Queudeville Manon, Handgretinger Rupert, Ebinger Martin
Department of Pediatric Hematology and Oncology, University Children's Hospital, University of Tübingen, Tübingen, Germany.
Onco Targets Ther. 2017 Jul 19;10:3567-3578. doi: 10.2147/OTT.S103470. eCollection 2017.
Patients with refractory or relapsed (R/R) acute lymphoblastic leukemia (ALL) have a dismal prognosis of around 5% long-term survival when treated with cytotoxic chemotherapy and allogenic stem cell transplantation. T-cell immunobased strategies open up new therapeutic perspectives. Blinatumomab is the first of a new class of antibody constructs that was labeled bispecific T-cell engager (BiTE): it consists of two single chain variable fragment connected with a flexible linker, one side binding CD3, the other CD19. The tight binding and the close proximity to the CD19-positive B-cells and leukemic cells leads to non-major histocompatibility complex-restricted T-cell activation, polyclonal T-cell expansion and direct target cell killing. Applied by continuous infusion, blinatumomab achieves morphological complete response rates ranging from 39% to 69% in R/R ALL patients (compared to 25% after second-line chemotherapy) with prolonged overall survival (blinatumomab median overall survival, 7.7 months vs chemotherapy, 4.0 months). In comparison to conventional cytotoxic second-line protocols blinatumomab has a favorable safety profile. The main adverse event is related to the mode of action of blinatumomab: the induction of a cytokine-release syndrome that can be managed by interruption and/or the application of steroids or tocilizumab. Another typical complication is the occurrence of neurological side effects, such as seizures and encephalopathy. This neurotoxicity is reversible after application of steroids and/or withdrawal of blinatumomab. Blinatumomab has proven to be a powerful therapeutic option in R/R ALL patients both adult and pediatric because of its efficacy and limited toxicity.
难治性或复发性（R/R）急性淋巴细胞白血病（ALL）患者接受细胞毒性化疗和异基因干细胞移植治疗时，长期生存率约为5%，预后不佳。基于T细胞免疫的策略开辟了新的治疗前景。博纳吐单抗是一类新型抗体构建体中的首个药物，被标记为双特异性T细胞衔接器（BiTE）：它由两个通过柔性接头连接的单链可变片段组成，一侧结合CD3，另一侧结合CD19。与CD19阳性B细胞和白血病细胞的紧密结合及近距离接触导致非主要组织相容性复合体限制的T细胞活化、多克隆T细胞扩增和直接靶细胞杀伤。通过持续输注应用，博纳吐单抗在R/R ALL患者中实现了39%至69%的形态学完全缓解率（相比二线化疗后的25%），总体生存期延长（博纳吐单抗的中位总体生存期为7.7个月，化疗为4.0个月）。与传统细胞毒性二线方案相比，博纳吐单抗具有良好的安全性。主要不良事件与博纳吐单抗的作用方式有关：诱导细胞因子释放综合征，可通过中断和/或应用类固醇或托珠单抗来处理。另一个典型并发症是出现神经副作用，如癫痫发作和脑病。应用类固醇和/或停用博纳吐单抗后，这种神经毒性是可逆的。由于其疗效和有限的毒性，博纳吐单抗已被证明是成人和儿童R/R ALL患者的一种有效治疗选择。
