Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Blood Cancer Discov. 2022 Sep 6;3(5):385-393. doi: 10.1158/2643-3230.BCD-21-0177.
To explore the role of clonal hematopoiesis (CH) in chimeric antigen receptor (CAR) T-cell therapy outcomes, we performed targeted deep sequencing on buffy coats collected during the 21 days before lymphodepleting chemotherapy from 114 large B-cell lymphoma patients treated with anti-CD19 CAR T cells. We detected CH in 42 (36.8%) pretreatment samples, most frequently in PPM1D (19/114) and TP53 (13/114) genes. Grade ≥3 immune effector cell-associated neurotoxicity syndrome (ICANS) incidence was higher in CH-positive patients than CH-negative patients (45.2% vs. 25.0%, P = 0.038). Higher toxicities with CH were primarily associated with DNMT3A, TET2, and ASXL1 genes (DTA mutations). Grade ≥3 ICANS (58.9% vs. 25%, P = 0.02) and ≥3 cytokine release syndrome (17.7% vs. 4.2%, P = 0.08) incidences were higher in DTA-positive than in CH-negative patients. The estimated 24-month cumulative incidence of therapy-related myeloid neoplasms after CAR T-cell therapy was higher in CH-positive than CH-negative patients [19% (95% CI, 5.5-38.7) vs. 4.2% (95% CI, 0.3-18.4), P = 0.028].
Our study reveals that CH mutations, especially those associated with inflammation (DNMT3A, TET2, and ASXL1), are associated with severe-grade neurotoxicities in lymphoma patients receiving anti-CD19 CAR T-cell therapy. Further studies to investigate the mechanisms and interventions to improve toxicities in the context of CH are warranted. See related content by Uslu and June, p. 382. This article is highlighted in the In This Issue feature, p. 369.
为了探究克隆性造血（CH）在嵌合抗原受体（CAR）T 细胞疗法中的作用，我们对 114 例接受抗 CD19 CAR T 细胞治疗的大 B 细胞淋巴瘤患者在淋巴清除化疗前 21 天采集的 buffy 涂层进行了靶向深度测序。我们在 42 例（36.8%）预处理样本中检测到 CH，最常见的是 PPM1D（19/114）和 TP53（13/114）基因。CH 阳性患者的 3 级及以上免疫效应细胞相关神经毒性综合征（ICANS）发生率高于 CH 阴性患者（45.2% vs. 25.0%，P=0.038）。CH 阳性患者与 CH 阴性患者相比，毒性更高，主要与 DNMT3A、TET2 和 ASXL1 基因（DTA 突变）相关。3 级及以上 ICANS（58.9% vs. 25%，P=0.02）和 3 级及以上细胞因子释放综合征（17.7% vs. 4.2%，P=0.08）发生率在 DTA 阳性患者中高于 CH 阴性患者。CAR T 细胞治疗后，CH 阳性患者治疗相关髓系肿瘤的 24 个月累积发生率高于 CH 阴性患者[19%（95%CI，5.5-38.7）vs. 4.2%（95%CI，0.3-18.4），P=0.028]。
我们的研究表明，CH 突变，特别是与炎症相关的突变（DNMT3A、TET2 和 ASXL1），与接受抗 CD19 CAR T 细胞治疗的淋巴瘤患者发生严重级别的神经毒性有关。进一步的研究需要探讨在 CH 背景下改善毒性的机制和干预措施。有关内容见 Uslu 和 June 的文章，第 382 页。本文是本期重点介绍文章，第 369 页。
