Combination targeted pulmonary hypertension therapy in the resolution of Dasatinib‐associated pulmonary arterial hypertension

Abstract

Dasatinib is a small-molecule tyrosine kinase inhibitor used in the treatment of hematological malignancies. Pulmonary arterial hypertension (PAH) is a rare but known complication. The mainstay of treatment is cessation of Dasatinib, and while clinical improvement is rapid, complete hemodynamic resolution of pulmonary hypertension (PH) still remains exceedingly uncommon. We present a case of Dasatinib-induced PAH in a woman with chronic myeloid leukemia, who demonstrated rapid and complete clinical and hemodynamic resolution following treatment with combination pulmonary vasodilator therapy using an endothelin receptor antagonist and a phosphodiesterase-5 inhibitor. This case suggests there may be an association between the use of targeted PH medication in combination and the complete resolution of dasatinib-associated PAH, but further investigation is required.

A narrative review on adverse effects of dasatinib with a focus on pharmacotherapy of dasatinib-induced pulmonary toxicities

“…Another proposed mechanism is related to SRC family kinases and platelet-derived growth factor (PDGF) pathway [54,62,64]. SRC family kinases have a role in smooth muscle cells reproduction and also reducing pulmonary artery tone while their inhibition result in apoptosis and raised vascular resistance.…”

“…It has been demonstrated that treatment with dasatinib causes a dose-dependent increase in production of mitochondrial ROS; resulting to endothelial apoptosis, pulmonary endothelial dysfunction and pulmonary hypertension. Another proposed mechanism is related to SRC family kinases and platelet-derived growth factor (PDGF) pathway [ 54 , 62 , 64 ]. SRC family kinases have a role in smooth muscle cells reproduction and also reducing pulmonary artery tone while their inhibition result in apoptosis and raised vascular resistance.…”

“…Discontinuation of dasatinib led to improvement in clinical status of all patients except 3 who required further pharmacotherapy [ 15 ]. Although PAH is clinically reversible, the hemodynamic of patients may not completely improve after discontinuation of therapy [ 64 ].…”

“…Early diagnosis of PAH and cessation treatment with dasatinib are strongly recommended [ 59 ]. Discontinuation of dasatinib leads to notable symptomatic improvement, however this may not be associated with a complete hemodynamic recovery [ 64 , 72 ]. Phosphodiesterase type-5 inhibitors, prostacyclin derivatives, and endothelin receptor antagonists (ERAs) are FDA approved pharmacological classes used for treatment of PAH.…”

“…Two other different dosage regimens of tadalafil and ambrisentan combination were used: “tadalafil (40 mg daily)+ambrisentan (10 mg daily)” and “tadalafil (20 mg daily)+ambrisentan (5 mg daily)”. Both revealed improvement in pulmonary symptoms, mPAP, 6-MWD, BNP level and WHO functional class [ 62 , 64 ].…”