2012年10月26日，美国食品与药物管理局（FDA）通过加速审批程序批准了“孤儿药”高三尖杉酯碱(omacetaxine mepesuccinate)用于治疗成人慢性髓性白血病（CML）。Synribo预期用于那些至少用2种酪氨酸激酶抑制剂药物(TKIs)治疗后疾病仍有进展的患者。 该药为皮下注射剂，2次/天，连续注射14天，28天为一疗程直至白细胞计数正常。只要患者能从治疗中获益，可继上述疗程后再连续注射7天，2次/天，28天为一疗程。 高三尖杉酯碱是过去两个月以来批准的第二个治疗CML的药物。FDA 于上月4日批准了“孤儿药”伯舒替尼（bosutinib）用于治疗CML 一项复合队列研究评估了高三尖杉酯碱的有效性。结果发现，使用高三尖杉酯碱治疗的患者表达费城（Ph）染色体基因突变的细胞百分率降低。14/76（18.4%）的患者在平均3.5个月的时间内实现了降低。中位降低时间为12.5个月。 在CML加速期阶段，研究通过一些经历了白细胞计数正常化和主要血液学缓解（MaHR）的患者确定了高三尖杉酯碱的有效性。结果发现，35名患者中的5名患者（14.3%）在平均2.3个月内实现了MaHR。这些患者MaHR的中位持续时间为4.7个月。 临床试验中报告的最常见的不良反应包括患者血小板减少，贫血，中性粒细胞减少（可能导致感染和发热），腹泻，恶心，疲乏无力，注射部位反应和淋巴细胞减少。 Pharmacological Class: Protein synthesis inhibitor. Active Ingredient(s): Omacetaxine mepesuccinate 3.5mg/vial; lyophilized powder for SC injection after reconstitution; contains mannitol; ­preservative-free. Company Teva Pharmaceuticals Indication(s): Treatment of adult patients with chronic or accelerated phase chronic myeloid leukemia (CML) with resistance and/or intolerance to two or more tyrosine kinase inhibitors (TKI). Pharmacology: The mechanism of action of omacetaxine mepesuccinate has not been fully elucidated but includes inhibition of protein synthesis and is independent of direct Bcr-Abl binding. Omacetaxine mepesuccinate binds to the A-site cleft in the peptidyl-transferase center of the large ribosomal subunit from a strain of archaebacteria. In vitro, omacetaxine mepesuccinate ­reduced protein levels of the Bcr-Abl oncoprotein and Mcl-1, an anti-apoptotic Bcl-2 family member. Clinical Trials: The efficacy of omacetaxine mepesuccinate was evaluated using a combined cohort of adult patients with CML from two trials. The combined cohort consisted of patients who had received 2 or more approved TKIs and had, at a minimum, documented evidence of resistance or intolerance to dasatinib and/or nilotinib. ­Patients were treated with omacetaxine mepesuccinate at a dose of 1.25mg/m2 administered subcutaneously twice daily for 14 consecutive days every 28 days (induction cycle). Responding patients were then treated with the same dose and twice daily schedule for 7 consecutive days every 28 days (maintenance cycle). Patients were allowed to continue to receive maintenance treatment for up to 24 months. In the first trial, a total of 76 patients with chronic phase CML were included in the efficacy analysis. Thirty-six (47%) patients had failed treatment with imatinib, dasatinib, and nilotinib. Most patients had also received prior non-TKI treatments, most commonly hydroxyurea (54%), interferon (30%), and/or cytarabine (29%). At efficacy endpoint, 18% (14/76) achieved a major cytogenetic response (MCyR) with a mean time to MCyR onset of 3.5 months. The median ­duration of MCyR for these patients was 12.5 months (Kaplan-Meier estimate). In the second trial, a total of 35 patients with accelerated phase CML were included in the efficacy analysis. Twenty-two (63%) of 35 patients with accelerated phase had failed treatment with imatinib, dasatinib, and nilotinib. Most patients had also received prior non-TKI treatments, most commonly hydroxyurea (43%), interferon (31%), and/or cytarabine (29%). At efficacy endpoint, 14% (5/35) achieved a major hematologic ­response (MaHR) with a mean time to response onset of 2.3 months. The median duration of MaHR for these patients was 4.7 months (Kaplan-Meier estimate). Legal Classification: Rx Adults: Induction: 1.25mg/m2 by SC injection twice daily for 14 consecutive days every 28 days, over a 28-day cycle. Repeat cycles every 28 days until hematologic response achieved. Maintenance: 1.25mg/m2 by SC injection twice daily for 7 consecutive days every 28 days, over a 28-day cycle. Dose adjustments and modifications: see full labeling. Children: Not established. Warnings/Precautions: Risk of myelosuppression (thrombocytopenia, neutropenia, anemia), hemorrhage. Monitor CBCs with platelets weekly during induction, initial maintenance cycles, and every 2 weeks during later cycles. Monitor glucose levels (esp. in diabetics). Avoid in poorly controlled diabetes until glycemic control is ­established. Elderly. Pregnancy (Cat. D); avoid. Nursing mothers: not recommended. Interaction(s) Avoid concomitant anticoagulants, aspirin, NSAIDs if platelets <50,000/microliters; may increase risk of bleeding. Adverse Reaction(s) Thrombocytopenia, anemia, neutropenia, diarrhea, nausea, fatigue, asthenia, injection site reaction, pyrexia, infection, lymphopenia; bleeding, hyperglycemia. How Supplied: Single-use vial—1 LAST UPDATED: 3/4/2013 http://www.drugs.com/pro/synribo.html