Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
University of Michigan, Comprehensive Cancer Center, Ann Arbor.
JAMA Oncol. 2018 May 1;4(5):652-659. doi: 10.1001/jamaoncol.2017.5818.
Myelofibrosis is a hematologic malignancy characterized by splenomegaly and debilitating symptoms. Thrombocytopenia is a poor prognostic feature and limits use of Janus kinase 1 (JAK1)/Janus kinase 2 (JAK2) inhibitor ruxolitinib.
To compare the efficacy and safety of JAK2 inhibitor pacritinib with that of best available therapy (BAT), including ruxolitinib, in patients with myelofibrosis and thrombocytopenia.
DESIGN, SETTING, AND PARTICIPANTS: For this phase 3 randomized international multicenter study-the PERSIST-2 study-of pacritinib vs BAT, 311 patients with myelofibrosis and platelet count 100 × 109/L or less were recruited for analysis. Crossover from BAT was allowed after week 24 or for progression of splenomegaly.
Patients were randomized 1:1:1 to pacritinib 400 mg once daily, pacritinib 200 mg twice daily, or BAT.
Coprimary end points were rates of patients achieving 35% or more spleen volume reduction (SVR) and 50% or more reduction in total symptom score (TSS) at week 24. Efficacy analyses were performed on the intention-to-treat efficacy population, comprising all patients with a randomization date allowing for week 24 data.
Overall, 311 patients (mean [SD] age, 63.70 [9.08] years; 171 men [55%] and 140 women [45%]) were included in the study; 149 patients (48%) had prior ruxolitinib. The most common BAT was ruxolitinib (44 patients [45%]); 19 patients (19%) received watchful-waiting only. The intention-to-treat efficacy population included 75 patients randomized to pacritinib once daily; 74, pacritinib twice daily, and 72, BAT. Pacritinib (arms combined) was more effective than BAT for 35% or more SVR (27 patients [18%] vs 2 patients [3%]; P = .001) and had a nonsignificantly greater rate of 50% or more reduction in TSS (37 patients [25%] vs 10 patients [14%]; P = .08). Pacritinib twice daily led to significant improvements in both end points over BAT (≥35% SVR: 16 patients [22%] vs 2 patients [3%]; P = .001; ≥50% reduction in TSS: 24 patients [32%] vs 10 patients [14%]; P = .01). Clinical improvement in hemoglobin and reduction in transfusion burden were greatest with pacritinib twice daily. For pacritinib once daily, pacritinib twice daily, and BAT, the most common (>10%) grade 3 or 4 adverse events were thrombocytopenia (32 patients [31%], 34 patients [32%], 18 patients [18%]), and anemia (28 patients [27%], 23 patients [22%], 14 patients [14%]). In the pacritinib once daily, twice daily, and BAT arms, discontinuation owing to adverse events occurred in 15 patients (14%), 10 patients (9%), and 4 patients (4%).
In patients with myelofibrosis and thrombocytopenia, including those with prior anti-JAK therapy, pacritinib twice daily was more effective than BAT, including ruxolitinib, for reducing splenomegaly and symptoms.
clinicaltrials.gov Identifier: NCT02055781.
骨髓纤维化是一种血液系统恶性肿瘤，其特征为脾肿大和使人虚弱的症状。血小板减少是预后不良的特征，并且限制了使用 Janus 激酶 1（JAK1）/Janus 激酶 2（JAK2）抑制剂芦可替尼。
比较 JAK2 抑制剂帕立替尼与最佳可用治疗（BAT），包括芦可替尼，在骨髓纤维化和血小板减少症患者中的疗效和安全性。
设计、地点和参与者：这是一项比较帕立替尼与 BAT 疗效和安全性的 3 期随机国际多中心研究——PERSIST-2 研究，共纳入 311 例血小板计数<100×10^9/L 的骨髓纤维化患者进行分析。允许在第 24 周或脾肿大进展后交叉使用 BAT。
患者按 1:1:1 的比例随机分为帕立替尼 400 mg 每日一次、帕立替尼 200 mg 每日两次或 BAT。
主要终点为第 24 周时脾脏体积减少 35%或更多（SVR）和总症状评分（TSS）减少 50%或更多的患者比例。疗效分析在意向治疗疗效人群中进行，包括所有具有允许第 24 周数据的随机日期的患者。
共有 311 例患者（平均[SD]年龄 63.70[9.08]岁；男性 171 例[55%]，女性 140 例[45%]）入组；其中 48%的患者有芦可替尼的使用史。最常见的 BAT 是芦可替尼（44 例[45%]）；19 例（19%）患者仅接受观察等待。意向治疗疗效人群包括 75 例随机接受帕立替尼每日一次；74 例、帕立替尼每日两次和 72 例接受 BAT。与 BAT 相比，帕立替尼（联合用药）对 SVR≥35%的疗效更显著（27 例[18%]与 2 例[3%]；P=0.001），TSS 降低≥50%的比例也显著更高（37 例[25%]与 10 例[14%]；P=0.08）。与 BAT 相比，帕立替尼每日两次在这两个终点都有显著改善（SVR≥35%：16 例[22%]与 2 例[3%]；P=0.001；TSS 降低≥50%：24 例[32%]与 10 例[14%]；P=0.01）。血红蛋白水平的临床改善和输血负担的降低以帕立替尼每日两次最为显著。对于帕立替尼每日一次、每日两次和 BAT，最常见（>10%）的 3 级或 4 级不良事件为血小板减少症（32 例[31%]、34 例[32%]、18 例[18%]）和贫血症（28 例[27%]、23 例[22%]、14 例[14%]）。在帕立替尼每日一次、每日两次和 BAT 组中，因不良事件而停药的患者分别有 15 例（14%）、10 例（9%）和 4 例（4%）。
在骨髓纤维化和血小板减少症患者中，包括那些有抗-JAK 治疗史的患者，与包括芦可替尼在内的 BAT 相比，帕立替尼每日两次在减少脾肿大和症状方面更有效。
clinicaltrials.gov 标识符：NCT02055781。
