选择性 JAK2 抑制剂 TG101348 治疗骨髓纤维化的安全性和疗效。
Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis.
机构信息
Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA.
出版信息
J Clin Oncol. 2011 Mar 1;29(7):789-96. doi: 10.1200/JCO.2010.32.8021. Epub 2011 Jan 10.
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.
目的
骨髓纤维化是一种与贫血、脾肿大和全身症状相关的髓系恶性肿瘤。患者常携带 JAK-STAT 激活突变，对 TG101348 敏感，TG101348 是一种选择性小分子 Janus 激酶 2（JAK2）抑制剂。
患者和方法
在一项多中心 I 期试验中，每天一次口服 TG101348 用于治疗高危或中危原发性或真性红细胞增多症/原发性血小板增多症后骨髓纤维化患者。
结果
59 例患者接受治疗，其中 28 例在剂量递增阶段。最大耐受剂量为 680mg/d，剂量限制性毒性为血清淀粉酶水平可逆性无症状升高。43 例（73%）患者在 6 个周期后继续治疗；TG101348 的中位累积暴露量为 380 天。不良事件包括恶心、呕吐、腹泻、贫血和血小板减少症；相应的 3 级到 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有一定影响，但超过一半的早饱、盗汗、乏力、瘙痒和咳嗽患者迅速且持久地改善了这些症状。在治疗 6 个和 12 个周期时，分别有 39%和 47%的患者根据国际工作组标准达到脾脏反应。大多数基线白细胞增多或血小板增多的患者（分别为 n=28 和 n=10）在治疗 6 个周期（分别为 57%和 90%）和 12 个周期（分别为 56%和 88%）后恢复正常血象。在 6 个月时，突变阳性患者（n=51）的 JAK2 V617F 等位基因负担显著下降（P=0.04），特别是在等位基因负担大于 20%的亚组（n=23；P<0.01）；12 个月时下降持续存在。
结论
TG101348 耐受性良好，可显著降低骨髓纤维化患者的疾病负担并带来持久的临床获益。
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