—Blincyto是全球首个BiTE免疫疗法，采用双特异性T细胞衔接系统（BiTE）技术开发的最新白血病治疗新药
2015年12月4日，欧盟委员会（EC）有条件批准安进旗下 Blincyto（blinatumomab），用于费城染色体阴性（Ph-）复发或难治性B细胞前体急性淋巴细胞白血病（ALL）成人患者治疗。Blincyto是一种双特异性靶向CD19的 CD3 T细胞衔接器（BiTE）抗体构建体，它可以特定性地与表达在B血统起源细胞表面的CD19及表达在T细胞表面的CD3相结合。
BiTE 抗体构建体是一种类型的免疫疗法，其被研究通过帮助人体免疫系统检查并以恶性细胞为靶点而抗击癌症。这种改良的抗体被设计同时针对两种不同的靶点，因而可以向癌细胞并置T细胞。BiTE抗体构建体帮助在靶细胞附近放置T细胞，目的是让T细胞注射毒素，并诱发癌细胞死亡（细胞凋亡）。BiTE 抗体构建体目前正被研究其潜能，用于治疗各种各样的癌症。
我们很高兴欧盟委员会有条件批准Blincyto，安进研发执行副总裁、医学博士Harper称。Blincyto治疗复发或难治性淋巴细胞白血病已证明有效，这是一种非常难以治疗的疾病，该疾病患者历来的治疗选择有限。这次批准代表了免疫疗法研究的一个重要里程碑。Blincyto是BiTE平台的首个临床验证，该平台是一种新的及创新型的途径，它可以帮助人体自身的免疫系统抗击癌症。
此次Blincyto的有条件批准基于两项2期研究，即211研究与206研究的结果。在关键的211试验中，42.9%的以Blincyto单药治疗的患者达到完全缓解或有部分血液学康复（CRh）的完全缓解。
BLINCYTO  二十多年来的首个重大进展
在淋巴细胞白血病中测试Blincyto，这们知道这种疾病是最具侵袭性的B细胞恶性肿瘤，试验中我们观察到了具有临床意义的缓解率，德国维尔茨堡医院的教授、医学博士Topp称。对于患有这种难以治疗癌症的患者来说，这是二十多年来取得的首个重大进展。
对于难以治疗或经历复发的淋巴细胞白血病患者来说，其预后是较差的，Blincyto为这些患者提供了一种新的治疗选择，巴黎圣路易斯的医院、巴黎大学的教授、医学博士Dombret称。对于临床医师及患者，有更多的治疗选择用于这种急性形式的白血病是非常重要的。

Blincyto (blinatumomab)
Drug SummaryAmgen Inc

Blincyto(blinatumomab)
BOXED WARNING
Cytokine release syndrome (CRS), which may be life-threatening or fatal, reported; interrupt or d/c therapy as recommended. Neurological toxicities, which may be severe, life-threatening, or fatal, reported; interrupt or d/c therapy as recommended.
THERAPEUTIC CLASS
CD19-directed CD3 T-cell engager
DEA CLASS
RX
ADULT DOSAGE & INDICATIONS
Acute Lymphoblastic Leukemia
Philadelphia Chromosome-Negative:
Relapsed or Refractory B-Cell Precursor:
>45kg:
Cycle 1: 9mcg/day on Days 1-7, and 28mcg/day on Days 8-28
Subsequent Cycles: 28mcg/day on Days 1-28
Single cycle of treatment consists of 4 weeks of continuous IV infusion followed by a 2-week treatment-free interval
Treatment course consists of up to 2 cycles for induction followed by 3 additional cycles for consolidation treatment (up to a total of 5 cycles)
PEDIATRIC DOSAGE & INDICATIONS
Acute Lymphoblastic Leukemia
Philadelphia Chromosome-Negative:
Relapsed or Refractory B-Cell Precursor:
Limited experience in pediatric patients
Evaluated in a dose-escalation study of 41 pediatric patients with relapsed or refractory B-precursor acute lymphoblastic leukemia (median age was 6 yrs [range: 2-17 yrs]). Administered at doses of 5-30mcg/m2/day. Recommended phase 2 regimen was 5mcg/m2/day on Days 1-7 and 15mcg/m2/day on Days 8-28 for cycle 1, and 15mcg/m2/day on Days 1-28 for subsequent cycles
Steady-state concentrations were comparable in adult and pediatric patients at the equivalent dose levels based on BSA-based regimens
DOSING CONSIDERATIONS
Adverse Reactions
If interruption after an adverse event is no longer than 7 days, continue same cycle to a total of 28 days of infusion inclusive of days before and after the interruption in that cycle. If an interruption due to an adverse event is >7 days, start a new cycle
Cytokine Release Syndrome:
Grade 3: Withhold until resolved, then restart at 9mcg/day. Escalate to 28mcg/day after 7 days if the toxicity does not recur
Grade 4: D/C permanently
Neurological Toxicity:
Seizure: D/C permanently if >1 seizure occurs
Grade 3: Withhold until no more than Grade 1 (mild) for at least 3 days, then restart at 9mcg/day. Escalate to 28mcg/day after 7 days if the toxicity does not recur. If the toxicity occurred at 9mcg/day, or if the toxicity takes >7 days to resolve, d/c permanently
Grade 4: D/C permanently
Other Clinically Relevant Adverse Reactions:
Grade 3: Withhold until no more than Grade 1 (mild), then restart at 9mcg/day. Escalate to 28mcg/day after 7 days if the toxicity does not recur. If the toxicity takes >14 days to resolve, d/c permanently
Grade 4: Consider discontinuing permanently
ADMINISTRATION
IV route
Premedicate with dexamethasone 20mg IV 1 hr prior to the 1st dose of each cycle, prior to a step dose (eg, Cycle 1 day 8), or when restarting an infusion after an interruption of >4 hrs.
