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白血病新药MYLOTARG（gemtuzumab ozogamicin，吉妥单抗）首款纳入儿童AML适应症的药物，也是唯一一种以CD33为靶点的AML治疗方法
近日，辉瑞（Pfizer）公司宣布，其新药Mylotarg（gemtuzumab ozogamicin）得到了美国FDA的批准，用于治疗表达CD33抗原的新诊断急性骨髓性白血病（AML）的成人患者。FDA同时也批准该药物用于治疗2岁及以上的CD33阳性AML患者，这些患者经历复发或对初始治疗没有响应。
值得一提的是，Mylotarg是首款包括儿童AML适应症的药物，也是唯一一款靶向CD33的AML治疗方法。
批准日期：2017年9月3日 公司：辉瑞（Pfizer）
注射用MYLOTARGTM(gemtuzumab ozogamicin)，为静脉使用
美国初次批准：2000
作用机制
Gemtuzumab ozogamicin是一个指向CD33-抗体-药物结合物(ADC)。抗体部分(hP67.6)识别人CD33抗原。小分子，N-乙酰 ɣ calicheamicin，是一个细胞毒剂是通过一个连接物共价地附着至抗体。非临床数据提示gemtuzumab ozogamicin的抗癌活性是由于ADC的结合至CD33-表达肿瘤细胞，接着ADC-CD33复合物的内化，和N-乙酰ɣ calicheamicin dimethyl hydrazide通过连接物的水解裂解的细胞内释放。N-乙酰ɣ calicheamicin dimethyl hydrazide的活化诱发双链DNA断裂，随后诱导细胞周期停止和凋亡细胞死亡。
适应证和用途
MYLOTARG是一个指向CD33抗体药物结合物适用为：
● 在成年中新诊断CD-33-阳性急性髓性白血病(AML)的治疗.
● 在成年和在儿童患者2岁和以上中复发或难治性CD33-阳性AML的治疗.
剂量和给药方法
● 新诊断，从头开始AML(组合方案)：
● 诱导：3mg/m2(直至一个4.5mg小瓶)在天1，4，和7与柔红霉素和阿糖胞苷联用.
● 巩固：3mg/m2在天1(直至一个4.5 mg小瓶)与柔红霉素和阿糖胞苷组合。
● 新诊断AML(单药方案)：
● 诱导：6mg/m2在天1和3 mg/m2在天8.
● 继续：对诱导后无疾病进展证据患者，直至8个继续疗程MYLOTARG 2mg/m2在天1每4周.
● 复发或难治性AML(单药方案)：
● 3mg/m2在天1，4，和7.
● 预先给药MYLOTARG的一小时前用一种皮质激素，抗组织胺，和对乙酰氨基酚。
剂型和规格
注射用：4.5mg作为一冻干饼或粉在一个单次-剂量小瓶为重建和稀释.
禁忌证
对MYLOTARG或它的任何组分超敏性。
警告和注意事项
● 出血：当MYLOTARG被用在推荐剂量可能发生严重，包括致命性，出血。频繁地监视血小板计数。
● 胚胎-胎儿毒性：可能致致命性危害。忠告生殖潜能女性对胚胎潜在风险和有效避孕的使用。
不良反应
最常见不良反应(大于15%)为出血，感染，发热，恶心，呕吐，便秘，头痛，增加AST，增加ALT，皮疹，和粘膜炎.
报告怀疑不良反应，联系Pfizer有限公司电话1-800-438-1985或FDA电话1-800-FDA-1088或www.fda.gov/medwatch。
在特殊人群中使用
哺乳：建议不要哺乳喂养。
包装规格/驻藏和处置
注射用MYLOTARG(gemtuzumab ozogamicin)是一种白色至灰白色冻干饼或粉在纸盒中供应(NDC 0008-4510-01)含一个4.5 mg单-剂量小瓶[见剂量和给药方法]。
贮存和处置
冰箱(2-8°C；36-46°F)MYLOTARG小瓶和贮存在原始纸盒以避光保护。不要冻结。
MYLOTARG 是一种细胞毒性药物。遵循可行的特殊处置和遗弃方法步骤1。
Mylotarg (Gemtuzumab Ozogamicin for Injection)
The approval includes both adult and pediatric patients The US Food and Drug Administration (FDA) has approved gemtuzumab ozogamicin (Mylotarg) for the first-line treatment of adults with CD33-positive acute myeloid leukemia (AML), and in pediatric patients, 2 years of age and older, with relapsed or refractory CD33-positive AML. Up to 90% of AML patients are positive for CD33.This marks the first approval for pediatric AML.
