Dasatinib‐induced pulmonary arterial hypertension

Abstract

Keywords adverse event, chronic myeloid leukaemia, dasatinib, pulmonary arterial hypertension, tyrosine kinase inhibitor Drug-induced (group 1) pulmonary hypertension (PH) is an important subgroup of PH involving dasatinib as a likely related agent, which is a second-generation tyrosine kinase inhibitor (TKI) used in the treatment of chronic myeloid leukaemia (CML). The mechanism of dasatinib-induced pulmonary arterial hypertension (PAH) is unclear. However, the occurrence of PAH with late onset in CML patients suggests a chronic pathological mechanism with an insidious onset rather than an acute inflammatory or cardiac aetiology. Dasatinib has a broader effect than other TKIs; the major known difference between dasatinib and other TKIs is the additional inhibition of Src family kinases. Therefore, Src inhibition was thought to play a role in the development of dasatinibinduced PAH. However, recently, it was also speculated that chronic dasatinib therapy may cause pulmonary endothelial damage, attenuate hypoxic pulmonary vasoconstriction responses and increase susceptibility to PAH independently of the Src family kinase-induced mechanism. Dasatinib-induced PAH usually seems to be reversible with the cessation of the drug, and sometimes with PAH-specific treatment strategies. Transthoracic echocardiography can be recommended as a routine screening prior to dasatinib initiation, and this non-invasive procedure can be utilized in patients having signs and symptoms attributable to PAH during dasatinib treatment.

Tyrosine Kinase Inhibitor–Induced Pulmonary Arterial Hypertension

“…It is worth mentioning that none of the patients required specific PAH treatment. 30 Shah et al showed that in 58% of the 41 patients reported with dasatinib-induced PAH confirmed by right heart catheterization, dasatinib cessation was followed by total remission of PAH. 10 Since 2016, cases of PAH have been reported with other TKIs: lapatinib, bosutinib, ponatinib, and lorlatinib, but the frequency of such occurrence is less defined.…”

“…In the case of dasatinib, reports suggest that PAH may be partially or completely reversible after the dasatinib discontinuation. 20,30 However, animal models have shown that dasatinib may induce irreversible vascular injury and remodeling. 33 The first histopathological proof of the presence of irreversible lesions comes from a case of a 32-year-old male who had dasatinib-induced PAH after a 3-year treatment with dasatinib for CML (BCR-ABL1+).…”

“…Currently, after dasatinib disruption, nilotinib or imatinib have been used with success, without relapse of PAH. 20,30,35,37,38 If another TKI therapy is used, close and long-term follow-up should be undertaken in order to identify recurrent PAH at an early stage.…”

“…1,20 In patients on TKI treatment, the occurrence of symptoms such as dyspnea, fatigue, chest pain, syncope, and signs of right heart failure should prompt further evaluation, including a chest x-ray and an echocardiogram. 26,30,46 The probability of PH is high if the peak tricuspid regurgitation velocity is >3.4 m/s or if it is between 2.9-3.4 m/s and associated with other echocardiographic findings suggestive of PH: right ventricle/left ventricle basal diameter ratio >1.0, flattening of the interventricular septum, right ventricular outflow Doppler acceleration time <105 msec, midsystolic notching, early diastolic pulmonary regurgitation velocity >2.2 m/sec; pulmonary artery Legend: TASK-1, TWIK-related acid sensitive potassium channel-1; ROS, reactive oxygen species; ER, endoplasmic reticulum; EC, endothelial cell; GRP78, glucose regulated protein 78; ATF6, activating transcription factor 6; XPB1, x-box binding protein-1; p-eIF2α, phosphorylated eukaryotic initiation factor 2α. diameter >25 mm, inferior vena cava diameter >21 mm with decreased inspiratory collapse, or right atrial area >18 cm 2 .…”

“…1,20,26 Although they do not have specificity for PAH, natriuretic peptide (BNP) or N-terminal pro-brain natriuretic peptide (NT-ProB-NP) should also be performed, as they can be predictive of prognosis and can be used to assess patients during follow-up. 30,46 CONCLUSION Treatment with TKIs may rarely cause PAH. Dasatinib is the most common TKI associated with PAH and in most cases, PAH improves or resolves after drug discontinuation.…”