Safety and Efficacy of TG101348, a Selective JAK2 Inhibitor, in Myelofibrosis
Safety and Efficacy of TG101348, a Selective JAK2 Inhibitor, in Myelofibrosis
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DOI：
10.1200/jco.2010.32.8021
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发表时间：
2011-03-01
影响因子：
45.3
通讯作者：
Tefferi, Ayalew
中科院分区：
文献类型：
--
作者：
Pardanani, Animesh;Gotlib, Jason R.;Tefferi, Ayalew
目的骨髓纤维化是一种伴有贫血、脾肿大和躯体症状的髓系恶性肿瘤。患者经常携带JAK-STAT激活突变，对选择性小分子Janus激酶2(JAK2)抑制剂TG101348敏感。患者与方法在一项多中心I期试验中，口服TG101348治疗高危或中危的原发或继发性真性红细胞增多症/原发性血小板增多症骨髓纤维化患者每天一次。最大耐受量为680 mg/d，剂量限制性毒性是血清淀粉酶水平的可逆性和无症状升高。43名患者(73%)继续治疗超过6个周期；TG101348累积暴露的中位数为380天。不良反应包括恶心、呕吐、腹泻、贫血和血小板减少；相应的3-4级发生率分别为3%、3%、10%、35%和24%。TG101348治疗对血清细胞因子水平的影响不大，但超过一半的早饱、盗汗、乏力、瘙痒和咳嗽的患者这些症状得到了迅速和持久的改善。经过6个周期和12个周期的治疗，分别有39%和47%的患者达到了国际工作组标准的脾反应。大多数白细胞增多或血小板增多的患者(分别为28例和10例)在6个周期(分别为57%和90%)和12个周期(分别为56%和88%)后血细胞计数恢复正常。突变阳性患者的JAK2 V617F等位基因负荷在6个月后显著降低(n=51；P=0.04)，尤其是等位基因负荷大于20%的亚组(n=23；P<；.01)，这种下降持续12个月。结论TG101348对骨髓纤维化患者具有良好的耐受性，可显著减轻疾病负担，获得持久的临床益处。J Clin Oncol29：789-796(C)2011年美国临床肿瘤学会
Purpose Myelofibrosis is a myeloid malignancy associated with anemia, splenomegaly, and constitutional symptoms. Patients frequently harbor JAK-STAT activating mutations that are sensitive to TG101348, a selective small-molecule Janus kinase 2 (JAK2) inhibitor.Patients and Methods In a multicenter phase I trial, oral TG101348 was administered once a day to patients with high-or intermediate-risk primary or post-polycythemia vera/essential thrombocythemia myelofibrosis.Results Fifty-nine patients were treated, including 28 in the dose-escalation phase. The maximum-tolerated dose was 680 mg/d, and dose-limiting toxicity was a reversible and asymptomatic increase in the serum amylase level. Forty-three patients (73%) continued treatment beyond six cycles; the median cumulative exposure to TG101348 was 380 days. Adverse events included nausea, vomiting, diarrhea, anemia, and thrombocytopenia; corresponding grades 3 to 4 incidence rates were 3%, 3%, 10%, 35%, and 24%. TG101348 treatment had modest effect on serum cytokine levels, but greater than half of the patients with early satiety, night sweats, fatigue, pruritus, and cough achieved rapid and durable improvement in these symptoms. By six and 12 cycles of treatment, 39% and 47% of patients, respectively, had achieved a spleen response per International Working Group criteria. The majority of patients with leukocytosis or thrombocytosis at baseline (n = 28 and n = 10, respectively) achieved normalization of blood counts after six (57% and 90%, respectively) and 12 (56% and 88%, respectively) cycles. A significant decrease in JAK2 V617F allele burden was observed at 6 months in mutation-positive patients (n = 51; P = .04), particularly in the subgroup with allele burden greater than 20% (n = 23; P < .01); the decrease was durable at 12 months.Conclusion TG101348 is well tolerated and produces significant reduction in disease burden and durable clinical benefit in patients with myelofibrosis. J Clin Oncol 29:789-796. (C) 2011 by American Society of Clinical Oncology