Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
Blood and Marrow Transplant Program, Miami Cancer Institute, Miami, Florida.
Transplant Cell Ther. 2022 Dec;28(12):829.e1-829.e8. doi: 10.1016/j.jtct.2022.09.009. Epub 2022 Sep 26.
Patients with renal impairment (RI) are typically excluded from trials evaluating chimeric antigen receptor (CAR) T cell therapies. We evaluated the outcomes of patients with RI receiving standard of care (SOC) CAR T cell therapy for relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL). In this retrospective, single-center cohort study of patients with R/R DLBCL treated with SOC axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) after 2 or more prior lines of therapy, renal and survival outcomes were compared based on RI and fludarabine dose reduction (DR) status. RI was defined by an estimated glomerular filtration rate <60 mL/min/1.73 m as determined by the Modification of Diet in Renal Disease equation using day -5 creatinine (Cr) values. Acute kidney injury (AKI) was identified and graded using standard Kidney Disease: Improving Global Outcomes criteria. Renal recovery was considered to occur if Cr was within .2 mg/mL of baseline by day +30. Fludarabine was considered DR if given at <90% of the recommended Food and Drug Administration label dose. Among 166 patients treated with CAR T cell therapy were 17 patients (10.2%) with baseline RI and 149 (89.8%) without RI. After CAR T cell infusion, the incidence of any grade AKI was not significantly different between patients with baseline RI and those without RI (42% versus 21%; P = .08). Similarly, severe grade 2/3 AKI was seen in 1 of 17 patients (5.8%) with baseline RI and in 11 of 149 patients (7.3%) without RI (P = 1). Decreased renal perfusion (28 of 39; 72%) was the most common cause of AKI, with cytokine release syndrome (CRS) contributing to 17 of 39 AKIs (44%). Progression-free survival (PFS) and overall survival (OS) did not differ between patients with RI and those without RI or between those who received standard-dose fludarabine and those who received reduced-dose fludarabine. In contrast, patients with AKI had worse clinical outcomes than those without AKI (multivariable PFS: hazard ratio [HR], 2.1; 95% confidence interval [CI], 1.2 to 3.7; OS: HR, 3.9; 95% CI, 2.1 to 7.4). Notably, peak inflammatory cytokine levels were higher in patients who experienced AKI. Finally, we describe 2 patients with end-stage renal disease (ESRD) on dialysis who received lymphodepletion and CAR T cell therapy. Baseline renal function did not affect renal or efficacy outcomes after CAR T cell therapy in DLBCL. On the other hand, patients with AKI went on to experience worse clinical outcomes. AKI was commonly related to CRS and high peak inflammatory cytokine levels. CAR T cell therapy is feasible in patients with ESRD and requires careful planning of lymphodepletion.
患有肾功能损害 (RI) 的患者通常被排除在评估嵌合抗原受体 (CAR) T 细胞疗法的临床试验之外。我们评估了接受标准治疗 (SOC) CAR T 细胞治疗复发性/难治性 (R/R) 弥漫性大 B 细胞淋巴瘤 (DLBCL) 的 RI 患者的结局。在这项回顾性、单中心队列研究中,对接受 SOC axi-cel 或 tisa-cel 治疗的 R/R DLBCL 患者进行了研究,这些患者在接受 SOC 治疗前接受了 2 次或更多次治疗,根据 RI 和氟达拉滨剂量减少 (DR) 状态比较了肾脏和生存结局。RI 是根据第 5 天肌酐 (Cr) 值使用改良肾脏病饮食研究方程定义的,估计肾小球滤过率 <60 mL/min/1.73 m。使用标准肾脏疾病:改善全球结果标准确定和分级急性肾损伤 (AKI)。如果第 30 天 Cr 恢复到基线的 0.2 mg/mL 以内,则认为肾功能恢复。如果氟达拉滨的给药剂量低于推荐的美国食品和药物管理局标签剂量的 90%,则认为氟达拉滨剂量减少。在接受 CAR T 细胞治疗的 166 名患者中,有 17 名 (10.2%) 患者基线时存在 RI,149 名 (89.8%) 患者不存在 RI。在接受 CAR T 细胞输注后,基线时存在 RI 的患者与不存在 RI 的患者之间任何等级 AKI 的发生率没有显著差异 (42%对 21%;P = 0.08)。同样,基线时存在 RI 的患者中有 1 例 (5.8%) 和不存在 RI 的患者中有 11 例 (7.3%) 发生严重 2/3 级 AKI (P = 1)。肾脏灌注减少 (28/39;72%) 是 AKI 的最常见原因,细胞因子释放综合征 (CRS) 导致 39 例 AKI 中的 17 例 (44%)。无 RI 患者的无进展生存期 (PFS) 和总生存期 (OS) 与 RI 患者或接受标准剂量氟达拉滨与接受降低剂量氟达拉滨的患者无差异。相比之下,发生 AKI 的患者的临床结局比未发生 AKI 的患者差(多变量 PFS:风险比 [HR],2.1;95%置信区间 [CI],1.2 至 3.7;OS:HR,3.9;95% CI,2.1 至 7.4)。值得注意的是,发生 AKI 的患者的炎症细胞因子峰值更高。最后,我们描述了 2 名接受透析治疗的终末期肾病 (ESRD) 患者接受了淋巴细胞耗竭和 CAR T 细胞治疗。CAR T 细胞治疗后,基线肾功能不影响 DLBCL 的肾脏或疗效结局。另一方面,发生 AKI 的患者的临床结局更差。AKI 通常与 CRS 和高炎症细胞因子峰值有关。CAR T 细胞治疗在 ESRD 患者中是可行的,但需要仔细规划淋巴细胞耗竭。
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