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米罗他（吉妥单抗注射液）-治疗急性白血病新药

2011-03-23 18:41:20 作者：新特药房来源：中国新特药网天津分站浏览次数：180 文字大小：【大】【中】【小】

简介： 吉妥单抗（gemtuzumab ozogamicin/Mylotarg）抗CD33 【别名】Mylotarg 、CMA676、GO 【来源】重组人源化抗CD33单抗与细胞毒药物卡奇霉素的复合物。其中单抗为人鼠源氨基酸序列，与细胞毒抗肿瘤抗生素 ...

关键字：米罗他吉妥单抗注射液急性白血病 Mylotarg

吉妥单抗（gemtuzumab ozogamicin/Mylotarg）
抗CD33
【别名】Mylotarg 、CMA676、GO

【来源】重组人源化抗CD33单抗与细胞毒药物卡奇霉素的复合物。其中单抗为人鼠源氨基酸序列，与细胞毒抗肿瘤抗生素（卡奇霉素）偶联而成。

【作用机制】CD33表达于80%以上的急性髓性白血病（AML）患者白血病细胞上。本品静脉注射后，偶联屋中的抗体与复合物可被靶细胞胞饮。在细胞内，卡奇霉素从偶联物上水解游离，与DNA结合，使其双螺旋断列，导致细胞死亡。本品对表达CD33抗原的细胞毒性是不表达该抗原细胞的7万余倍。另外，由于造血干细胞不受药物治疗的影响，因而骨髓抑制较轻。作为一线药物治疗老年AML和高危MDS，Mylotarg 单药疗效不及化疗。目前正在进行Mylotarg 与氟达拉滨+阿糖胞苷、拓扑替康+阿糖胞苷和IL-11联合用药的临床研究。
【药动学】首次推荐剂量9mg/m2,静脉点滴持续2小时，半衰期45小时。第二次予以9mg/m2,半衰期延长至60小时，曲线下面积也比初次用药后增加一倍。
【适应症】首次复发的60岁以上CD33抗原阳性的急性髓细胞性白血病或不宜用细胞毒性药物治疗的CD33阳性的AML患者。
【不良反应】
全身反应：腹痛、乏力、背痛、寒战、发热、头痛、败血症、肿瘤溶解综合征。
循环系统：低血压、高血压、心律失常。
消化系统：食欲不振、恶心、呕吐、便秘、腹泻、腹胀、消化不良、胃炎、肝毒性、肝静脉血栓。
血液系统；骨髓抑制（较严重）、贫血、血小板减少、出血（鼻出血、脑出血、瘀斑、颅内出血、血尿、阴道出血）、弥漫性血管内凝血。
代谢系统：低钾血症、低镁血症、乳酸脱氢酶升高、高血糖。
肌肉骨骼：关节痛。
神经系统：抑郁、失眠、眩晕。
呼吸系统：呼吸困难、低氧血症、肺炎、咳嗽加重、咽炎、鼻炎。
皮肤及附属物：单纯疱疹、皮疹、局部反应、周围水肿。
【禁忌症】禁用于对本品或者本品中其他组成成分过敏的患者。
【规格】针剂，5mg/20ml；冻干粉剂。

【开发公司】Wyeth-Ayerst

【原产地英文商品名】MYLOTARG 5mg/20mL Vial
【原产地英文药品名】GEMTUZUMAB OZOGAMICIN
【中文参考商品译名】米罗他 5毫克/20毫升/瓶
中文参考药品译名】吉姆单抗奥佐米星
【生产厂家中文参考译名】美国惠氏
【生产厂家英文名】Wyeth Pharmaceuticals

MYLOTARG^® (gemtuzumab ozogamicin for Injection)

Indication and Usage

MYLOTARG is indicated for the treatment of patients with CD33+ acute myeloid leukemia in first relapse who are 60 years of age or older and who are not considered candidates for other cytotoxic chemotherapy. The safety and efficacy of MYLOTARG in patients with poor performance status and organ dysfunction has not been established.
The effectiveness of MYLOTARG is based on overall response rates. There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival, compared to any other treatment.

Important Safety Information

WARNINGS: MYLOTARG should be administered under the supervision of physicians experienced in the treatment of acute leukemia and in facilities equipped to monitor and treat leukemia patients. There are no controlled trials demonstrating efficacy and safety using MYLOTARG in combination with other chemotherapeutic agents. Therefore, MYLOTARG should only be used as single agent chemotherapy and not in combination chemotherapy regimens outside clinical trials. Severe myelosuppression occurs when MYLOTARG is used at recommended doses.

