Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany.
Department of Medicine II, Goethe University, Frankfurt, Germany.
Lancet Oncol. 2015 Jan;16(1):57-66. doi: 10.1016/S1470-2045(14)71170-2. Epub 2014 Dec 16.
BACKGROUND: Adults with relapsed or refractory B-precursor acute lymphoblastic leukaemia have an unfavourable prognosis. Blinatumomab is a bispecific T-cell engager antibody construct targeting CD19, an antigen consistently expressed on B-lineage acute lymphoblastic leukaemia cells. We aimed to confirm the activity and safety profile of blinatumomab for acute lymphoblastic leukaemia. METHODS: In a multicentre, single-arm, open-label phase 2 study, we enrolled adult patients with Philadelphia-chromosome-negative, primary refractory or relapsed (first relapse within 12 months of first remission, relapse within 12 months after allogeneic haemopoietic stem-cell transplantation [HSCT], or no response to or relapse after first salvage therapy or beyond) leukaemia. Patients received blinatumomab (9 μg/day for the first 7 days and 28 μg/day thereafter) by continuous intravenous infusion over 4 weeks every 6 weeks (up to five cycles), per protocol. The primary endpoint was complete remission (CR) or CR with partial haematological recovery of peripheral blood counts (CRh) within the first two cycles. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT01466179. FINDINGS: Between Jan 13, 2012, and Oct 10, 2013, 189 patients were enrolled and treated with blinatumomab. After two cycles, 81 (43%, 95% CI 36-50) patients had achieved a CR or CRh: 63 (33%) patients had a CR and 18 (10%) patients had a CRh. 32 (40%) of patients who achieved CR/CRh underwent subsequent allogeneic HSCT. The most frequent grade 3 or worse adverse events were febrile neutropenia (48 patients, 25%), neutropenia (30 patients, 16%), and anaemia (27 patients, 14%). Three (2%) patients had grade 3 cytokine release syndrome. Neurologic events of worst grade 3 or 4 occurred in 20 (11%) and four (2%) patients, respectively. Three deaths (due to sepsis, Escherichia coli sepsis, and Candida infection) were thought to be treatment-related by the investigators. INTERPRETATION: Single-agent blinatumomab showed antileukaemia activity in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia characterised by negative prognostic factors. Further assessment of blinatumomab treatment earlier in the course of the disease and in combination with other treatment approaches is warranted. FUNDING: Amgen.
背景：复发或难治性 B 前体急性淋巴细胞白血病成人患者预后不良。blinatumomab 是一种针对 CD19 的双特异性 T 细胞衔接抗体构建体，CD19 是 B 系急性淋巴细胞白血病细胞上持续表达的抗原。我们旨在证实 blinatumomab 对急性淋巴细胞白血病的活性和安全性。
方法：在一项多中心、单臂、开放标签的 2 期研究中，我们招募了费城染色体阴性、原发性难治性或复发（首次缓解后 12 个月内复发、异基因造血干细胞移植 [HSCT] 后 12 个月内复发、首次挽救治疗后无反应或复发或复发后）的白血病成年患者。根据方案，患者接受blinatumomab（第 1 天至第 7 天 9 μg/天，此后 28 μg/天）连续静脉输注 4 周，每 6 周 1 次（最多 5 个周期）。主要终点是在前两个周期内达到完全缓解（CR）或伴有外周血计数部分恢复的完全缓解（CRh）。分析采用意向治疗。该试验在 ClinicalTrials.gov 上注册，编号为 NCT01466179。
结果：2012 年 1 月 13 日至 2013 年 10 月 10 日，共纳入 189 例患者接受blinatumomab 治疗。在两个周期后，81 例（43%，95%CI 36-50）患者达到 CR 或 CRh：63 例（33%）患者达到 CR，18 例（10%）患者达到 CRh。32 例（40%）达到 CR/CRh 的患者随后接受了异基因 HSCT。最常见的 3 级或更高级别的不良事件是发热性中性粒细胞减少症（48 例，25%）、中性粒细胞减少症（30 例，16%）和贫血症（27 例，14%）。3 例（2%）患者发生 3 级细胞因子释放综合征。最严重的 3 级或 4 级神经系统事件分别发生在 20 例（11%）和 4 例（2%）患者中。3 例死亡（研究者认为与败血症、大肠杆菌败血症和念珠菌感染有关）被认为与治疗有关。
解释：单药blinatumomab在具有阴性预后因素的复发或难治性 B 前体急性淋巴细胞白血病成人患者中表现出抗白血病活性。进一步评估 blinatumomab 在疾病早期的治疗以及与其他治疗方法的联合治疗是值得的。
资金来源：安进公司。
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