Department of Medicine, University of Washington, Seattle, WA.
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
Blood. 2018 Jan 4;131(1):121-130. doi: 10.1182/blood-2017-07-793760. Epub 2017 Oct 16.
Lymphodepletion chemotherapy with CD19-targeted chimeric antigen receptor-modified T (CAR-T)-cell immunotherapy is a novel treatment for refractory or relapsed B-cell malignancies. Infectious complications of this approach have not been systematically studied. We evaluated infections occurring between days 0 to 90 in 133 patients treated with CD19 CAR-T cells in a phase 1/2 study. We used Poisson and Cox regression to evaluate pre- and posttreatment risk factors for infection, respectively. The cohort included patients with acute lymphoblastic leukemia (ALL; n = 47), chronic lymphocytic leukemia (n = 24), and non-Hodgkin lymphoma (n = 62). There were 43 infections in 30 of 133 patients (23%) within 28 days after CAR-T-cell infusion with an infection density of 1.19 infections for every 100 days at risk. There was a lower infection density of 0.67 between days 29 and 90 ( = .02). The first infection occurred a median of 6 days after CAR-T-cell infusion. Six patients (5%) developed invasive fungal infections and 5 patients (4%) had life-threatening or fatal infections. Patients with ALL, ≥4 prior antitumor regimens, and receipt of the highest CAR-T-cell dose (2 × 10 cells per kg) had a higher infection density within 28 days in an adjusted model of baseline characteristics. Cytokine release syndrome (CRS) severity was the only factor after CAR-T-cell infusion associated with infection in a multivariable analysis. The incidence of infections was comparable to observations from clinical trials of salvage chemoimmunotherapies in similar patients. This trial was registered at www.clinicaltrials.gov as #NCT01865617.
以 CD19 为靶点的嵌合抗原受体修饰 T (CAR-T)细胞免疫疗法联合淋巴细胞耗竭化疗是治疗复发/难治性 B 细胞恶性肿瘤的一种新方法。尚未对该方法的感染并发症进行系统研究。我们评估了 133 例接受 CD19 CAR-T 细胞治疗的 1 期/2 期研究患者在第 0 至 90 天之间发生的感染。我们分别使用泊松和 Cox 回归评估治疗前和治疗后的感染风险因素。该队列包括急性淋巴细胞白血病 (ALL；n=47)、慢性淋巴细胞白血病 (n=24)和非霍奇金淋巴瘤 (n=62)患者。在 CAR-T 细胞输注后 28 天内，30 例患者中有 43 例发生感染 (23%)，感染密度为每 100 天风险 1.19 例。在第 29 天至第 90 天，感染密度较低为 0.67（=0.02）。首次感染发生在 CAR-T 细胞输注后中位数 6 天。6 例患者 (5%)发生侵袭性真菌感染，5 例患者 (4%)发生危及生命或致命感染。在调整基线特征的模型中，ALL、≥4 种既往抗肿瘤方案和接受最高 CAR-T 细胞剂量 (2×10 细胞/kg) 的患者在 28 天内的感染密度更高。在多变量分析中，CAR-T 细胞输注后细胞因子释放综合征 (CRS) 的严重程度是唯一与感染相关的因素。感染发生率与类似患者接受挽救性化疗免疫治疗的临床试验观察结果相当。该试验在 www.clinicaltrials.gov 上注册，编号为 #NCT01865617。
