of CH (variant allele frequency [VAF] 2%). Multivariable logistic regression was used to examine the association between CH and absolute neutrophil count (ANC) recovery at day +30 and +60, maximum grade CRS and ICANS, grade <2 versus 2+, and OS and PFS at 1y. Covariates considered were age at CART, baseline ANC, sex, race, CAR-HEMATOTOX, LDH, bridging therapy (Y/N), and number of prior lines of therapy. Fifteen (24%) patients had at least one pathogenic CH mutation; 2 (13%) had 2 CH mutations concurrently. DMT3A mutations were the most common; 29% of mutations had VAFs >10%. Patients with CH were significantly more likely to develop grade 2 CRS (60% versus 28%, p = .03) compared to those without CH (odds ratio [OR] 3.9, 95% CI 1.2-13.2; p = .027). Accounting for baseline ANC (which was higher among the CH cohort and associated with delayed ANC recovery, p = .02) patients with CH did not have a significantly different rate of delayed ANC recovery compared to those without CH (adjusted OR 0.37, 95% CI 0.09-1.5; p = .17). There was no association between CH and ICANS, nor with 1y PFS or OS. CH was frequent (24%) in this cohort of CAR T recipients and was associated with a higher risk of development of grade 2 CRS after CAR T. Additional validation studies are currently underway, which may set the stage for consideration of pre-CAR T CH as a biomarker for risk stratification towards more proactive CRS prophylaxis. Translational studies could aim to prove a direct relationship between CH-mutated myeloid cells and CRS.
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