Division of Pediatric Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN.
Division of Biostatistics, University of Minnesota School of Public Health, Minneapolis, MN.
Blood Adv. 2023 Feb 28;7(4):541-548. doi: 10.1182/bloodadvances.2022007246.
Remarkable complete response rates have been shown with tisagenlecleucel, a chimeric antigen receptor (CAR) T-cell therapy targeting CD19, in patients up to age 26 years with refractory/relapsed B-cell acute lymphoblastic leukemia; it is US Food and Drug Administration approved for this indication. Currently, patients receive a single dose of tisagenlecleucel across a wide dose range of 0.2 to 5.0 × 106 and 0.1 to 2.5 × 108 CAR T cells per kg for patients ≤50 and >50 kg, respectively. The effect of cell dose on survival and remission is not yet well established. Our primary goal was to determine if CAR T-cell dose affects overall survival (OS), event-free survival (EFS), or relapse-free-survival (RFS) in tisagenlecleucel recipients. Retrospective data were collected from Pediatric Real World CAR Consortium member institutions and included 185 patients infused with commercial tisagenlecleucel. The median dose of viable transduced CAR T cells was 1.7 × 106 CAR T cells per kg. To assess the impact of cell dose, we divided responders into dose quartiles: 0.134 to 1.300 × 106 (n = 48 [27%]), 1.301 to 1.700 × 106 (n = 46 [26%]), 1.701 to 2.400 × 106 (n = 43 [24%]), and 2.401 to 5.100 × 106 (n = 43 [24%]). OS, EFS, and RFS were improved in patients who received higher doses of tisagenlecleucel (P = .031, .0079, and .0045, respectively). Higher doses of tisagenlecleucel were not associated with increased toxicity. Because the current tisagenlecleucel package insert dose range remains broad, this work has implications in regard to targeting higher cell doses, within the approved dose range, to optimize patients' potential for long-standing remission.
在接受靶向 CD19 的嵌合抗原受体(CAR)T 细胞疗法 tisagenlecleucel 治疗的 26 岁及以下难治/复发 B 细胞急性淋巴细胞白血病患者中,已显示出显著的完全缓解率;tisagenlecleucel 已获美国食品和药物管理局批准用于该适应证。目前,对于体重≤50kg 和>50kg 的患者,分别给予 0.2 至 5.0×106 和 0.1 至 2.5×108 CAR T 细胞/kg 的广泛剂量范围内的 tisagenlecleucel 单次剂量。细胞剂量对生存和缓解的影响尚未得到充分证实。我们的主要目标是确定 tisagenlecleucel 受者的 CAR T 细胞剂量是否影响总生存(OS)、无事件生存(EFS)或无复发生存(RFS)。从儿科真实世界 CAR 联盟成员机构中收集了回顾性数据,纳入了 185 例接受商业 tisagenlecleucel 输注的患者。活转导 CAR T 细胞的中位数剂量为 1.7×106 CAR T 细胞/kg。为了评估细胞剂量的影响,我们将应答者分为剂量四分位组:0.134 至 1.300×106(n=48[27%])、1.301 至 1.700×106(n=46[26%])、1.701 至 2.400×106(n=43[24%])和 2.401 至 5.100×106(n=43[24%])。接受较高 tisagenlecleucel 剂量的患者 OS、EFS 和 RFS 均得到改善(P=0.031、0.0079 和 0.0045)。较高剂量的 tisagenlecleucel 与毒性增加无关。由于当前 tisagenlecleucel 说明书中的剂量范围仍然很广,因此这项工作对于在批准的剂量范围内靶向更高的细胞剂量以优化患者长期缓解的潜力具有重要意义。
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