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首页> 外文期刊>Blood: The Journal of the American Society of Hematology >Treatment optimization and genomic outcomes in refractory severe aplastic anemia treated with eltrombopag
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Treatment optimization and genomic outcomes in refractory severe aplastic anemia treated with eltrombopag

机译：用EltromboPag处理难治性严重血栓性贫血中的治疗优化和基因组结果

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Eltrombopag (EPAG) received approval from the US Food and Drug Administration for the treatment of refractory severe aplastic anemia (rSAA) based on treatment of 43 patients with doses escalating from 50 to 150 mg daily for 12 weeks. Response kinetics suggested that more prolonged administration of EPAG at a dose of 150 mg could speed and improve response rates. We enrolled 40 patients with rSAA in a study of EPAG 150 mg daily, with a primary end point of response at 24 weeks. Twenty (50%) of 40 patients responded at 24 weeks; 5 (25%) of 20 would have been deemed nonresponders at 12 weeks, the end point of the previous study. Fifteen of the 19 responding patients continuing on EPAG had drug discontinued for robust response; 5 of the 15 required EPAG re-initiation for relapse, with all recovering response. To analyze risk of clonal progression, we combined long-termdata from the 83 patients with rSAA enrolled in both studies. Evolution to an abnormal karyotype occurred in 16 (19%), most within 6 months of EPAG initiation. Targeted deep sequencing/whole-exome sequencing was performed pre-EPAG and at primary response end point and/or time of clonal evolution or longest follow-up. Cytogenetic evolution did not correlate with mutational status, and overall mutated allele fractions of myeloid cancer genes did not increase on EPAG. In summary, extended administration of EPAG at a dose of 150 mg for 24 weeks rescued responses in some patients with rSAA not responding at 12 weeks. The temporal relationship between clonal evolution and drug exposure suggests that EPAG may promote expansion of dormant preexisting clones with an aberrant karyotype.
机译：Eltompagag（EPAG）获得了美国食品和药物管理局的批准，用于治疗难治性严重的血栓性贫血（RSAA），基于43例剂量每天升级为50至150毫克的患者12周。响应动力学表明，在150mg的剂量下更长时间地施用EPAG可以速度，提高反应率。我们每天在EPAG 150毫克研究中注册了40名RSAA患者，24周的主要响应点。二十（50％）40例患者在24周内作出反应; 5（25％）的20个将在12周内被视为非反应者，前一项研究的终点。继续对EPAG继续进行的19例响应患者的十五次因鲁棒反应而停止毒品; 15个所需的ePAG重新启动中的5个，全部恢复响应。为了分析克隆进展的风险，我们将83例RSAA患者的长期组合在两项研究中。在ePAG发起的6个月内，16（19％）发生异常核型的进化发生。靶向的深度测序/全外末端测序在前EPAG和初级响应终点和/或时间的克隆演化或最长的随访中进行。细胞遗传学进化与突变状态无关，骨髓癌基因的整体突变等位基因部分在EPAG没有增加。总之，延长施用EPAG的剂量为150毫克，24周的患者在12周内没有响应的一些患者救出。克隆演化和药物暴露之间的时间关系表明，EPAG可以促进具有异常核型的休眠预先存在的克隆的扩张。

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