Statins May Improve Outcomes and Toxicities in Patients Undergoing CD19-Specific CAR T-Cell Therapy for Aggressive B-Cell Lymphomas

Introduction: Statins are both immunomodulatory and anti-inflammatory, and in-vivo studies have demonstrated pro-apoptotic effects in lymphoma cell lines. Moreover, they reduce T-cell exhaustion, which often limits anti-tumor activity and impacts the tumor microenvironment. While statin exposure has been associated with improved outcomes in patients receiving immune check-point inhibitors for solid tumor malignancies, it has not been evaluated in patients undergoing chimeric antigen receptor T-cell (CAR-T) therapy. Herein, we present an analysis of patient outcomes stratified by statin exposure in patients receiving CAR-T therapy targeting CD19 for aggressive B-cell lymphoma. Methods: Patients diagnosed with aggressive B-cell lymphomas (high grade B-cell lymphoma or diffuse large B-cell lymphoma) who received CD19-CAR-T cells from January 2018 to May 2024 were included. Data was stratified based on statin vs non-statin exposure from time of cell collection to 12 -weeks after CAR-T cell infusion. Demographics, therapy data, treatment toxicities, rescue medications, standard lab parameters, and outcomes data were collected. Median overall survival (OS) and progression free survival (PFS) with 95% confidence interval (CI) were analyzed using Kaplan Meier methodology, and log-rank tests compared survival distributions. P<0.05 was considered statistically significant. Results: There were 84 patients included, with a median age of 65 (24-78) years. Of these, 34 (40.5%) were females. A total of 32 (38.1%) patients had statin exposure and 52 (61.9%) had no statin exposure. The median ages of statin and non-statin cohorts were 71 (49-78) and 63 (24-77), respectively. Axicabtagene ciloleucel was used in 23 (71.8%) in statin and 42 (80.7%) in non-statin arm. Median prior lines of therapy were 2 (1-4) in both cohorts. Most patients received moderate (59.4%) and high intensity (34.4%) statins. At last follow-up, 10 (31.2%) patients in the statin group and 22 (42.3%) in non-statin group had progressed, and 7 (21.9%) and 22 (42.3%) patients died, respectively. In the statin and non-statin arms, median PFS was not reached (NR) and 16.7 months (95% CI 4.6, 28.9) (p=0.026), respectively, and median OS was NR vs 17.8 months (95% CI 10.3, 25.3) (p=0.032), respectively. Cytokine release syndrome (CRS) and immune effector cell neurotoxicity syndrome (ICANS) of any grade were reported in 75.0% and 80.8% (p=0.537) and 21.9% and 34.6% (p=0.220) in the statin and non-statin cohorts, respectively. Median grade CRS was 1 (1-2) and ICANS was 1 (1-2) in both cohorts; utilization of tocilizumab was 43.8% vs 63.5% (p=0.079) and dexamethasone was 40.6% vs 53.8% (p=0.21) in statin and non-statin cohorts, respectively. Inflammatory markers, including ferritin (p=0.256) and CRP (p=0.655), did not significantly differ. Conclusion: Patients with aggressive B-cell lymphomas and statin exposure along with CD19-CAR-T had a significant improvement in PFS and OS, similar rate of toxicities, and a trend toward lower utilization of tocilizumab. Statin use may enhance efficacy and mitigate toxicities, and its role should be assessed in prospective trials.

引言：他汀类药物具有免疫调节和抗炎作用，体内研究已证实其在淋巴瘤细胞系中有促凋亡作用。此外，它们可减轻T细胞耗竭，而T细胞耗竭常常限制抗肿瘤活性并影响肿瘤微环境。虽然他汀类药物暴露与接受免疫检查点抑制剂治疗实体肿瘤恶性肿瘤患者的预后改善有关，但在接受嵌合抗原受体T细胞（CAR - T）疗法的患者中尚未进行评估。在此，我们对接受针对CD19的CAR - T疗法治疗侵袭性B细胞淋巴瘤的患者按他汀类药物暴露情况进行分层，并对患者预后进行分析。 方法：纳入2018年1月至2024年5月期间接受CD19 - CAR - T细胞治疗且被诊断为侵袭性B细胞淋巴瘤（高级别B细胞淋巴瘤或弥漫性大B细胞淋巴瘤）的患者。从细胞采集时间到CAR - T细胞输注后12周，根据他汀类药物暴露与否对数据进行分层。收集人口统计学资料、治疗数据、治疗毒性、挽救性用药、标准实验室参数和预后数据。采用Kaplan - Meier方法分析中位总生存期（OS）和无进展生存期（PFS）及其95%置信区间（CI），并通过对数秩检验比较生存分布。P < 0.05被认为具有统计学意义。 结果：共纳入84例患者，中位年龄为65岁（24 - 78岁）。其中，34例（40.5%）为女性。共有32例（38.1%）患者有他汀类药物暴露史，52例（61.9%）无他汀类药物暴露史。他汀类药物组和非他汀类药物组的中位年龄分别为71岁（49 - 78岁）和63岁（24 - 77岁）。他汀类药物组中有23例（71.8%）使用阿基仑赛，非他汀类药物组中有42例（80.7%）使用。两个组的既往治疗中位线数均为2线（1 - 4线）。大多数患者接受中强度（59.4%）和高强度（34.4%）他汀类药物。 在最后一次随访时，他汀类药物组中有10例（31.2%）患者病情进展，非他汀类药物组中有22例（42.3%）患者病情进展；他汀类药物组中有7例（21.9%）患者死亡，非他汀类药物组中有22例（42.3%）患者死亡。在他汀类药物组和非他汀类药物组中，中位PFS分别为未达到（NR）和16.7个月（95%CI 4.6，28.9）（p = 0.026），中位OS分别为未达到和17.8个月（95%CI 10.3，25.3）（p = 0.032）。 他汀类药物组和非他汀类药物组中任何级别的细胞因子释放综合征（CRS）和免疫效应细胞神经毒性综合征（ICANS）的发生率分别为75.0%和80.8%（p = 0.537）以及21.9%和34.6%（p = 0.220）。两个组的中位CRS级别均为1级（1 - 2级），中位ICANS级别均为1级（1 - 2级）；他汀类药物组和非他汀类药物组中托珠单抗的使用率分别为43.8%和63.5%（p = 0.079），地塞米松的使用率分别为40.6%和53.8%（p = 0.21）。包括铁蛋白（p = 0.256）和C反应蛋白（p = 0.655）在内的炎症标志物无显著差异。 结论：伴有他汀类药物暴露的侵袭性B细胞淋巴瘤患者在接受CD19 - CAR - T治疗时，PFS和OS有显著改善，毒性发生率相似，且托珠单抗使用率有降低趋势。他汀类药物的使用可能提高疗效并减轻毒性，其作用应在前瞻性试验中进行评估。