Córdoba Raúl, Bayés-Genís Antoni, Muntañola Ana, Colomer Dolors, Castro Jorge, Leiva Carolina, Álvarez Esther, Zatarain-Nicolas Eduardo
Department of Hematology, Fundación Jiménez Díaz University Hospital, Health Research Institute IIS-FJD, Madrid, 28040, Spain.
Heart Institute, Germans Trias i Pujol University Hospital, Badalona, CIBERCV, Spain.
Sci Rep. 2025 Jul 31;15(1):28040. doi: 10.1038/s41598-025-07756-2.
Ibrutinib and acalabrutinib are first- and next-generation Bruton Tyrosine Kinase inhibitors (BTKi), respectively, approved for chronic lymphocytic leukemia (CLL). Ibrutinib has been associated with cardiovascular events, including atrial fibrillation (AF) and hypertension. Acalabrutinib has demonstrated non-inferior progression-free survival than ibrutinib in relapsed/refractory CLL patients, with a lower cardiovascular event incidence. These adverse events seem to be derived from off-targets rather than BTK inhibition. Machine learning algorithms were applied to identify targets likely to trigger AF and hypertension in simulated CLL patients receiving acalabrutinib or ibrutinib. Common ibrutinib and acalabrutinib off-targets showed association with AF through structural remodeling and electrophysiology/ectopic activity mechanisms (TEC and ERBB4). There was association with hypertension through inflammation (ERBB4) and oxidative stress and endothelial dysfunction (ERBB4 and RIPK2). Ibrutinib-specific off-targets showed association with AF through structural remodeling (HCK, FGR, LYN, FYN, YES1, and FLT3) and electrophysiology activity (LYN and SRC), and with hypertension through inflammation (LCK, JAK3, and FLT3) and oxidative stress and endothelial dysfunction (ERBB2, BLK, SRC, and CSK). No acalabrutinib-specific off-targets were identified for AF or hypertension. This study supports that BTKi off-target selectivity may justify the different AF and hypertension incidences, suggesting their association with several ibrutinib-specific off-targets and identifying no acalabrutinib-specific ones.
依鲁替尼和阿卡拉布替尼分别是第一代和第二代布鲁顿酪氨酸激酶抑制剂（BTKi），已被批准用于治疗慢性淋巴细胞白血病（CLL）。依鲁替尼与心血管事件有关，包括心房颤动（AF）和高血压。在复发/难治性CLL患者中，阿卡拉布替尼的无进展生存期已证明不劣于依鲁替尼，且心血管事件发生率较低。这些不良事件似乎源于脱靶效应而非BTK抑制。应用机器学习算法来识别在接受阿卡拉布替尼或依鲁替尼治疗的模拟CLL患者中可能引发AF和高血压的靶点。依鲁替尼和阿卡拉布替尼常见的脱靶效应通过结构重塑以及电生理学/异位活动机制（TEC和ERBB4）与AF相关。通过炎症（ERBB4）以及氧化应激和内皮功能障碍（ERBB4和RIPK2）与高血压相关。依鲁替尼特异性脱靶效应通过结构重塑（HCK、FGR、LYN、FYN、YES1和FLT3）和电生理活动（LYN和SRC）与AF相关，通过炎症（LCK、JAK3和FLT3）以及氧化应激和内皮功能障碍（ERBB2、BLK、SRC和CSK）与高血压相关。未发现阿卡拉布替尼特异性脱靶效应与AF或高血压有关。这项研究支持BTKi脱靶选择性可能解释了不同的AF和高血压发生率，表明它们与几种依鲁替尼特异性脱靶效应有关，且未发现阿卡拉布替尼特异性脱靶效应。