“Today is an important day for patients, their families, and the entire AML community, as the approval of Mylotarg brings forth a long-awaited treatment option that may lead to deeper, more durable remissions for patients with AML,” said Jorge Cortes, MD, of the University of Texas MD Anderson Cancer Center in Houston, in a press release. “After many years, we are finally seeing progress in the treatment of AML, which has renewed my hope in improving outcomes for my patients. I am pleased that I can now offer many adult and pediatric patients targeted treatment with Mylotarg.”
The approval of gemtuzumab ozogamicin is based on a number of clinical trials, including AML-19, MyloFrance-1, and ALFA-0701.
AML-19
This randomized, open-label, phase III trial compared single-agent gemtuzumab ozogamicin (n = 118) vs best supportive care (n = 119) in elderly patients who could not tolerate other AML therapies. On day 1 of initial treatment, patients in the experimental arm received 6-mg/m2 gemtuzumab ozogamicin, then 3-mg/m2 gemtuzumab ozogamicin on day 8. If patients showed no evidence of progressive disease, they received 2-mg/m2 gemtuzumab ozogamicin every 4 weeks as continued treatment. Patients treated with gemtuzumab ozogamicin had a median overall survival of 4.9 months compared with 3.6 months among those receiving best supportive care, for a hazard ratio (HR) of 0.69 (95% CI, 0.53–0.90; 2-sided P = .005).
MyloFrance-1
This phase II trial included adult AML patients in first relapse. All 57 patients were treated with single-agent gemtuzumab ozogamicin on days 1, 4, and 7 at a dose of 3 mg/m2. The trial reported a complete remission rate of 26% (15 patients); median relapse-free survival was 11.6 months.
ALFA-0701
This phase III open-label trial studied gemtuzumab ozogamicin in newly diagnosed de novo AML. Patients were randomized 1:1 to either chemotherapy alone (n = 136) or chemotherapy plus gemtuzumab ozogamicin (n = 135) at a lower fractionated dose of 3 mg/m2 on days 1, 4 and 7. Patients who received gemtuzumab ozogamicin had an event-free survival of 17.3 months compared with 9.5 months among patients receiving chemotherapy alone (HR, 0.56; 95% CI, 0.42–0.76).
First Approval
In 2000, Mylotarg received accelerated approval as a treatment for older CD33-positive AML patients in first relapse, but the agent was voluntarily withdrawn from the market after confirmatory trials failed to verify its benefit while also demonstrating safety concerns, including a high number of early patient deaths. The new approval includes both a lower recommended dose and a different treatment schedule than the original approval.
“We are approving Mylotarg after a careful review of the new dosing regimen, which has shown that the benefits of this treatment outweigh the risk,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, in a press release. “Mylotarg’s history underscores the importance of examining alternative dosing, scheduling, and administration of therapies for patients with cancer, especially in those who may be most vulnerable to the side effects of treatment.”
The most common adverse events (AEs) related to gemtuzumab ozogamicin include constipation, elevated liver function tests, headache, hemorrhage, infection, nausea, neutropenia, pyrexia, rash, stomatitis, thrombocytopenia, and vomiting. Serious AEs include hepatic veno-occlusive disease, infections, infusion-related reactions, liver damage, low blood counts, and severe bleeding.
Pregnant or breastfeeding women are advised not to take gemtuzumab ozogamicin due to risks to the fetus or baby.
The FDA has included a boxed warning for hepatotoxicity, including severe or fatal hepatic veno-occlusive disease, which has been reported in 5% of patients treated with either gemtuzumab ozogamicin alone or with chemotherapy.
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