CAR-T（CAR-T）细胞疗法在非肿瘤性疾病中的应用
Chimeric antigen receptor T (CAR-T) cell therapy in non-oncological diseases.
CAR-T（CAR-T）细胞在血液系统恶性肿瘤中的应用推动了这种免疫治疗形式的显著进展。
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
最佳氟达拉滨淋巴细胞清除与 CAR-T 细胞治疗后结局改善相关
英文原题：Optimal fludarabine lymphodepletion is associated with improved outcomes after CAR T-cell therapy.
查看英文原题
Optimal fludarabine lymphodepletion is associated with improved outcomes after CAR T-cell therapy.
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中文摘要
嵌合抗原受体（CAR）T细胞为血液系统恶性肿瘤提供了一种治疗选择。然而，初始缓解后的治疗失败率接近50%。在异基因造血细胞移植中，最佳的氟达拉滨暴露可改善免疫重建，从而降低非复发死亡率并提高生存率。
我们假设，在CAR-T 细胞治疗前淋巴细胞清除化疗中，最佳的氟达拉滨暴露会改善结局。在一项回顾性分析中，纳入接受环磷酰胺/氟达拉滨淋巴细胞清除化疗后输注CAR-T 细胞（tisagenlecleucel）的复发/难治性B细胞急性淋巴细胞白血病患者，我们使用经过验证的群体药代动力学（PK）模型估算氟达拉滨暴露，即曲线下面积（AUC；mg h/L）。氟达拉滨暴露与总生存期（OS）、累积复发率（CIR）以及复合终点（B细胞再生障碍[B-cell aplasia, BCA]丧失或复发）相关。符合条件的患者（n = 152）中位年龄为12.5岁（范围，<1至26），缓解率为86%（n = 131/152），12个月OS为75.1%（95%置信区间[CI]，67.6%至82.6%），12个月CIR为36.4%（95% CI，27.5%至45.2%）。
最佳氟达拉滨暴露确定为AUC 13.8 mg h/L。在多变量分析中，与最佳氟达拉滨暴露的患者相比，AUC <13.8 mg h/L的患者CIR高2.5倍（风险比[HR]，2.45；95% CI，1.34-4.48；P = .005），复发或BCA丧失风险高2倍（HR，1.96；95% CI，1.19-3.23；P = .01）。输注前高疾病负荷也与复发风险增加（HR，2.66；95% CI，1.45-4.87；P = .001）和死亡风险增加（HR，4.77；95% CI，2.10-10.9；P < .001）相关。个体化PK导向给药以实现最佳氟达拉滨暴露应在前瞻性试验中检验，基于本分析，这可能减少CAR-T 细胞治疗后的疾病复发。
展开英文摘要原文
Chimeric antigen receptor (CAR) T cells provide a therapeutic option in hematologic malignancies.
However, treatment failure after initial response approaches 50%. In allogeneic hematopoietic cell transplantation, optimal fludarabine exposure improves immune reconstitution, resulting in lower nonrelapse mortality and increased survival.
We hypothesized that optimal fludarabine exposure in lymphodepleting chemotherapy before CAR T-cell therapy would improve outcomes. In a retrospective analysis of patients with relapsed/refractory B-cell acute lymphoblastic leukemia undergoing CAR T-cell (tisagenlecleucel) infusion after cyclophosphamide/fludarabine lymphodepleting chemotherapy, we estimated fludarabine exposure as area under the curve (AUC; mg h/L) using a validated population pharmacokinetic (PK) model. Fludarabine exposure was related to overall survival (OS), cumulative incidence of relapse (CIR), and a composite end point (loss of B-cell aplasia [BCA] or relapse). Eligible patients (n = 152) had a median age of 12. 5 years (range, <1 to 26), response rate of 86% (n = 131 of 152), 12-month OS of 75. 1% (95% confidence interval [CI], 67.
6% to 82. 6%), and 12-month CIR of 36. 4% (95% CI, 27. 5% to 45. 2%). Optimal fludarabine exposure was determined as AUC 13. 8 mg h/L. In multivariable analyses, patients with AUC <13. 8 mg h/L had a 2. 5-fold higher CIR (hazard ratio [HR], 2. 45; 95% CI, 1. 34-4. 48; P = . 005) and twofold higher risk of relapse or loss of BCA (HR, 1. 96; 95% CI, 1. 19-3. 23; P = . 01) compared with those with optimal fludarabine exposure.
High preinfusion disease burden was also associated with increased risk of relapse (HR, 2. 66; 95% CI, 1. 45-4. 87; P = . 001) and death (HR, 4. 77; 95% CI, 2. 10-10. 9; P < . 001). Personalized PK-directed dosing to achieve optimal fludarabine exposure should be tested in prospective trials and, based on this analysis, may reduce disease relapse after CAR T-cell therapy.
论文信息
- 作者
- Fabrizio VA、Boelens JJ、Mauguen A、Baggott C、Prabhu S、Egeler E、Mavroukakis S、Pacenta H
- 第一作者单位
- Colorado Children's Hospital, Anschutz Medical Campus, University of Colorado, Aurora, CO.
- 通讯作者单位
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY.United States
- 文献类型
- 美国 NIH 资助研究 · 非美国政府资助研究
- 期刊
- Blood advances2022 Apr 12
- 原文标识
- PubMed 34788386 · DOI 10.1182/bloodadvances.2021006418
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