Incidence and risk factors of bleeding-related adverse events in patients with chronic lymphocytic leukemia treated with ibrutinib
Incidence and risk factors of bleeding-related adverse events in patients with chronic lymphocytic leukemia treated with ibrutinib
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DOI：
10.3324/haematol.2015.126672
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发表时间：
2015-11-01
期刊：
影响因子：
10.1
通讯作者：
Wiestner, Adrian
中科院分区：
文献类型：
--
作者：
Lipsky, Andrew H.;Farooqui, Mohammed Z. H.;Wiestner, Adrian
伊布替尼与≥ 3级事件的出血相关不良事件相关。为了研究出血机制并识别高危患者，我们前瞻性地评估了血小板功能和凝血因子在我们的单药伊克替尼治疗慢性淋巴细胞白血病的临床试验中的作用。在中位随访24个月时，我们记录到发生了3级事件。至事件发生的中位时间为49天。事件的累积发生率在6个月后达到稳定水平，表明出血风险随着持续治疗而降低。在基线时，血管性血友病因子和因子VIII水平通常较高，治疗后恢复正常。通过血小板功能分析仪（PFA-100（TM））测量的血小板功能在基线时有22例患者受损，在另外19例接受伊鲁替尼治疗的患者中受损（通常为一过性）。胶原和二磷酸腺苷诱导的血小板聚集使用全血聚集测定法进行测试。与正常对照组相比，所有慢性淋巴细胞白血病患者对两种激动剂的反应均降低，无论是否使用伊曲替尼。与未经治疗的慢性淋巴细胞白血病患者相比，对胶原蛋白的反应显示出对伊布替尼的进一步轻度降低，而对腺苷二磷酸的反应有所改善。基线时存在与出血相关事件风险显著增加相关的所有参数，包括肾上腺素关闭时间延长（HR 2.74，P=0.012）、血管性血友病因子活性水平降低（HR 2.73，P=0.009）和因子VIII水平降低（HR 3.73，P=0.0004）。总之，疾病和治疗相关因素都会影响出血风险。出血风险较高的患者
Ibrutinib is associated with bleeding-related adverse events of grade = 3 events. To investigate the mechanisms of bleeding and identify patients at risk, we prospectively assessed platelet function and coagulation factors in our investigator-initiated trial of single-agent ibrutinib for chronic lymphocytic leukemia. At a median follow-up of 24 months we recorded grade = 3 events occurred. Median time to event was 49 days. The cumulative incidence of an event plateaued by 6 months, suggesting that the risk of bleeding decreases with continued therapy. At baseline, von Willebrand factor and factor VIII levels were often high and normalized on treatment. Platelet function measured via the platelet function analyzer (PFA-100 (TM) ) was impaired in 22 patients at baseline and in an additional 19 patients on ibrutinib (often transiently). Collagen and adenosine diphosphate induced platelet aggregation was tested using whole blood aggregometry. Compared to normal controls, response to both agonists was decreased in all patients with chronic lymphocytic leukemia, whether on ibrutinib or not. Compared to untreated chronic lymphocytic leukemia patients, response to collagen showed a mild further decrement on ibrutinib, while response to adenosine diphosphate improved. All parameters associated with a significantly increased risk of bleeding-related events were present at baseline, including prolonged epinephrine closure time (HR 2.74, P=0.012), lower levels of von Willebrand factor activity (HR 2.73, P=0.009) and factor VIII (HR 3.73, P=0.0004). In conclusion, both disease and treatment-related factors influence the risk of bleeding. Patients at greater risk for bleeding of grade