Abstract：
Although anti-CD19 chimeric antigen receptor (CAR) T cell therapy has achieved satisfactory results in relapsed/refractory (R/R) follicular lymphoma (FL), patients with R/R FL and high-risk disease characteristics, previous hematopoietic stem cell transplantation, bulky disease, and progression of disease within 2 years (POD24) had a low complete response (CR). Twenty-seven patients with R/R FL, later disease stages, higher tumor burden, or higher previous treatment lines who had received Bruton tyrosine kinase (BTK) inhibitors before anti-CD19 CAR T cell therapy, or received BTK inhibitors as combination therapy, were included in this study. The clinical response and adverse events (AEs) in anti-CD19 CAR T cell therapy were observed. All patients with R/R FL who received BTK inhibitors combined with anti-CD19-CAR T cell therapy had later disease stages, higher tumor burden, and higher treatment lines than those who did not receive BTK inhibitor combination therapy. However, no difference in the clinical response was found between the two groups. The clinical response in the POD24 group was lower than that in the non-POD24 group; however, no difference in the clinical response was found between the FL and transformed FL (tFL) groups, between the follicular lymphoma international prognostic index (FLIPI) 1 1-2 and FLIPI 1 3-5 groups, and between the FLIPI 2 1-2 and FLIPI 2 3-5 groups. The mean anti-CD19 CAR T cell peak was higher in the CAR-T group with BTK inhibitor than in the CAR-T group without BTK inhibitor. Meanwhile, a higher proportion of patients in the non-POD24 group, FL group, and PR group achieved CR after 2 months. No difference in cytokine secretion was found between the CAR-T group with and without BTK inhibitors. It was higher in the non-POD24 group, FLIPI 1 3-5 group, and FLIPI 2 3-5 group. No difference in cytokine release syndrome and immune effector cell-associated neurotoxic syndrome grades was found between the CAR-T groups with or without BTK inhibitors and between the other groups. Poor prognostic factors, other than POD24, did not affect the clinical response to BTK inhibitors in combination with anti-CD19 CAR T cell therapy in patients with R/R FL. Therefore, BTK inhibitors combined with anti-CD19 CAR-T therapy may be an effective and safe approach for patients with R/R FL and high-risk factors.Trial registration: The study was registered at http://www.chictr.org.cn/index.aspx as ChiCTR-ONN-16009862 and http://www.chictr.org.cn/index.aspx as ChiCTR1800019622.
摘要：
尽管抗CD19嵌合抗原受体（CAR）T细胞治疗在复发/难治性（R/R）滤泡性淋巴瘤（FL）中取得了令人满意的结果，具有R/RFL和高危疾病特征的患者，以前的造血干细胞移植，庞大的疾病，2年内疾病进展（POD24）的完全反应（CR）较低。27例R/RFL患者，晚期疾病阶段，更高的肿瘤负担，在抗CD19CART细胞治疗之前接受过Bruton酪氨酸激酶（BTK）抑制剂或更高的先前治疗线，或接受BTK抑制剂作为联合治疗，包括在这项研究中。观察抗CD19CART细胞治疗中的临床反应和不良事件(AE)。所有接受BTK抑制剂联合抗CD19-CAR-T细胞治疗的R/RFL患者的疾病分期较晚，更高的肿瘤负担，与未接受BTK抑制剂联合治疗的患者相比，治疗线更高。然而,两组间临床反应无差异.POD24组的临床反应低于非POD24组;然而,FL和转化FL（tFL）组之间的临床反应没有差异，在滤泡性淋巴瘤国际预后指数（FLIPI）11-2和FLIPI13-5组之间，在FLIPI21-2和FLIPI23-5组之间。具有BTK抑制剂的CAR-T组的平均抗CD19CART细胞峰高于不具有BTK抑制剂的CAR-T组。同时,非POD24组患者比例较高，FL组,PR组2个月后达到CR。在有和没有BTK抑制剂的CAR-T组之间没有发现细胞因子分泌的差异。非POD24组较高，FLIPI13-5组，和FLIPI23-5组。在有或没有BTK抑制剂的CAR-T组之间以及在其他组之间没有发现细胞因子释放综合征和免疫效应细胞相关的神经毒性综合征等级的差异。不良预后因素，除POD24外，R/RFL患者对BTK抑制剂联合抗CD19CART细胞疗法的临床反应无影响。因此,BTK抑制剂联合抗CD19CAR-T治疗可能是R/RFL和高危因素患者的有效和安全的方法。试验注册：该研究已在http://www上注册。chictr.org.cn/index。aspx为ChiCTR-ONN-16009862和http://www。chictr.org.cn/index。aspx为ChiCTR1800019622。
