美国FDA批准安进BiTE免疫疗法Blincyto治疗儿科急性淋巴细胞白血病（ALL） Blincyto（blinatumomab）是全球首个BiTE免疫疗法，基于安进最先进的双特异性T细胞衔接系统（BiTE）开发，这是一种双特异性抗体，能够通过将肿瘤细胞上的CD19蛋白呈递给T细胞特异表达的CD3蛋白，进而激活免疫系统识别并杀灭肿瘤细胞。 FDA的药品评价和研究中心血液学和肿瘤学产品室主任Richard Pazdur，医学博士说：“免疫治疗，尤其是Blincyto有其独特的作用机制，对有白血病患者尤其鼓舞人有前途。“”“认识到这个新治疗的潜能，FDA与承办单位在我们突破性治疗指定程序下主动共事便于批准这个新型药物。” 突破性治疗指定，优先审评和孤儿产品指定，加速批准程序。 批准日期：2014年12月3日；公司：Amgen Inc. BLINCYTO(blinatumomab)冻干粉注射剂  为静脉使用 在美国初次批准：2014 适应证和用途 BLINCYTO是一种圣特异性指向CD19 CD3 T-细胞衔接器适用为费城染色体-阴性复发性或难治性B-细胞前体急性淋巴母细胞白血病(ALL)的治疗。这个适应证是在加速批准下被批准的。继续批准这个适应证可能取决于在随后试验中临床获益的确证。 剂量和给药方法 ⑴ 剂量–建议对第一个疗程的头9天和第二个疗程的头2天住院。 ⒈治疗的单个疗程由连续静脉输注4周接着自由间隔2周治疗组成。 ⒉ 对体重至少45 kg患者，在疗程1中，在第1–7天给予BLINCYTO在9g/day和在第8–28天28g/day。对随后疗程，在第1–28天给予BLINCYTO在28g/day。 ⑵ 给药 ⒈在每个疗程BLINCYTO的首次剂量前1小时，前一步剂量前(例如疗程1第8天)，或一次4或更多小时的中断后重新开始输注，静脉用地塞米松[dexamethasone]20mg预先给药。 ⒉利用一个输注泵在恒速连续静脉输注给予。 ⒊静脉IV袋应被历时24小时或48小时输注。 ⒋BLINCYTO应通过一个专门的管腔输注。 ⑶ 制备 – 提供静脉溶液稳定剂和加入重建的BLINCYTO前用于涂层预充液IV袋。 ⒈只用注射用无菌注射用水，USP重建BLINCYTO。 ⒉当制备为输注溶液时必须严格无菌术观察因为BLINCYTO不含抗微生物防腐剂。 ⒊ 使用在混合指导中描述的专门容积。 剂型和规格 注射用：为重建35g冻干粉在一次性使用小瓶中。 禁忌证 对blinatumomab或对产品剂型的任何组分已知超敏性。 BLINCYTO 35mcg/vial Blinatumomab for Injection BLINCYTO 35 mcg single-use vial containing a sterile, preservative-free, white to off-white lyophilized powder and One IV Solution Stabilizer 10mL single-use glass vial containing a sterile, preservative-free, colorless to slightly yellow, clear solution. Do not use the IV Solution Stabilizer to reconstitute BLINCYTO. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=38b482a8-960b-4591-9857-5031ecb830aa BLINCYTO Rx Pharmacological Class: Bispecific CD19-directed CD3 T-cell engager. Active Ingredient(s): Blinatumomab 35mcg; per vial; lyophilized pwd for IV infusion after reconstitution; preservative-free. Company Amgen, Inc Indication(s): Philadelphia chromosome-negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL). Pharmacology: Blinatumomab binds to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells. It activates endogenous T cells by connecting CD3 in the T-cell receptor complex with CD19 on benign and malignant B cells. It mediates the formation of a synapse between the T cell and the tumor cell, upregulation of cell adhesion molecules, production of cytolytic proteins, release of inflammatory cytokines, and proliferation of T cells, which result in redirected lysis of CD19+ cells. Clinical Trials: The safety and efficacy of Blincyto were evaluated in an open-label, multi-center, single-arm study (N=185). Patients were given Blincyto 9mcg/day for Week 1, then 28mcg/day for the remaining 3 weeks. The target dose of 28mcg/day was given in Cycle 2 and subsequent cycles. The primary endpoint was complete remission/complete remission with partial hematological recovery (CR/CRh*) rate within 2 cycles of treatment with Blincyto. Results showed 77/185 (41.6%) patients achieved CR/CRh* within the first 2 cycles, with 81% of responses occurring within Cycle 1 of treatment. Minimal residual disease response was seen in 75.3% of the CR/CRh* group (95% CI: 64.2–84.4). Duration of response/relapse-free survival was 6.7 months (range: 0.46–16.5) in the CR group and 5.9 months (range: 0.13–16.5) in the CR/CRh* group. For more clinical trial data, see full labeling. Legal Classification: Rx Adults: Strictly follow preparation and administration