Phase 2 study of subcutaneous omacetaxine mepesuccinate after TKI failure in patients with chronic-phase CML with T315I mutation
Phase 2 study of subcutaneous omacetaxine mepesuccinate after TKI failure in patients with chronic-phase CML with T315I mutation
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DOI：
10.1182/blood-2012-03-415307
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发表时间：
2012-09-27
期刊：
影响因子：
20.3
通讯作者：
Kantarjian, Hagop
中科院分区：
文献类型：
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作者：
Cortes, Jorge;Lipton, Jeff H.;Kantarjian, Hagop
具有bcr-abl T315I突变的慢性髓系白血病(CML)患者不能从目前批准的酪氨酸激酶抑制剂的治疗中受益。甲基丁二酸奥马西辛是一种蛋白质合成抑制剂，已在携带T315I突变的细胞中显示出活性。这项2期试验评估了奥马西辛对T315I和酪氨酸激酶抑制剂失效的慢性粒细胞白血病患者的疗效。患者皮下注射奥马克辛1.25 mg/m(2)，每日2次，第1~14天，每28天一次，直至血液学缓解或最多6个周期，然后每28天维持1~7天。本文报告了慢性期患者的治疗结果。62例患者平均接受7个周期(范围1-41个周期)。48例患者血液学完全缓解(77%；95%可信下限，65%)；中位反应持续时间为9.1个月。14名患者(23%；95%的可信下限，13%)实现了主要的细胞遗传学应答，包括10例(16%)的完全细胞遗传学应答。中位无进展生存时间为7.7个月。3/4级血液学毒性包括血小板减少(76%)、中性粒细胞减少(44%)和贫血(39%)，通常可通过减少剂量来控制。非血液学不良反应多为1/2级，包括感染(42%)、腹泻(40%)和恶心(34%)。奥乙酰克辛可能为T315I突变的CML患者提供一种安全有效的治疗方法。这项研究在www.Clinicaltrials.gov上注册为NCT00375219。(血。2012；120(13)：2573-2580)
Chronic myeloid leukemia (CML) patients with the BCR-ABL T315I mutation do not benefit from therapy with currently approved tyrosine kinase inhibitors. Omacetaxine mepesuccinate is a protein synthesis inhibitor that has demonstrated activity in cells harboring the T315I mutation. This phase 2 trial assessed the efficacy of omacetaxine in CML patients with T315I and tyrosine kinase inhibitor failure. Patients received subcutaneous omacetaxine 1.25 mg/m(2) twice daily, days 1-14, every 28 days until hematologic response or a maximum of 6 cycles, and then days 1-7 every 28 days as maintenance. Results for patients treated in chronic phase are reported here. Patients (n = 62) received a median of 7 (range, 1-41) cycles. Complete hematologic response was achieved in 48 patients (77%; 95% lower confidence limit, 65%); median response duration was 9.1 months. Fourteen patients (23%; 95% lower confidence limit, 13%) achieved major cytogenetic response, including complete cytogenetic response in 10 (16%). Median progression free-survival was 7.7 months. Grade 3/4 hematologic toxicity included thrombocytopenia (76%), neutropenia (44%), and anemia (39%) and was typically manageable by dose reduction. Nonhematologic adverse events were mostly grade 1/2 and included infection (42%), diarrhea (40%), and nausea (34%). Omacetaxine may provide a safe and effective treatment for CML patients with T315I mutation. This study is registered at www.clinicaltrials.gov as NCT00375219. (Blood. 2012; 120(13):2573-2580)