HYPERSENSITIVITY REACTIONS INCLUDING ANAPHYLAXIS, INFUSION REACTIONS, PULMONARY EVENTS: MYLOTARG administration can result in severe hypersensitivity reactions (including anaphylaxis), and other infusion-related reactions which may include severe pulmonary events. Infrequently, hypersensitivity reactions and pulmonary events have been fatal. In most cases, infusion-related symptoms occurred during the infusion or within 24 hours of administration of MYLOTARG and resolved. MYLOTARG infusion should be interrupted for patients experiencing dyspnea or clinically significant hypotension. Patients should be monitored until signs and symptoms completely resolve. Discontinuation of MYLOTARG treatment should be strongly considered for patients who develop anaphylaxis, pulmonary edema, or acute respiratory distress syndrome. Since patients with high peripheral blast counts may be at greater risk for pulmonary events and tumor lysis syndrome, physicians should consider leukoreduction with hydroxyurea or leukapheresis to reduce the peripheral white count to below 30,000/µL prior to administration of MYLOTARG. (See WARNINGS.)

HEPATOTOXICITY: Hepatotoxicity, including severe hepatic veno-occlusive disease (VOD), has been reported in association with the use of MYLOTARG as a single agent, as part of a combination chemotherapy regimen, and in patients without a history of liver disease or hematopoietic stem-cell transplant (HSCT). Patients who receive MYLOTARG either before or after HSCT, patients with underlying hepatic disease or abnormal liver function, and patients receiving MYLOTARG in combinations with other chemotherapy are at increased risk for developing VOD, including severe VOD. Death from liver failure and from VOD has been reported in patients who received MYLOTARG. Physicians should monitor their patients carefully for symptoms of hepatotoxicity, particularly VOD. These symptoms can include: rapid weight gain, right upper quadrant pain, hepatomegaly, ascites, elevations in bilirubin and/or liver enzymes. However, careful monitoring may not identify all patients at risk or prevent the complications of hepatotoxicity. (See WARNINGS and ADVERSE REACTIONS sections.)

MYLOTARG is contraindicated in patients with a known hypersensitivity to gemtuzumab ozogamicin or any of its components and in lactating mothers. MYLOTARG may cause fetal harm when administered to a pregnant woman. The reported rate of Grade 3 or 4 thrombocytopenia, neutropenia, anemia, and bleeding were 99%, 98%, 52%, and 13%, respectively. Thirty percent of patients experienced severe infections, including sepsis (17%) and pneumonia (8%).
The most common adverse events (≥20%) were fever (82%), nausea (68%), chills (66%), vomiting (58%), thrombocytopenia (50%), leukopenia (47%), headache (37%), asthenia (36%), abdominal pain (32%), diarrhea (32%), epistaxis (28%), dyspnea (26%), hypokalemia (26%), sepsis (26%), anorexia (25%), stomatitis (25%), liver function tests abnormal (24%), constipation (23%), anemia (22%), local reaction (22%), herpes simplex (21%), and hypotension (20%).
MYLOTARG can produce a postinfusion symptom complex of fever and chills, and less commonly hypotension and dyspnea during the first 24 hours after administration. Patients should receive diphenhydramine 50 mg po and acetaminophen 650-1000 mg po 1 hour before MYLOTARG administration. Two additional doses of acetaminophen 650-1000 mg po every 4 hours may be given. Fever and chills were commonly reported despite premedication with diphenhydramine and acetaminophen. Vital signs should be monitored during infusion and for 4 hours following infusion. Methylprednisolone given prior to MYLOTARG infusion may ameliorate infusion-related symptoms.
Severe myelosuppression will occur in all patients given the recommended dose of this agent. Careful hematologic monitoring is required. Systemic infections should be treated.

吉姆单抗／奥佐米星治疗急性白血病的基础与临床研究进展（综述）

摘要：
吉姆单抗／奥佐米星（GO）由人源化IgG4抗CD33单克隆抗体与细胞毒药物刺孢霉素的衍生物结合形成．为美国Wyeth公司生产。2000年5月美国食品及药品管理局（FDA）批准GO单药治疗年龄大于60岁的CD33阳性急性髓系白血病（AML）首次复发患者，缓解率约30％。GO的联合治疗方案进入临床试验后，也显示出良好的治疗效果．应用范围有所扩大。近年来GO的基础研究和临床研究互相促进，本文对此进行综述。
[第一段] —— 全文请见本药内容附件
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Mylotarg抑制ＡＭＬ新药物

