Between October 2007 and July 2013, 183 Mayo Clinic patients (median age 65 years; 58% males) with high/intermediate risk myelofibrosis (MF) were enrolled in consecutive phase 1/2 JAK2 inhibitor (JAKi) clinical trials with momelotinib (n = 79), ruxolitinib (n = 50), fedratinib (n = 23) and BMS-911543 (n = 31). Using conventional criteria, the respective response rates for spleen and “transfusion-dependent anemia” were 47%, 32%, 83%, 62% and 51%, 30%, 10%, 44%, respectively, favoring momelotinib for anemia response (p = 0.02) and fedratinib for spleen response (p < 0.01). All study patients were followed to death or 2022, during which time 177 (97%) drug discontinuations, 27 (15%) leukemic transformations, and 22 (12%) allogeneic stem cell transplants (ASCT) were recorded. 5/10-year survival rate for all 183 patients was 41%/16% and not significantly different across the four drug cohorts (p = 0.33). Multivariable analysis of pre-treatment variables identified age >65 years (HR 3.5), absence of type 1/like CALR mutation (HR 2.8), baseline transfusion need (HR 2.1), and presence of ASXL1/SRSF2 mutation (HR 1.6) as risk factors for overall survival; subsequent HR-based modeling segregated three risk categories with 5/10-year survival rates of 84%/60%, 44%/14%, and 21%/5% (p < 0.01). In addition, spleen (p < 0.01) and anemia (p = 0.01) responses were independently associated with improved short-term survival while long-term survival was secured only by ASCT (5/10-year survival rate 91%/45% vs 47%/19% in non-transplanted patients; p < 0.01). The current retrospective study suggests the value of specific pre-treatment variables in identifying long-lived MF patients receiving JAKi and also confirms recent observations on the favorable impact of treatment response on short-term and of ASCT on long-term survival.
2007年10月至2013年7月期间，183名梅奥诊所的高危/中危骨髓纤维化患者（中位年龄65岁；58%为男性）连续参加了1/2期JAK2抑制剂临床试验，分别使用莫莫洛替尼（n=79）、鲁索替尼（n=50）、菲卓替尼（n=23）和BMS-911543（n=31）。根据常规标准，脾脏反应率和“输血依赖性贫血”反应率分别为47%、32%、83%、62%和51%、30%、10%、44%，其中莫莫洛替尼在贫血反应方面表现更佳（p=0.02），菲卓替尼在脾脏反应方面更优（p<0.01）。所有研究患者均随访至死亡或2022年，期间记录了177例（97%）停药、27例（15%）白血病转化和22例（12%）异基因干细胞移植。183名患者的5年/10年总生存率为41%/16%，四种药物组间无显著差异（p=0.33）。对治疗前变量的多因素分析显示，年龄>65岁（风险比3.5）、无1型或类似CALR突变（风险比2.8）、基线需要输血（风险比2.1）以及存在ASXL1/SRSF2突变（风险比1.6）是总生存的风险因素；基于风险比的后续模型将患者分为三个风险层级，其5年/10年生存率分别为84%/60%、44%/14%和21%/5%（p<0.01）。此外，脾脏反应（p<0.01）和贫血反应（p=0.01）与短期生存改善独立相关，而长期生存仅通过异基因干细胞移植实现（移植患者5年/10年生存率为91%/45%，未移植患者为47%/19%；p<0.01）。本回顾性研究表明特定治疗前变量对识别接受JAK抑制剂治疗的长期生存骨髓纤维化患者具有价值，并证实了近期关于治疗反应对短期生存及异基因干细胞移植对长期生存积极影响的观察结果。
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