Turtle Cameron J, Hay Kevin A, Hanafi Laïla-Aïcha, Li Daniel, Cherian Sindhu, Chen Xueyan, Wood Brent, Lozanski Arletta, Byrd John C, Heimfeld Shelly, Riddell Stanley R, Maloney David G
Cameron J. Turtle, Kevin A. Hay, Laïla-Aïcha Hanafi, Shelly Heimfeld, Stanley R. Riddell, and David G. Maloney, Fred Hutchinson Cancer Research Center; Cameron J. Turtle, Sindhu Cherian, Xueyan Chen, Brent Wood, Stanley R. Riddell, and David G. Maloney, University of Washington; Daniel Li, Juno Therapeutics, Seattle, WA; and Arletta Lozanski and John C. Byrd, The Ohio State University, Columbus, OH.
J Clin Oncol. 2017 Sep 10;35(26):3010-3020. doi: 10.1200/JCO.2017.72.8519. Epub 2017 Jul 17.
Purpose We evaluated the safety and feasibility of anti-CD19 chimeric antigen receptor-modified T (CAR-T) cell therapy in patients with chronic lymphocytic leukemia (CLL) who had previously received ibrutinib. Methods Twenty-four patients with CLL received lymphodepleting chemotherapy and anti-CD19 CAR-T cells at one of three dose levels (2 × 10, 2 × 10, or 2 × 10 CAR-T cells/kg). Nineteen patients experienced disease progression while receiving ibrutinib, three were ibrutinib intolerant, and two did not experience progression while receiving ibrutinib. Six patients were venetoclax refractory, and 23 had a complex karyotype and/or 17p deletion. Results Four weeks after CAR-T cell infusion, the overall response rate (complete response [CR] and/or partial response [PR]) by International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria was 71% (17 of 24). Twenty patients (83%) developed cytokine release syndrome, and eight (33%) developed neurotoxicity, which was reversible in all but one patient with a fatal outcome. Twenty of 24 patients received cyclophosphamide and fludarabine lymphodepletion and CD19 CAR-T cells at or below the maximum tolerated dose (≤ 2 × 10 CAR-T cells/kg). In 19 of these patients who were restaged, the overall response rate by IWCLL imaging criteria 4 weeks after infusion was 74% (CR, 4/19, 21%; PR, 10/19, 53%), and 15/17 patients (88%) with marrow disease before CAR-T cells had no disease by flow cytometry after CAR-T cells. Twelve of these patients underwent deep IGH sequencing, and seven (58%) had no malignant IGH sequences detected in marrow. Absence of the malignant IGH clone in marrow of patients with CLL who responded by IWCLL criteria was associated with 100% progression-free survival and overall survival (median 6.6 months follow-up) after CAR-T cell immunotherapy. The progression-free survival was similar in patients with lymph node PR or CR by IWCLL criteria. Conclusion CD19 CAR-T cells are highly effective in high-risk patients with CLL after they experience treatment failure with ibrutinib therapy.
目的 我们评估了抗CD19嵌合抗原受体修饰的T（CAR-T）细胞疗法在先前接受过依鲁替尼治疗的慢性淋巴细胞白血病（CLL）患者中的安全性和可行性。方法 24例CLL患者接受了淋巴细胞清除化疗，并接受了三种剂量水平之一（2×10、2×10或2×10 CAR-T细胞/kg）的抗CD19 CAR-T细胞治疗。19例患者在接受依鲁替尼治疗时出现疾病进展，3例对依鲁替尼不耐受，2例在接受依鲁替尼治疗时未出现进展。6例患者对维奈克拉耐药，23例具有复杂核型和/或17p缺失。结果 CAR-T细胞输注后4周，根据慢性淋巴细胞白血病国际研讨会（IWCLL）标准，总体缓解率（完全缓解[CR]和/或部分缓解[PR]）为71%（24例中的17例）。20例患者（83%）发生细胞因子释放综合征，8例患者（33%）发生神经毒性，除1例患者死亡外，其余所有患者的神经毒性均可逆转。24例患者中有20例接受了环磷酰胺和氟达拉滨淋巴细胞清除以及最大耐受剂量（≤2×10 CAR-T细胞/kg）或以下的CD19 CAR-T细胞治疗。在这些接受重新分期的19例患者中，输注后4周根据IWCLL影像学标准的总体缓解率为74%（CR，4/19，21%；PR，10/19，53%），17例CAR-T细胞治疗前有骨髓疾病的患者中有15例（88%）在CAR-T细胞治疗后通过流式细胞术检测无疾病。其中12例患者进行了深度IGH测序，7例（58%）在骨髓中未检测到恶性IGH序列。根据IWCLL标准有反应的CLL患者骨髓中无恶性IGH克隆与CAR-T细胞免疫治疗后的100%无进展生存期和总生存期（中位随访6.6个月）相关。根据IWCLL标准有淋巴结PR或CR的患者的无进展生存期相似。结论 CD19 CAR-T细胞在依鲁替尼治疗失败的高危CLL患者中具有高度有效性。
