骨髓纤维化
原发性血小板增多症
鲁索利替尼
真性红细胞增多症
医学
内科学
胃肠病学
血液学
血小板增多症
骨髓增生性肿瘤
代理终结点
JAK2 V617F
Janus激酶2
肿瘤科
血小板
骨髓
受体
作者
Paola Guglielmelli,Barbara Mora,Francesca Gesullo,Francesco Mannelli,Giuseppe Gaetano Loscocco,Leonardo Signori,Chiara Pessina,Ilaria Colugnat,Raffaela Aquila,Manjola Balliu,Chiara Maccari,Simone Romagnoli,Chiara Paoli,Elena Nacca,Lorenzo Fagiolo,Margherita Maffioli,Tiziano Barbui,Francesco Passamonti,Alessandro M. Vannucchi
摘要
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.
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