Abstract：
The variant allele frequency (VAF) of driver mutations (JAK2, CALR) in myeloproliferative neoplasms is associated with features of advanced disease and complications. Ruxolitinib and interferon were reported to variably reduce the mutant VAF, but the long-term impact of molecular responses (MR) remains debated. We prospectively measured changes in JAK2 and CALR VAF in 77 patients with polycythemia vera and essential thrombocythemia, treated with ruxolitinib for a median of 8 years, and assessed correlation with complete clinical and hematological response (CCHR) and outcomes. At last observation time, JAK2 VAF reduced overall from a median of 68% (range, 20%-99%) to 3.5% (0%-98%). A profound and durable MR (DMR; defined as a VAF stably ≤2%), including complete MR in 8%, was achieved in 20% of the patients, a partial MR (PMR; VAF reduction >50% of the baseline level) in 25%, and 56% had no molecular response (NMR). A CCHR was reached by 69% overall, independently of any degree of MR achieved; conversely, a DMR correlated with longer duration of CCHR and, most importantly, with reduced rate of progression to myelofibrosis and with longer myelofibrosis-free, event-free and progression-free survival. Achievement of PMR also had some favorable impact on outcomes, compared to NMR. A baseline JAK2 VAF <50%, and a VAF reduction of ≥35% after 2 years of treatment, predicted for the achievement of DMR and reduced progression to myelofibrosis. Overall, these findings support the clinical value of achieving profound, durable MR and its consideration as surrogate endpoint in future clinical trials.
摘要：
骨髓增殖性肿瘤中驱动突变（JAK2，CALR）的变异等位基因频率（VAF）与晚期疾病和并发症的特征相关。据报道，Ruxolitinib和干扰素可可变地减少VAF突变体，但分子反应(MR)的长期影响仍存在争议。我们前瞻性测量了77例真性红细胞增多症和原发性血小板增多症患者JAK2和CALRVAF的变化，用鲁索替尼治疗的中位数为8年，并评估与完全临床和血液学反应（CKR）和结局的相关性。在最后的观察时间，JAK2VAF总体上从68%的中位数降低(范围，20%-99%）至3.5%（0%-98%）。深刻而持久的MR（DMR；定义为VAF稳定≤2％），包括8%的完全MR，在20%的患者中实现了目标，部分MR（PMR；VAF减少>基线水平的50％）在25％，56%无分子响应(NMR)。总体上达到了69%的CHR，独立于任何程度的MR；相反，DMR与较长的CHR持续时间相关，最重要的是,骨髓纤维化进展率降低，无骨髓纤维化时间更长，无事件和无进展生存期。PMR的成就也对结果产生了一些有利的影响，与NMR相比。基线JAK2VAF<50%,治疗2年后VAF降低≥35%，预测实现DMR并减少骨髓纤维化的进展。总的来说,这些发现支持了实现深远的临床价值，持久MR及其在未来临床试验中作为替代终点的考虑。
