Department for Biomedical Research (DBMR), University of Bern, 3008 Bern, Switzerland.
Department of Medical Oncology, University Hospital Bern, 3010 Bern, Switzerland.
Curr Oncol. 2023 Dec 13;30(12):10463-10476. doi: 10.3390/curroncol30120762.
Chimeric antigen receptor T (CAR T)-cell therapy has become a standard treatment option for patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL). Mutations in the gene, a frequent driver alteration in clonal hematopoiesis (CH), lead to a gain of function of PPM1D/Wip1 phosphatase, impairing p53-dependent G1 checkpoint and promoting cell proliferation. The presence of mutations has been correlated with reduced response to standard chemotherapy in lymphoma patients. In this study, we analyzed the impact of low-frequency mutations on the safety and efficacy of CD19-targeted CAR T-cell therapy in a cohort of 85 r/r DLBCL patients. In this cohort, the prevalence of gene mutations was 20% with a mean variant allele frequency (VAF) of 0.052 and a median VAF of 0.036. CAR T-induced cytokine release syndrome (CRS) and immune effector cell-associated neuro-toxicities (ICANS) occurred at similar frequencies in patients with and without mutations. Clinical outcomes were globally worse in the mutated (PPM1Dmut) vs. wild type (PPM1Dwt) subset. While the prevalent treatment outcome within the PPM1Dwt subgroup was complete remission (56%), the majority of patients within the PPM1Dmut subgroup had only partial remission (60%). Median progression-free survival (PFS) was 3 vs. 12 months ( = 0.07) and median overall survival (OS) was 5 vs. 37 months ( = 0.004) for the PPM1Dmut and PPM1Dwt cohort, respectively. Our data suggest that the occurrence of mutations in the context of CH may predict worse outcomes after CD19-targeted CAR T-cell therapy in patients with r/r DLBCL.
嵌合抗原受体 T（CAR T）细胞疗法已成为复发或难治性弥漫性大 B 细胞淋巴瘤（r/r DLBCL）患者的标准治疗选择。基因中的突变是克隆性造血（CH）中的常见驱动改变，导致 PPM1D/Wip1 磷酸酶功能获得，破坏 p53 依赖性 G1 检查点并促进细胞增殖。在淋巴瘤患者中，基因的突变与对标准化疗的反应降低有关。在这项研究中，我们分析了低频突变对 85 例 r/r DLBCL 患者中 CD19 靶向 CAR T 细胞治疗的安全性和疗效的影响。在该队列中，基因的突变率为 20%，平均变异等位基因频率（VAF）为 0.052，中位数 VAF 为 0.036。在有和没有突变的患者中，CAR T 诱导的细胞因子释放综合征（CRS）和免疫效应细胞相关神经毒性（ICANS）的发生频率相似。在突变（PPM1Dmut）与野生型（PPM1Dwt）亚组中，临床结局总体较差。虽然在 PPM1Dwt 亚组中，主要治疗结局是完全缓解（56%），但在 PPM1Dmut 亚组中，大多数患者只有部分缓解（60%）。中位无进展生存期（PFS）为 3 个月 vs. 12 个月（=0.07），中位总生存期（OS）为 5 个月 vs. 37 个月（=0.004）分别为 PPM1Dmut 和 PPM1Dwt 队列。我们的数据表明，在 CH 背景下发生突变可能预示着 r/r DLBCL 患者接受 CD19 靶向 CAR T 细胞治疗后的结局更差。
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