Department of Leukemia, MD Anderson Cancer Center, University of Texas, Houston, TX; and.
Division of Hematology/Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
Blood Adv. 2022 Aug 23;6(16):4905-4913. doi: 10.1182/bloodadvances.2022007524.
Myelofibrosis (MF) can present with symptomatic splenomegaly and/or cytopenias including thrombocytopenia. Disease-related thrombocytopenia is a poor prognostic factor with a median overall survival of less than 2 years. Currently approved JAK1/2 inhibitors have not been evaluated in patients with platelets ≤ 50 × 109/L and in fact could potentiate thrombocytopenia because of their combined JAK1/2 inhibitory activity. Pacritinib (PAC), a selective JAK2, fms-like tyrosine kinase 3, interleukin-1 receptor-associated kinase 1 multikinase inhibitor was developed to meet this unmet need. PAC was evaluated in 2 randomized phase 3 trials in the frontline setting (PERSIST-1, PAC 400 mg daily vs best available therapy) and second-line setting in patients with MF with platelets ≤ 100 × 109/L (PERSIST-2, PAC 400 mg daily or 200 mg twice daily vs best available therapy). PERSIST-1 met its primary end point; however, the development of PAC hit a brief pause because of a US Food and Drug Administration-mandated clinical hold for excess of bleeding and cardiac events in the PAC 400 mg daily arm in the PERSIST-1 study. Although the PERSIST-2 study was terminated abruptly because of this clinical hold, it met its splenic response end point and demonstrated a trend toward symptom improvement. Subsequent, diligent review of the PERSIST-1 and PERSIST-2 studies did not confirm an excess of severe bleeding or cardiac events on the PAC arm. Additionally, the dose finding PAC203 study endorsed the safety and efficacy of 200 mg twice daily, leading to the approval of PAC for the treatment of patients with MF with platelets ≤ 50 × 109/L.
骨髓纤维化 (MF) 可表现为有症状的脾肿大和/或细胞减少症，包括血小板减少症。与疾病相关的血小板减少症是预后不良的因素，总体中位生存期不到 2 年。目前批准的 JAK1/2 抑制剂尚未在血小板 ≤ 50×109/L 的患者中进行评估，事实上，由于其联合的 JAK1/2 抑制活性，可能会加重血小板减少症。帕克里替尼 (PAC) 是一种选择性 JAK2、fms 样酪氨酸激酶 3、白细胞介素-1 受体相关激酶 1 多激酶抑制剂，旨在满足这一未满足的需求。PAC 在两项一线治疗（PERSIST-1，PAC 每天 400mg 与最佳可用疗法比较）和二线治疗（MF 患者血小板 ≤ 100×109/L，PERSIST-2，PAC 每天 400mg 或每天 2 次 200mg 与最佳可用疗法比较）的随机 3 期临床试验中进行了评估。PERSIST-1 达到了主要终点；然而，由于 PAC 每天 400mg 臂在 PERSIST-1 研究中出现出血和心脏事件过多，美国食品和药物管理局下令暂停临床试验，PAC 的开发短暂停顿。尽管由于该临床搁置，PERSIST-2 研究突然终止，但它达到了脾脏反应终点，并显示出症状改善的趋势。随后，对 PERSIST-1 和 PERSIST-2 研究的仔细审查并未证实 PAC 臂有严重出血或心脏事件过多。此外，剂量发现 PAC203 研究证实了每天两次 200mg 的安全性和有效性，这导致 PAC 被批准用于治疗血小板 ≤ 50×109/L 的 MF 患者。
