Cell Therapy and Transplant Program, Division of Hematology-Oncology and Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA.
Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA.
Blood Adv. 2022 Nov 8;6(21):5774-5785. doi: 10.1182/bloodadvances.2022007317.
In chronic lymphocytic leukemia (CLL) patients who achieve a complete remission (CR) to anti-CD19 chimeric antigen receptor T cells (CART-19), remissions are remarkably durable. Preclinical data suggesting synergy between CART-19 and the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib prompted us to conduct a prospective single-center phase 2 trial in which we added autologous anti-CD19 humanized binding domain T cells (huCART-19) to ibrutinib in patients with CLL not in CR despite ≥6 months of ibrutinib. The primary endpoints were safety, feasibility, and achievement of a CR within 3 months. Of 20 enrolled patients, 19 received huCART-19. The median follow-up for all infused patients was 41 months (range, 0.25-58 months). Eighteen patients developed cytokine release syndrome (CRS; grade 1-2 in 15 of 18 subjects), and 5 developed neurotoxicity (grade 1-2 in 4 patients, grade 4 in 1 patient). While the 3-month CR rate among International Working Group on CLL (iwCLL)-evaluable patients was 44% (90% confidence interval [CI], 23-67%), at 12 months, 72% of patients tested had no measurable residual disease (MRD). The estimated overall and progression-free survival at 48 months were 84% and 70%, respectively. Of 15 patients with undetectable MRD at 3 or 6 months, 13 remain in ongoing CR at the last follow-up. In patients with CLL not achieving a CR despite ≥6 months of ibrutinib, adding huCART-19 mediated a high rate of deep and durable remissions. ClinicalTrials.gov number, NCT02640209.
在接受抗 CD19 嵌合抗原受体 T 细胞（CART-19）治疗后达到完全缓解（CR）的慢性淋巴细胞白血病（CLL）患者中，缓解持续时间非常长。临床前数据表明，CART-19 与布鲁顿酪氨酸激酶（BTK）抑制剂伊布替尼之间存在协同作用，这促使我们开展了一项前瞻性单中心 2 期临床试验，在未达到 CR 且至少接受了 6 个月伊布替尼治疗的 CLL 患者中，我们将自体抗 CD19 人源化结合域 T 细胞（huCART-19）与伊布替尼联合使用。主要终点为安全性、可行性以及在 3 个月内达到 CR。20 名入组患者中，19 名接受了 huCART-19。所有输注患者的中位随访时间为 41 个月（范围，0.25-58 个月）。18 名患者发生细胞因子释放综合征（CRS；18 名患者中的 15 名出现 1-2 级，4 名患者出现 3-4 级），5 名患者发生神经毒性（4 名患者出现 1-2 级，1 名患者出现 4 级）。在国际慢性淋巴细胞白血病工作组（iwCLL）可评估患者中，3 个月时的 CR 率为 44%（90%置信区间[CI]，23-67%），而在 12 个月时，72%的患者检测到无残留疾病（MRD）。48 个月时的总生存率和无进展生存率分别为 84%和 70%。在 3 个月或 6 个月时 MRD 不可测的 15 名患者中，13 名在最后一次随访时仍处于持续 CR 中。在至少接受了 6 个月伊布替尼治疗但未达到 CR 的 CLL 患者中，添加 huCART-19 可导致深度且持久的缓解率较高。临床试验注册号：NCT02640209。
