A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis.
A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis.
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DOI：
10.1056/nejmoa1110557
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发表时间：
2012-03-01
期刊：
影响因子：
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通讯作者：
Kantarjian HM
中科院分区：
文献类型：
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作者：
Verstovsek S;Mesa RA;Gotlib J;Levy RS;Gupta V;DiPersio JF;Catalano JV;Deininger M;Miller C;Silver RT;Talpaz M;Winton EF;Harvey JH Jr;Arcasoy MO;Hexner E;Lyons RM;Paquette R;Raza A;Vaddi K;Erickson-Viitanen S;Koumenis IL;Sun W;Sandor V;Kantarjian HM
Ruxolitinib是一种选择性JAK 1和JAK 2抑制剂，在骨髓纤维化中具有临床显著活性。在一项双盲试验中，中度-2或高风险骨髓纤维化患者随机接受每日两次口服ruxolitinib（n=155）或安慰剂（n=154）。主要终点是通过磁共振成像评估的24周时脾脏体积减少≥35%的患者比例。次要终点包括缓解的持久性、症状负担的变化（通过总症状评分[TSS]评估）和总生存期。在ruxolitinib组中，41.9%达到了主要终点，而安慰剂组为0.7%（P<0.001）。服用鲁索利替尼时，脾脏反应得以维持：67%的反应患者维持反应≥48周。24周时，45.9%的鲁索利替尼治疗患者与5.3%的安慰剂治疗患者TSS改善≥50%（P<0.001）。ruxolitinib组有13例死亡，安慰剂组有24例死亡（风险比，0.50; 95%CI，0.25-0.98; P=0.04）。两组因不良事件而停药的情况相似（各11%）。在接受鲁索替尼治疗的患者中，贫血和血小板减少是最常见的不良事件，但很少导致停药（每种事件1例患者）。两名患者发生了急性髓性白血病（AML）的转化，均在ruxolitinib组。Ruxolitinib通过减小脾脏大小、改善衰弱性骨髓纤维化相关症状和改善总生存期，为骨髓纤维化患者提供了显著的临床获益。改善是以治疗早期更频繁的贫血和血小板减少为代价的。AML转化的不平衡需要在进一步的研究中予以关注。（由Incyte Corporation资助; ClinicalTrials.gov，NCT 00952289）
Ruxolitinib, a selective JAK1 and JAK2 inhibitor, has clinically significant activity in myelofibrosis. In a double-blind trial, patients with intermediate-2 or high-risk myelofibrosis were randomized to twice-daily oral ruxolitinib (n=155) or placebo (n=154). The primary endpoint was the proportion of patients with ≥35% spleen volume reduction at 24 weeks assessed by magnetic resonance imaging. Secondary endpoints included durability of response, changes in symptom burden (assessed by Total Symptom Score [TSS]), and overall survival. In the ruxolitinib group, 41.9% achieved the primary endpoint versus 0.7% in the placebo group (P<0.001). Spleen response was maintained while taking ruxolitinib: 67% of responding patients maintained response for ≥48 weeks. A ≥50% improvement in TSS at 24 weeks was achieved by 45.9% of ruxolitinib-treated versus 5.3% of placebo-treated patients (P<0.001). Thirteen deaths occurred in the ruxolitinib and 24 in the placebo group (hazard ratio, 0.50; 95% CI, 0.25–0.98; P=0.04). Discontinuations for adverse events were similar between groups (11% each). Among ruxolitinib-treated patients, anemia and thrombocytopenia were the most common adverse events, but rarely led to discontinuation (1 patient for each event). Two patients underwent transformation to acute myeloid leukemia (AML), both in the ruxolitinib group. Ruxolitinib provided significant clinical benefits in patients with myelofibrosis by reducing spleen size, improving debilitating myelofibrosis-related symptoms, and improving overall survival. Improvement came at a cost of more frequent anemia and thrombocytopenia in the early part of the treatment period. The imbalance in AML transformation requires attention in further studies. (Funded by Incyte Corporation; ClinicalTrials.gov, NCT00952289)