Bryan Jeffrey C, Verstovsek Srdan
Pharmacy Clinical Programs, Division of Pharmacy, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA.
Division of Cancer Medicine, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Cancer Chemother Pharmacol. 2016 Jun;77(6):1125-42. doi: 10.1007/s00280-016-3012-z. Epub 2016 Mar 26.
Myelofibrosis (MF) and polycythemia vera (PV) are BCR-ABL1-negative myeloproliferative neoplasms associated with somatic hematopoietic stem cell mutations leading to over activation of JAK-STAT signaling. MF and PV are pathogenically related and share specific clinical features such as splenomegaly and constitutional symptoms. The MF phenotype is dominated by the effects of progressive bone marrow fibrosis resulting in shortened survival. In contrast, elevated thrombosis risk due to erythrocytosis is the primary clinical concern in PV. Ruxolitinib, an oral JAK1/JAK2 inhibitor, is approved in the USA for the treatment of patients with intermediate- or high-risk MF and patients with PV who have had an inadequate response to or are intolerant of hydroxyurea. For MF, results of two phase III studies demonstrated that ruxolitinib therapy reduced spleen volume and MF-related symptom burden, improved quality-of-life measures, and was associated with prolonged overall survival. Treatment benefits were generally sustained with continued therapy. Dose-dependent cytopenias were common but generally manageable with transfusions (for anemia), dose reduction, or treatment interruption. Optimal dosing management is critical to maintain long-term treatment benefit, because cessation of therapy resulted in rapid return of symptoms to baseline levels. Results of the phase III PV trial showed that ruxolitinib was significantly more effective than standard therapy in controlling hematocrit levels and improving splenomegaly and PV-related symptoms. Only 1 of 110 patients in the ruxolitinib arm compared with 6 of 112 patients in the control arm experienced a thromboembolic event through week 32. Grade ≥3 cytopenias were uncommon.
骨髓纤维化（MF）和真性红细胞增多症（PV）是BCR-ABL1阴性骨髓增殖性肿瘤，与导致JAK-STAT信号过度激活的体细胞造血干细胞突变相关。MF和PV在发病机制上相关，具有脾肿大和全身症状等特定临床特征。MF的表型主要由进行性骨髓纤维化的影响主导，导致生存期缩短。相比之下，红细胞增多症导致的血栓形成风险升高是PV的主要临床关注点。芦可替尼是一种口服JAK1/JAK2抑制剂，在美国被批准用于治疗中高危MF患者以及对羟基脲反应不足或不耐受的PV患者。对于MF，两项III期研究结果表明，芦可替尼治疗可缩小脾脏体积并减轻与MF相关的症状负担，改善生活质量指标，并延长总生存期。持续治疗通常可维持治疗益处。剂量依赖性血细胞减少很常见，但一般可通过输血（治疗贫血）、减少剂量或中断治疗来控制。最佳剂量管理对于维持长期治疗益处至关重要，因为停止治疗会导致症状迅速恢复至基线水平。III期PV试验结果显示，芦可替尼在控制血细胞比容水平、改善脾肿大和与PV相关的症状方面明显比标准治疗更有效。在第32周时，芦可替尼组110例患者中只有1例发生血栓栓塞事件，而对照组112例患者中有6例发生。≥3级血细胞减少并不常见。
