Univ. Paris-Sud, Faculté de Médecine, Le Kremlin-Bicêtre, France.
Circulation. 2012 May 1;125(17):2128-37. doi: 10.1161/CIRCULATIONAHA.111.079921. Epub 2012 Mar 26.
The French pulmonary hypertension (PH) registry allows the survey of epidemiological trends. Isolated cases of precapillary PH have been reported in patients who have chronic myelogenous leukemia treated with the tyrosine kinase inhibitor dasatinib.
This study was designed to describe incident cases of dasatinib-associated PH reported in the French PH registry. From the approval of dasatinib (November 2006) to September 30, 2010, 9 incident cases treated by dasatinib at the time of PH diagnosis were identified. At diagnosis, patients had moderate to severe precapillary PH with functional and hemodynamic impairment. No other incident PH cases were exposed to other tyrosine kinase inhibitors at the time of PH diagnosis. Clinical, functional, or hemodynamic improvements were observed within 4 months of dasatinib discontinuation in all but 1 patient. Three patients required PH treatment with endothelin receptor antagonist (n=2) or calcium channel blocker (n=1). After a median follow-up of 9 months (min-max 3-36), the majority of patients did not demonstrate complete clinical and hemodynamic recovery, and no patients reached a normal value of mean pulmonary artery pressure (≤20 mm Hg). Two patients (22%) died at follow-up (1 of unexplained sudden death and 1 of cardiac failure in the context of septicemia, respectively, 8 and 12 months after dasatinib withdrawal). The lowest estimate of incident PH occurring in patients exposed to dasatinib in France was 0.45%.
Dasatinib may induce severe precapillary PH fulfilling the criteria of pulmonary arterial hypertension, thus suggesting a direct and specific effect of dasatinib on pulmonary vessels. Improvement is usually observed after withdrawal of dasatinib.
法国肺动脉高压（PH）登记处允许对流行病学趋势进行调查。在接受酪氨酸激酶抑制剂达沙替尼治疗的慢性髓性白血病患者中，已有报道称存在孤立的毛细血管前 PH 病例。
本研究旨在描述法国 PH 登记处报告的达沙替尼相关 PH 的偶发病例。自达沙替尼批准（2006 年 11 月）至 2010 年 9 月 30 日，共发现 9 例在 PH 诊断时接受达沙替尼治疗的偶发病例。在 PH 诊断时，患者存在中至重度毛细血管前 PH，伴有功能和血流动力学损害。在 PH 诊断时，没有其他偶发病例接触过其他酪氨酸激酶抑制剂。除 1 例患者外，所有患者在停用达沙替尼后 4 个月内均观察到临床、功能或血流动力学改善。3 例患者需要 PH 治疗，分别使用内皮素受体拮抗剂（n=2）或钙通道阻滞剂（n=1）。在中位数为 9 个月（最小最大值 3-36）的随访中，大多数患者没有表现出完全的临床和血流动力学恢复，并且没有患者达到平均肺动脉压的正常值（≤20mmHg）。2 例患者（22%）在随访时死亡（1 例为不明原因的猝死，1 例为败血症时的心衰，分别在停用达沙替尼后 8 个月和 12 个月）。法国达沙替尼暴露患者中偶发 PH 的最低估计发生率为 0.45%。
达沙替尼可能引起符合肺动脉高压标准的严重毛细血管前 PH，提示达沙替尼对肺血管有直接和特异的作用。停药后通常会改善。