Administer as a continuous IV infusion at a constant flow rate using an infusion pump that is programmable, lockable, non-elastomeric, and has an alarm.
Infusion bags should be infused over 24 hrs or 48 hrs.
Infuse the total 240mL sol according to the instructions on the pharmacy label on the bag at 1 of the following constant infusion rates:
Infusion rate of 10mL/hr for a duration of 24 hrs, or 5mL/hr for a duration of 48 hrs.
Refer to PI for further administration, reconstitution, and preparation instructions.
HOW SUPPLIED
Inj: 35mcg  38.5mcg
CONTRAINDICATIONS
Known hypersensitivity to blinatumomab or to any component of the product formulation.
WARNINGS/PRECAUTIONS
Hospitalization is recommended for the first 9 days of the 1st cycle and the first 2 days of the 2nd cycle. For all subsequent cycle starts and reinitiation (eg, if treatment is interrupted for ≥4 hrs), supervision by a healthcare professional or hospitalization is recommended. Infusion reactions may occur and may be clinically indistinguishable from manifestations of CRS. Disseminated intravascular coagulation (DIC), capillary leak syndrome (CLS), and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) reported in the setting of CRS. Serious infections (eg, sepsis, pneumonia, bacteremia, opportunistic infections, catheter-site infections) reported; administer prophylactic antibiotics and employ surveillance testing during treatment as appropriate. Tumor lysis syndrome (TLS) reported; use appropriate prophylactic measures, including pretreatment nontoxic cytoreduction and on-treatment hydration; may require either temporary interruption or discontinuation of therapy. Neutropenia and febrile neutropenia, including life-threatening cases, reported; interrupt therapy if prolonged neutropenia occurs. Risk for loss of consciousness. Associated with transient elevations in liver enzymes; interrupt therapy if the transaminases rise to >5X ULN or if bilirubin rises to >3X ULN. Cranial magnetic resonance imaging changes showing leukoencephalopathy observed, especially in patients with prior treatment with cranial irradiation and antileukemic chemotherapy (including systemic high-dose methotrexate or intrathecal cytarabine); clinical significance of this is unknown. Preparation and administration errors reported; follow instructions strictly to minimize medication errors. Potential for immunogenicity. Caution in elderly.
ADVERSE REACTIONS
CRS, neurological toxicities, pyrexia, headache, peripheral edema, febrile neutropenia, nausea, hypokalemia, constipation, anemia, diarrhea, fatigue, bacterial infections, tremor, cough.
DRUG INTERACTIONS
May suppress CYP450 enzymes; highest risk during the first 9 days of the 1st cycle and the first 2 days of the 2nd cycle in patients receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index; monitor for toxicity (eg, warfarin) or drug concentrations (eg, cyclosporine) and adjust dose of concomitant drug PRN.
PREGNANCY AND LACTATION
Category C, not for use in nursing.
MECHANISM OF ACTION
Bispecific CD19-directed CD3 T-cell engager; binds to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells. Activates endogenous T cells by connecting CD3 in the T-cell receptor complex with CD19 on benign and malignant B cells. Mediates formation of a synapse between the T cell and the tumor cell, up-regulation of cell adhesion molecules, production of cytolytic proteins, release of inflammatory cytokines, and proliferation of T cells, resulting in redirected lysis of CD19+ cells.
PHARMACOKINETICS
Distribution: Vd=4.52L. Elimination: T1/2=2.11 hrs.
ASSESSMENT
Assess for known hypersensitivity to drug or to any component of the formulation, prior treatment with cranial irradiation and antileukemic chemotherapy, pregnancy/nursing status, and possible drug interactions. Obtain baseline WBC count, absolute neutrophil count (ANC), ALT, AST, gamma-glutamyl transferase (GGT), and total bilirubin.
MONITORING
Monitor for signs/symptoms of CRS, DIC, CLS, HLH/MAS, neurological toxicities, infections, TLS, loss of consciousness, and other adverse reactions. Monitor for neutropenia/febrile neutropenia; monitor lab parameters (eg, WBC count, ANC) during infusion. Monitor ALT, AST, GGT, and total blood bilirubin during therapy.
PATIENT COUNSELING
Advise to contact physician for any signs/symptoms of CRS or infusion reactions, neurological toxicities, or infections (eg, pneumonia). Advise to refrain from driving and engaging in hazardous occupations/activities (eg, operating heavy/potentially dangerous machinery) while on therapy and inform that neurological events may be experienced. Inform that it is very important to keep area around the IV catheter clean to reduce the risk of infection. Advise to not adjust setting on the infusion pump; inform that any changes to pump function may result in dosing errors. Instruct to contact physician or nurse immediately if there is a problem with the infusion pump or the pump alarms.
STORAGE
2-8°C (36-46°F). Protect from light until time of use. Do not freeze. May store lyophilized vial and IV sol stabilizer for a max of 8 hrs at room temperature. Reconstituted Vial: 23-27°C (73-81°F) for 4 hrs, or 2-8°C (36-46°F) for 24 hrs. Protect from light. Prepared IV Bag Containing Sol for Infusion: 23-27°C (73-81°F) for 48 hrs (storage time includes infusion time; if not administered within the time frames and temperatures indicated, discard and do not refrigerate again), or 2-8°C (36-46°F) for 8 days. Ship in packaging that has been validated to maintain temperature of the contents at 2-8°C (36-46°F). Do not freeze.
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=38b482a8-960b-4591-9857-5031ecb830aa