instructions. Pre-medicate with IV dexamethasone 20mg 1 hour prior to 1st dose of each cycle, prior to a step dose, or when restarting infusion after interruption (≥4 hours). Hospitalization recommended for first 9 days of Cycle 1 and first 2 days of Cycle 2. One single cycle = 4 weeks of continuous IV infusion followed by a 2-week treatment-free interval. ≥18 years (≥45kg): Give by continuous IV infusion at a rate of 10mL/hr for 24 hours or 5mL/hr for 48 hours. Cycle 1: 9mcg/day on Days 1–7 and 28mcg/day on Days 8–28. Subsequent cycles: 28mcg/day on Days 1–28. Treat up to a total of 5 cycles. Dose adjustments: see full labeling. Children: <18 years: not established. Warnings/Precautions: Monitor for signs/symptoms of cytokine release syndrome or neurological toxicities; interrupt or discontinue as recommended (see full labeling). Monitor for infections; give antibiotic prophylaxis as appropriate. Monitor for tumor lysis syndrome; interrupt or discontinue as needed. Obtain lab tests (including WBC, ANC) during infusion; interrupt if prolonged neutropenia occurs. Monitor ALT, AST, GGT, and total bilirubin prior to and during treatment; interrupt if transaminases rise >5XULN or if bilirubin rises >3XULN. Risk of leukoencephalopathy, esp. in those with prior treatment with cranial irradiation and antileukemic chemotherapy (including high-dose methotrexate or intrathecal cytarabine). Renal impairment (CrCl <30mL/min) or hemodialysis. Elderly. Pregnancy (Category C). Nursing mothers: not recommended. Interaction(s) Caution with concomitant CYP450 substrates (esp. drugs with narrow therapeutic index); adjust dose as needed. Monitor for toxicity with warfarin. Monitor cyclosporine. Adverse Reaction(s) Pyrexia, headache, peripheral edema, febrile neutropenia, nausea, hypokalemia, tremor, rash, constipation; pneumonia, sepsis, neutropenia, device-related infection, tremor, encephalopathy, confusion, overdose, possible immunogenicity. How Supplied: Pack—1 (single-use vial + IV solution stabilizer) LAST UPDATED: 3/13/2015 安进BiTE单抗Blinatumomab（Blincyto）获得美国FDA速批准上市， 为全球首个抗CD19药物 2015年1月5日，美国FDA批准首个的肿瘤免疫疗法—双特异性T-细胞结合蛋白（BiTE）Blinatumomab（商品名：Blincyto）上市，治疗费氏染色体阴性的前体B细胞急性淋巴细胞白血病。Blincyto由生物制药巨头安进开发，是第一个上市的BiTE单链抗体。 Blinatumomab最初由德国的Micromet公司研发，Blinatumomab（AMG103）是利用DNA重组技术制备的一种双特异性的单链抗体BiTE，通过一条多肽链把靶向肿瘤细胞和T细胞表面抗原的两种单克隆抗体的可变区连接起来，这样和其它靶向肿瘤细胞抗原的单抗一样，Blinatumomab选择性地靶向B细胞表面抗原CD19，但是和其它抗癌单抗不同的是，Blinatumomab同时特异性地结合T细胞表面抗原CD3从而激活T细胞，活化的T细胞是杀伤肿瘤细胞的主要效应细胞。因为主要由两条单链抗体连接而成，BiTE的分子量较小（55-60kDa），容易渗透肿瘤组织。同时BiTE缺乏Fc段因而免疫源性较低。2014年7月，Blinatumomab获得美国FDA的“突破性药物”资格，治疗急性淋巴细胞白血病（ALL）。2014年10月，FDA又给予Blinatumomab“优先评审”（priority review）认定，处方费用户法案日期被定为2015年5月19日。 前体B细胞淋巴细胞白血病（Precursor B-cell lymphoblastic leukemia）是一种进展迅速的白血病，临床表现为骨髓产生太多B细胞淋巴母细胞。按照美国癌症研究院的数据，美国每年大约有6000人诊断为ALL，2014年的死亡人数大约为1440。在一个有185名费城染色体阴性的前体B细胞ALL患者参与的临床实验中，这些患者之前都经过治疗但都不再表现应答，经过Blincyto治疗（输注）四周或以上，有32%的患者在平均6.7个月内没有检测到肿瘤细胞的存在（完全缓解）。 药源刚刚讨论过，肿瘤免疫疗法的进展日新月异，Blinatumomab是美国FDA批准的首个双特异性T细胞结合蛋白，为肿瘤的免疫疗法又增加了一个上市品种。和免疫哨卡抑制剂Keytruda一样，Blinatumomab享受了FDA所有的审批优惠，包括优先评审、加速批准、突破性药物认定、和孤儿药。Blinatumomab比预期的批准日期提前了5个多月。因为是加速批准，美国FDA要求厂家继续进行Blinatumomab的临床研究，验证本品是否能提高这些复发性或难治性的，费城染色体阴性的前B细胞ALL患者的生存率。同时Blinatumomab伴有警告，提醒患者和医护人员一些试用者在该药早期经历低血压和呼吸困难（细胞因子释放综合征）、短期的思考困难、以及其它神经系统副作用。最常见不良事件包括发热、头痛、组织肿胀（外周水肿）、恶心、低钾、疲劳、便秘、腹泻和震颤等。