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美国FDA批准Blincyto用于治疗罕见急性白血病
12月3日，美国FDA批准Blincyto (blinatumomab)用于治疗费城染色体阴性前体B细胞急性淋巴细胞白血病(B-cell ALL)患者，这种疾病是一种不常见形式的ALL。
前体B-cell ALL是一种增长快速的癌症，该病患者的骨髓产生太多的B细胞淋巴母细胞，这种细胞是一种不成熟的白细胞。费城染色体是有时发生在白血病患者骨髓中的一种异常。国家癌症研究所预测，2014年将有6020名美国人被确诊患有ALL，有1440人将死于这种疾病。
Blincyto是一种免疫治疗药物，这类药物可利用人体某部分免疫系统来抗击疾病如癌症。Blincyto是获批的首款通过人体T细胞来毁灭白血病细胞的药物，T细胞是一种白细胞或淋巴细胞。
这款药物可作为CD19蛋白与CD3蛋白之间的一种连接器，CD19被发现于大多数B细胞淋巴母细胞表面，而CD3是T细胞表面的一种蛋白质。这款药物适用于治疗后癌症又恶化（复发性）或对先前治疗无效（难治性）的患者。
“免疫治疗药物，尤其是拥有独特作用机制的Blincyto，对于白血病患者特别有前景，”FDA药物评价与研究中心代谢与肿瘤产品办公室主任、医学博士Pazdur称。“由于认识到了这种新型治疗药物的潜能，FDA在突破性治疗药物资格计划下积极与药物申请者一起努力促使这种新型药物获得批准。”
由于申请者通过初步临床前证据证明这款药物与现有可供使用治疗药物相比，可能会提供实质性疾病改善；这款药物在被提交上市申请时，对一种严重疾病治疗的安全性或有效性可能有明显改善；以及这款药物旨在治疗一种罕见疾病，所以FDA分别授予Blincyto突破性治疗药物资格、优先审评及孤儿药资格。
Blincyto的获批时间与其处方药申请者付费目标日期2015年5月19日相比提前了5个多月，处方药申请者付费目标日期是FDA计划完成药物审评的日期。
Blincyto的安全性及有效性在一项有185名费城染色体阴性复发或难治性前体B-cell ALL患者参与的临床研究中得到评价。所有患者均以Blincyto输液（一种通常利用针头将药物注射入血流中的方式）治疗至少4周。结果显示，32%的受试者大约在6.7个月的时间未出现疾病证据（完全缓解）。
Blincyto是在FDA加速批准计划下得到批准的，这一计划允许FDA基于显示一款药物对一种合理可能预测患者临床收益的代理终点有效的临床数据来批准该药物治疗一种危及生命的疾病。
这一计划可以更早地让患者获取有前景的新药，但申请该药物的公司需要进行确证性临床试验。FDA要求Blincyto生产商进行一项研究，以证实这款药物可以改善复发或难治性费城染色体阴性前体B-cell ALL受试者的生存期。
Blincyto带有一项黑框警告，提醒患者及卫生保健专业人员，一些临床试验受试者出现低血压及治疗初期呼吸困难问题，并经历短期思维困难（脑病）或其它神经系统副作用。
在Blincyto治疗患者中，最常见的副作用有发烧(发热)、头痛、组织肿胀(外围性水肿)、白细胞数量低引起发热(发热性中性粒细胞减少)、恶心、低钾(低钾血症)、疲劳、便秘、腹泻及震颤。
FDA批准Blincyto时带有一项风险评估及减灾策略(REMS)，它包含一项沟通计划，用以告知卫生保健供应商有关产品的严重风险及准备和管理差错的可能性。Blincyto由位于美国加利福尼亚州千橡市的安进上市销售。
Dosing Forms & Strengths
lyophilized powder for reconstitution
35mcg/vial
Acute Lymphoblastic Leukemia
Indicated for Philadelphia chromosome-negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL)
Dosage regimen
A single cycle of treatment consists of 4 weeks of continuous IV infusion followed by a 2-week treatment-free interval
≥45 kg
Cycle 1: 9 mcg/day continuous IV infusion on Days 1-7, THEN 28 mcg/day on Days 8-28
Subsequent cycles: 28 mcg/day continuous IV infusion on Days 1-28
Allow for at least a 2 week treatment-free interval between cycles
A 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)
Administration warnings
Hospitalization is recommended for the first 9 days of the first cycle and the first 2 days of the second cycle
For all subsequent cycle starts and reinitiation (eg, if treatment is interrupted for ≥4 hr), supervision by a healthcare professional or hospitalization is recommended
Do not flush the infusion line, especially when changing infusion bags; flushing when changing bags or at completion of infusion can result in excess dosage and complications thereof
Preparation and administration errors resulting in overdose have occurred (see Administration)
Premedicate with dexamethasone 20 mg IV 1 hr prior to the first dose of each cycle, prior to a step dose (eg, Cycle 1 day 8), or when restarting an infusion after an interruption of ≥4 hr
Dosage Modifications
If the interruption after an adverse event is ≤7 days, continue the 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 9 mcg/day; escalate to 28 mcg/day after 7 days if the toxicity does not recur
Grade 4: Discontinue permanently
Neurological toxicity
Seizure: Discontinue permanently if >1 seizure occurs
