基于二代测序技术分析骨髓纤维化患者基因突变对芦可替尼疗效的影响

Analysis of the effect of gene mutations on the efficacy of ruxolitinib in patients with myelofibrosis based on second-generation sequencing technology

目的评估基因突变对芦可替尼治疗骨髓纤维化(MF)疗效的影响。方法回顾性分析2017年7月至2020年12月服用芦可替尼治疗并应用二代测序技术检测127个血液肿瘤相关基因突变的56例MF患者的临床资料,分析突变基因与芦可替尼疗效的关系。结果①56例患者中,原发性骨髓纤维化(PMF)36例、真性红细胞增多症(PV)后骨髓纤维化(PPV-MF)9例,原发性血小板增多症(ET)后骨髓纤维化(PET-MF)11例。②50例(89.29%)携带驱动基因突变,22例(39.29%)携带基因突变≥3个,29例(51.79%)检出高危基因突变(HMR)。③对于基因突变≥3个的MF患者,芦可替尼仍有较好的改善体质性症状及缩小脾脏的效果(P=0.001,P<0.001)。与基因突变<3个组比较,基因突变≥3个组停药前持续用药时间(TTF)及无进展生存期(PFS)明显缩短[356(55~1061)d对471.5(50~1270)d,z=-2.701,P=0.007;444(91~4109)d对1248.5(91~7061)d,z=-2.030,P=0.042]。④与未检出HMR的患者比较,≥2个HMR患者的芦可替尼缩脾效果较差(t=10.471,P=0.034),TTF及PFS明显缩短(P<0.001,P=0.001)。⑤在携带ASXL1、EZH2、SRSF2等附加基因突变患者中,芦可替尼缩脾、症状改善及稳定骨髓纤维化作用较差,携带ASXL1、EZH2突变患者TTF[ASXL1:360(55~1270)d对440(55~1268)d,z=-3.115,P=0.002;EZH2:327(55~975)d对404(50~1270)d,z=-3.219,P=0.001]及PFS较未携带者明显缩短(ASXL1:457(50~1331)d对574(55~1437)d,z=-3.219,P=0.001;EZH2:428(55~1331)d对505(55~1437)d,z=-2.576,P=0.008]。结论MF患者携带的基因突变类型、数量以及HMR对芦可替尼疗效有一定影响。

Objective To assess the effect of gene mutations on the efficacy of ruxolitinib for treating myelofibrosis(MF).Methods We retrospectively analyzed the clinical data of 56 patients with MF treated with ruxolitinib from July 2017 to December 2020 and applied second-generation sequencing(NGS)technology to detect 127 hematologic tumor-related gene mutations.Additionally,we analyzed the relationship between mutated genes and the efficacy of ruxolitinib.Results①Among the 56 patients,there were 36 cases of primary bone marrow fibrosis(PMF),9 cases of bone marrow fibrosis(ppv-mf)after polycythemia vera,and 11 cases of bone marrow fibrosis(PET-MF)after primary thrombocytosis(ET).②Fifty-six patients with MF taking ruxolitinib underwent NGS,among whom,50(89.29%)carried driver mutations,22(39.29%)carried≥3 mutations,and 29(51.79%)carried high-risk mutations(HMR).③For patients with MF carrying≥3 mutations,ruxolitinib still had a better effect of improving somatic symptoms and shrinking the spleen(P=0.001,P<0.001),but TTF and PFS were significantly shorter in patients carrying≥3 mutations(P=0.007,P=0.042).④For patients carrying≥2 HMR mutations,ruxolitinib was less effective in shrinking the spleen than in those who did not carry HMR(t=10.471,P=0.034),and the TTF and PFS were significantly shorter in patients carrying≥2 HMR mutations(P<0.001,P=0.001).⑤Ruxolitinib had poorer effects on spleen reduction,symptom improvement,and stabilization of myelofibrosis in patients carrying additional mutations in ASXL1,EZH2,and SRSF2.Moreover,patients carrying ASXL1 and EZH2 mutations had significantly shorter TTF[ASXL1:360(55−1270)d vs 440(55−1268)d,z=−3.115,P=0.002;EZH2:327(55−975)d vs 404(50−1270)d,z=−3.219,P=0.001],and significantly shorter PFS compared to non-carriers[ASXL1:457(50−1331)d vs 574(55−1437)d,z=−3.219,P=0.001);428(55−1331)d vs 505(55−1437)d,z=−2.576,P=0.008].Conclusion The type and number of mutations carried by patients with myelofibrosis and HMR impact the efficacy of ruxolitinib.