Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis.
Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis.
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DOI：
10.1056/nejmoa1002028
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发表时间：
2010-09-16
期刊：
影响因子：
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通讯作者：
Tefferi A
中科院分区：
文献类型：
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作者：
Verstovsek S;Kantarjian H;Mesa RA;Pardanani AD;Cortes-Franco J;Thomas DA;Estrov Z;Fridman JS;Bradley EC;Erickson-Viitanen S;Vaddi K;Levy R;Tefferi A
骨髓纤维化是一种费城染色体阴性的骨髓增生性肿瘤，与细胞减少、脾肿大、生活质量差和生存期缩短有关。大约一半的骨髓纤维化患者携带Janus激酶2基因(JAK2 V617F)的功能获得突变，这与疾病的病理生理有关。INCB018424是一种有效的、选择性的Janus激酶1(JAK1)和JAK2抑制剂。我们在JAK2 V617F阳性或JAK2 V617F阴性的原发性骨髓纤维化、原发性血小板增多症后骨髓纤维化或真性红细胞增多症后骨髓纤维化患者中进行了INCB018424的1-2期试验。共有153名患者接受INCB018424治疗，中位持续时间超过14.7个月。最初的剂量递增阶段根据可逆性血小板减少症确定每天两次25毫克或每天一次100毫克为最大耐受量。野生型JAK2患者和JAK2 V617F突变患者的JAK信号转导和转录激活因子3(STAT3)呈剂量依赖性抑制。我们研究了额外的剂量，发现15毫克的起始剂量，每天两次，然后进行个体化剂量滴定，是最有效和最安全的剂量方案。在这个剂量下，33名患者中有17名(52%)有持续12个月或更长时间的快速客观反应(≥将脾肿大缩小50%)，这种治疗与不到10%的患者的3级或4级不良反应(主要是骨髓抑制)有关。有衰弱症状的患者，包括体重减轻、疲劳、盗汗和瘙痒，病情迅速改善。临床益处与循环炎症细胞因子水平的显著降低有关，后者通常在骨髓纤维化中升高。INCB018424与骨髓纤维化患者的显著和持久的临床益处有关，这些患者目前还没有得到批准的治疗方法。
Myelofibrosis is a Philadelphia chromosome–negative myeloproliferative neoplasm associated with cytopenias, splenomegaly, poor quality of life, and shortened survival. About half of patients with myelofibrosis carry a gain-of-function mutation in the Janus kinase 2 gene (JAK2 V617F) that contributes to the pathophysiology of the disease. INCB018424 is a potent and selective Janus kinase 1 (JAK1) and JAK2 inhibitor. We conducted a phase 1–2 trial of INCB018424 in patients with JAK2 V617F–positive or JAK2 V617F–negative primary myelofibrosis, post–essential thrombocythemia myelofibrosis, or post–polycythemia vera myelofibrosis. A total of 153 patients received INCB018424 for a median duration of more than 14.7 months. The initial dose-escalation phase established 25 mg twice daily or 100 mg once daily as maximum tolerated doses, on the basis of reversible thrombocytopenia. A dose-dependent suppression of phosphorylated signal transducer and activator of transcription 3 (STAT3), a marker of JAK signaling, was demonstrated in patients with wild-type JAK2 and in patients with the JAK2 V617F mutation. We studied additional doses and established that a 15-mg twice-daily starting dose, followed by individualized dose titration, was the most effective and safest dosing regimen. At this dose, 17 of 33 patients (52%) had a rapid objective response (≥50% reduction of splenomegaly) lasting for 12 months or more, and this therapy was associated with grade 3 or grade 4 adverse events (mainly myelosuppression) in less than 10% of patients. Patients with debilitating symptoms, including weight loss, fatigue, night sweats, and pruritus, had rapid improvement. Clinical benefits were associated with a marked diminution of levels of circulating inflammatory cytokines that are commonly elevated in myelofibrosis. INCB018424 was associated with marked and durable clinical benefits in patients with myelofibrosis for whom no approved therapies existed.