Grade 3: Withhold until ≤Grade 1 (mild) for at least 3 days, then restart at 9 mcg/day; escalate to 28 mcg/day after 7 days if the toxicity does not recur; if the toxicity occurred at 9 mcg/day, or if the toxicity takes >7 days to resolve, discontinue permanently
Grade 4: Discontinue permanently
Other clinically relevant adverse reactions
Grade 3: Withhold until ≤Grade 1 (mild), then restart at 9 mcg/day; escalate to 28 mcg/day after 7 days if the toxicity does not recur; if the toxicity takes >14 days to resolve, discontinue permanently
Grade 4: Consider discontinuing permanently
Renal impairment
Baseline CrCl ≥30 mL/min: No dose reduction required
CrCl <30 mL/min or on hemodialysis: No information available
Hepatic impairment
No formal pharmacokinetic studies conducted
Dosing Considerations
Approved under accelerated approval; continued approval for this indication may be contingent upon verification of clinical benefit in subsequent trials
Acute Lymphoblastic LeukemiaLimited experience in pediatric patients; enroll patient in clinical trial
eva luated in a dose-escalation study of 41 pediatric patients with relapsed or refractory B-precursor ALL (median age was 6 yr [range: 2-17 yr])
Administered at doses of 5-30 mcg/m²/day
Recommended phase 2 regimen was 5 mcg/m²/day on Days 1-7 and 15 mcg/m²/day on Days 8-28 for cycle 1, and 15 mcg/m²/day on Days 1-28 for subsequent cycles
At a higher dose, a fatal cardiac failure event occurred in the setting of life-threatening cytokine release syndrome (see Cautions)
The steady-state concentrations of blinatumomab were comparable in adult and pediatric patients at the equivalent dose levels based on body surface area (BSA)-based regimens
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New Drugs Online Report for blinatumomab
Information
Generic Name: blinatumomab
Trade Name: Blincyto
Entry Type: New molecular entity
Developmental Status
UK: Phase II Clinical Trials
EU: Phase II Clinical Trials
US: Approved (Licensed)
UK launch Plans: Available only to registered users
Actual UK launch date:
Comments
Dec 14: US FDA approves blinatumomab (Blincyto) to treat pts with Philadelphia chromosome-negative precursor B-cell acute lymphoblastic leukaemia (B-cell ALL) [12].
04/12/2014 13:21:09
Oct 14: Granted priority review in the US; decision expected by May 15 [11].
13/10/2014 11:03:07
Sep 14: Filed in the US [10].
22/09/2014 17:33:17
Jun 14: Awarded breakthrough therapy status in the US [9].
02/07/2014 11:05:56
Apr 14: Amgen are starting discussions with the FDA on whether the company can file on positive PII results [8]
23/04/2014 21:49:46
Mar 12: Micromet became a wholly owned subsidiary of Amgen [12].
07/06/2012 11:29:52
Oct 11: Micromet met with the FDA & subsequently initiated a clinical development programme intended to support US regulatory approval of blinatumomab in adults with B-precursor relapsed/refractory ALL. It is expected that the programme will comprise a single-arm PII trial & a randomised, controlled, PIII trial. Data from the planned PIII trial, if positive, are intended to support a full BLA submission [7].
07/06/2012 11:29:10
Aug 09: Granted orphan drug status in the EU [2].
