文章：

接受鲁索替尼或羟基脲治疗的骨髓纤维化患者的突变谱

Mutation landscape in patients with myelofibrosis receiving ruxolitinib or hydroxyurea

原文发布日期：2018-11-22

DOI: 10.1038/s41408-018-0152-x

类型: Article

开放获取: 是

英文摘要：

Refractoriness to ruxolitinib in patients with myelofibrosis (MF) was associated with clonal evolution; however, whether genetic instability is promoted by ruxolitinib remains unsettled. We evaluated the mutation landscape in 71 MF patients receiving ruxolitinib (n = 46) and hydroxyurea (n = 25) and correlated with response. A spleen volume response (SVR) was obtained in 57% and 12%, respectively. Highly heterogenous patterns of mutation acquisition/loss and/or changes of variant allele frequency (VAF) were observed in the 2 patient groups without remarkable differences. In patients receiving ruxolitinib, driver mutation type and high-molecular risk profile (HMR) at baseline did not impact on response rate, while HMR and sole ASXL1 mutations predicted for SVR loss at 3 years. In patients with SVR, a decrease of ≥ 20% of JAK2V617F VAF predicted for SVR duration. VAF increase of non-driver mutations and clonal progression at follow-up correlated with SVR loss and treatment discontinuation, and clonal progression also predicted for shorter survival. These data indicate that (i) ruxolitinib does not appreciably promote clonal evolution compared with hydroxyurea, (ii) VAF increase of pre-existing and/or (ii) acquisition of new mutations while on treatment correlated with higher rate of discontinuation and/or death, and (iv) reduction of JAK2V617F VAF associated with SVR duration.

摘要翻译： 

骨髓纤维化患者对鲁索替尼的耐药性与克隆演变相关，但鲁索替尼是否会促进遗传不稳定性仍无定论。我们评估了71例接受鲁索替尼（n=46）和羟基脲（n=25）治疗的MF患者的突变谱系，并分析其与治疗反应的相关性。两组患者分别获得57%和12%的脾体积缓解率。在两个患者组中均观察到高度异质性的突变获得/缺失模式和（或）变异等位基因频率变化，但未见显著差异。在鲁索替尼治疗组中，基线时的驱动突变类型和高分子风险谱不影响缓解率，而HMR和单纯的ASXL1突变可预测3年时的脾体积缓解丧失。获得脾体积缓解的患者中，JAK2V617F变异等位基因频率降低≥20%可预测脾体积缓解持续时间。非驱动突变的变异等位基因频率增加及随访中的克隆进展与脾体积缓解丧失和治疗终止相关，克隆进展也预示较短生存期。这些数据表明：（i）与羟基脲相比，鲁索替尼不会显著促进克隆演变；（ii）治疗期间既有突变变异等位基因频率增加和（或）新突变获得与较高治疗终止率和（或）死亡风险相关；（iv）JAK2V617F变异等位基因频率降低与脾体积缓解持续时间相关。

原文链接：

Mutation landscape in patients with myelofibrosis receiving ruxolitinib or hydroxyurea