Dasatinib-induced pulmonary arterial hypertension – A rare late complication

Abstract

Dasatinib is a dual Src/Abl tyrosine kinase inhibitor approved for frontline and second line treatment of chronic phase chronic myelogenous leukemia. Pulmonary arterial hypertension is defined by an increase in mean pulmonary arterial pressure >25 mmHg at rest. Dasatinib-induced pulmonary hypertension has been reported in less than 1% of patients on chronic dasatinib treatment for chronic myelogenous leukemia. The pulmonary arterial hypertension from dasatinib may be categorized as either group 1 (drug-induced) or group 5 based on various mechanisms that may be involved including the pathogenesis of the disease process of chronic myelogenous leukemia. There have been reports of dasatinib-induced pulmonary arterial hypertension being reversible. We report a case of pulmonary arterial hypertension in a 46-year-old female patient with chronic phase chronic myelogenous leukemia on dasatinib treatment for over 10 years. She had significant improvement in symptoms after discontinuation of dasatinib and initiation of vasodilators. Several clinical questions arise once patients experience significant adverse effects as discussed in our case.

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.…”

“…Dasatinib-induced PAH predominantly occurs in women and is often concomitant with previous or present PE [ 15 ]. PAH in a CML patient may be drug-induced (group 1) or related to CML pathophysiology [ 15 , 61 - 63 ]. 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.…”

“…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.…”

“…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 ].…”

Dasatinib-induced pulmonary arterial hypertension in pediatric acute lymphoblastic leukemia with Philadelphia chromosome: A report of two cases

“…Additionally, dasatinib also shows higher selectivity and affinity to the BCR/ABL kinase domain than imatinib, and dasatinib can cross the blood-brain barrier to prevent and eradicate central nervous system leukemia. It is used to treat patients with imatinib resistance or relapse while receiving imatinib [8] . According to the Chinese Children's Cancer Group study ALL-2015 (CCCG-ALL-2015), patients treated with dasatinib had significantly higher rates of 4-year EFS (71.0% vs 48.9%) and OS (88.4% vs 69.2%) and lower relapse rates (19.8% vs 34.4%) than the 97 patients treated with imatinib [4] .…”