10/03/2010 12:34:08
Trial or other data
Dec 14: Results of a multicentre, single-arm, PII study of blinatumomab in adult patients with relapsed or refractory B-precursor ALL have been published in the Lancet. A total of 189 patients were enrolled and treated with blinatumomab (9 μg/day for the first 7 days and 28 μg/day thereafter). After two cycles, 43% (81) of patients had a complete remission (CR) or a CR with partial haematological recovery of peripheral blood counts (CRh): 33% (63) had a CR and 10% (18) had a CRh. 40% of the patients who achieved CR/CRh underwent subsequent allogeneic HSCT. [13]
18/12/2014 11:12:59
Dec 13: NCT02003222 is a randomized PIII trial study of combination chemotherapy with blinatumomab vs induction chemotherapy alone in treating 360 patients with newly diagnosed breakpoint cluster region (BCR)-c-abl oncogene 1, non-receptor tyrosine kinase (ABL)-negative B lineage ALL undergoing allogeneic hematopoietic stem cell transplantation. The primary outcome is overall survival. The study starts Nov 13 and is due to complete Jun 18 [8].
09/12/2013 09:47:03
Jun 12: International PIII registrational trial of blinatumomab in adults with B-precursor relapsed/refractory ALL due to start Dec 12 [7].
07/06/2012 11:32:19
May 12: Updated results from a single arm dose-ranging PII study report that 72% of adult patients (26/36) with relapsed or refractory B-precursor ALL achieved a complete response (CR) or CR with partial haematologic recovery (CRh*). All but two patients achieved a molecular response. At the time of the analysis, median survival was 9.0 (8.2, 15.8) months with a median follow-up of 10.7 months. In patients who received the selected dose, median survival was 8.5 months. The median duration of response in the 26 patients who responded to treatment was 8.9 months. In patients on the selected dose and schedule, the most common AEs were grade 1 or 2 and included pyrexia (70%), headache (39%), tremor (30%) and fatigue (30%). Reversible CNS events led to treatment interruptions in 6 patients with 2 permanently discontinuing treatment. Cytokine release syndrome led to treatment interruption in 2 patients. One patient had a fatal fungal infection that the investigator considered related to treatment [6].
30/05/2012 17:23:33
June 11: Interim data from a Phase II, single-arm trial of blinatumomab in adult patients with ALL. 75% of patients (9/12) achieved a complete remission or CR with partial recovery of blood counts (CRh) following treatment with blinatumomab. All nine responding patients achieved a complete molecular response, or had no evidence of leukemic cells in their bone marrow, a key prognostic factor for patient survival. Notably, four patients with genetic abnormalities typically associated with poorer outcomes all achieved a CR or CRh. [5]
10/06/2011 16:35:43
Jun 10: Updated results from a PII trial in adult patients with MRD positive ALL. As of April 2010, 6 of 9 eva luable, MRD responding, non-transplanted patients were in haematological remission for up to 23 months [4].
15/06/2010 21:45:46
Mar 10: Company intends to initiate three trials in 2010, including a European pivotal trial in MRD-positive adult ALL, a PII trial in relapsed/refractory adult ALL and a PII trial in relapsed/refractory adult chronic lymphocytic leukemia. It expects to discuss its regulatory strategy for blinatumomab in paediatric ALL with the FDA and EMA during the course of 2010 [3].
12/03/2010 19:28:51
Dec 09: Phase II trial results: blinatumomab for B-precursor Acute Lymphoblastic Leukaemia (ALL). After receiving extensive chemotherapy, 21 patients had ALL malignant cells persisting in their bone marrow, (minimal residual disease, MRD). 80% of the eva luable patients (16/20 patients) achieved the main outcome - the elimination of cancer cells to an undetectable level in at least 22% of patients, all of them already during the first treatment cycle. The responses appear to be durable, with patients free of relapse for currently up to 15 months. Generally, blinatumomab was well tolerated. The commonest adverse events included lymphopenia, leukopenia, pyrexia and hypoimmunoglobulinemia. One patient had to discontinue treatment due to a fully reversible neurological adverse event, and was not eva luable for response assessment. The data was presented at the 51st Annual Meeting of the American Society of Haematology (ASH) in New Orleans, US. (1)
10/12/2009 10:23:48
Evidence Based eva luations
NHSC/NIHR http://www.hsc.nihr.ac.uk/topics/blinatumomab-for-relapsed-or-refractory-philadelph/
References
Available only to registered users
Category
BNF Category: Drugs affecting the immune response (08.02)
Pharmacology: CD19-specific, T cell-engaging BiTE antibody designed to direct a patients own T cells against cancer cells inducing a self-destruction process in cancer cells
Epidemiology: 5-year survival rate for adult ALL patients after 1st relapse is 7%. After chemotherapy, the risk of relapse is 6% in MRD-negative patients vs 89% in MRD positive patients.
Indication: Acute lymphoblastic leukaemia (ALL)
Additional Details:
Method(s) of Administration
Intravenous infusion
Company Information
Name: Amgen
US Name: Amgen
NICE Information
Anticipated Commissioning route (England) -
In timetable: - |
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