A63-32 Unintended Consequences of Targeted Therapy: Dasatinib-associated Severe Pulmonary Arterial Hypertension

Abstract Introduction Dasatinib is the tyrosine-kinase inhibitor (TKI) most frequently associated with drug-induced pulmonary arterial hypertension (PAH), a rare complication reported in 0.45% of exposed patients, typically manifesting after three years of therapy. This case illustrates an uncommon presentation, underscoring the pathophysiologic complexity of this reversible vascular toxicity. Case Description A 57-year-old man with chronic myeloid leukemia (CML) treated with dasatinib for three years presented with progressive exertional dyspnea over three months. Transthoracic echocardiography demonstrated a severely dilated right ventricle with markedly reduced systolic function and systolic-diastolic septal flattening consistent with advanced pressure overload. Right-heart catheterization confirmed severe pre-capillary pulmonary arterial hypertension with low cardiac output (mPAP 59 mmHg, PCWP 10 mmHg, PVR 14 WU, CI 1.5). Evaluation for secondary causes of pulmonary hypertension was negative. In the context of prolonged tyrosine-kinase-inhibitor exposure, the findings were suggestive of drug-induced PAH. Dasatinib was switched to asciminib, and triple therapy with intravenous treprostinil, macitentan, and tadalafil led to marked hemodynamic improvement (mPAP 31 mmHg, PCWP 10 mmHg, PVR 4.77 WU, CI 2.63) with recovery of right-ventricular function. After treprostinil withdrawal, macitentan and tadalafil were continued; selexipag and sotatercept were subsequently added, achieving sustained clinical and hemodynamic stability. Conclusion The proposed mechanism of dasatinib-associated PAH involves endothelial injury from off-target Src-kinase inhibition, leading to nitric oxide dysregulation, endothelin-mediated vasoconstriction, and vascular remodeling with right-ventricular overload. Early recognition is essential, as stopping dasatinib, switching to lower-toxicity TKIs like imatinib or asciminib, and initiating targeted PAH therapy can reverse remodeling in most patients, though fixed vascular changes may persist in up to one-third of cases. This abstract is funded by: None