Mylotarg(gemtuzumab ozogamicin 注射剂)获得FDA的核准

美国家庭產品公司研发出一种新的化疗药物Mylotarg（gemtuzumab ozogamicin注射剂），这是依据单细胞繁殖抗体科技所研发而成的药物，已经获得美国食品暨药物管理局（ＦＤＡ）的核准。
Mylotarg是种有效但却不受经销商青睞的药品。急性骨髓细胞白血病（ＡＭＬ）」呈CD33阳性反应且第一次復发之60岁以上病患，倘若无法接受毒素细胞化学治疗，便可以服用经证实有效的Mylotarg。
ＡＭＬ就是俗称的血癌，是因為骨髓中白血球不受控制地增生所致。美国癌症协会预估，今年在美国将有9700件ＡＭＬ的新病例。
ＡＭＬ患者的平均年龄是65岁，且大约只有20%到30%病患的病情能获得缓和控制。
美国家庭產品公司（ＡＨＰ）所自行製造之Mylotarg，是一种经过重组的人化抗体与一种称為 calicheamicin的强效抗肿瘤抗生素之连结。惠氏药厂的研究人员从德州取得智利硝矿土样本，而后从矿土中的一种细菌身上离析出所谓的 calicheamicin。
这项药物将由ＡＨＰ的製药部门─惠氏大药厂来经营销售。
Mylotarg之所以有效，是因為它抗体上某部位的黏合剂能绊住骨髓白血病细胞快速產生的糖蛋白─CD33。惠氏药厂从佛莱德‧哈奇森癌症研究中心合法取得这种抗体，而后又经由Celltech公司将抗CD33的抗体人化。
虽然Mylotarg是第一种核准用来治疗復发性ＡＭＬ病患之药物，ＡＨＰ却指出：「Mylotarg的效力是根据客观回应率而来，且没有任何经过控制的试验证实它具临床上的好处。与其他的治疗相较，这些好处是指疾病症状的改善或存活率的提高等。」
ＡＨＰ表示，在第二阶段的三个试验裡，共有 142名60岁以上、第一次復发ＡＭＬ且CD33呈阳性的病患服用了Mylotarg。整体来看，有 26%病患的症状终於缓解；此外，存活期限的中位数则為5.9个月。
服用Mylotarg来治疗的病患中，有 47%出现了贫血的症状，另有 98%罹患「嗜中性白血球减少症」、 99%遭遇严重的血小板减少症。其他与Mylotarg有关的逆向副作用还包括了严重的骨髓抑制，假若给予孕妇服用这项药物，有可能会伤及胎儿。
　　
抗体靶向性化疗可安全有效地治疗CD33＋急性髓样细胞性白血病复发（J Clin Oncol 2001;19:3244-3254）WESTPORT, 6月29日（路透社医学新闻）一种抗体偶联的化疗药gemtuzumab ozogamicin （Mylotarg）可以诱导CD33＋的髓样细胞性白血病在初次复发后获得缓解，而且无显著的不良效应。

7月1日出版的《临床肿瘤学杂志》报道，Mylotarg （美国费城Wyeth 实验室的产品）由专利抗癌抗生素calicheamicin偶联人源抗CD33单克隆抗体组成。

西雅图华盛顿大学的Eric L. Sievers博士与其同事进行了gemtuzumab ozogamicin 的II期临床试验，试验选取了142例初次复发的CD33＋髓样细胞白血病患者。所有的病人均接受了2小时gemtuzumab ozogamicin静脉输注，剂量为9 mg/m2，间隙2周。
在这些病人中有42例（30％）获得完全缓解（即骨髓中的原始细胞少于5％，中性粒细胞恢复至1500/μL以上，不需要输注红细胞和血小板），缓解率与传统的化疗相近。23％的病人有骨髓抑制或3/4级的高胆红素血症，17％的病人出现了转氨酶升高。感染的发病率为28％，3/4级的粘膜炎发病率只有4％。其他不良反应包括严重恶心呕吐的发生率为11％。此外没有治疗相关的心脏毒性、脑毒性或脱发。

Sievers博士称：“Mylotarg治疗并非没有毒性，但是许多病人在接受这种方法治疗后能够接受更为有效的移植治疗。”比较明确的是那些接受干细胞移植的病人无病生存时间至少为8.9个月，而未移植者只有2.1个月。

西雅图研究人员最近开发出免疫结合型新药Mylotarg，把人源化抗CD33－IgG4单抗与一种强力抗肿瘤药calicheamicin结合而成。Ⅰ期剂量递增试验报告40例难治复发患者接受剂量0.25－9mg/㎡/次，隔14天1次，共3次；剂量达6mg/㎡以上时，血幼稚细胞比例明显下降，20％（8/40例）骨髓幼稚细胞消失。Ⅱ期临床试验报道142例第一次复发患者接受Mylotarg 9mg/㎡，第1、第14天，大部分表现发热、高血压（多在8小时内症状消失）、3-4度粘膜炎（4%）、恶心、呕吐（11%）、严重感染(28%)、短暂转氨酶升高(17％)，1例死于肝静脉阻塞病（VOD），总缓解率30%。目前FDA已批准Mylotarg用于第一次复发、60岁以上不能耐受强烈化疗的CD33（＋）AML患者。体外AML细胞培养中加环胞霉素A及Mylotarg可显著增加凋亡。有报道Mylotarg联合环胞霉素，再加阿糖胞苷或加阿糖胞苷及蒽环类，作为老年患者非清髓干细胞移植前及年轻患者的缓解后治疗。Frankle等研制一种包含GM-CSF的融合蛋白，与白喉毒素结合，靶向特定髓细胞，正进行Ⅰ期剂量递增试验，3/26例表现骨髓幼稚细胞下降90%以上，毒性为发热、寒战。