Clinical features of pulmonary arterial hypertension in patients receiving dasatinib

Abstract

The prognosis of most leukemia patients treated with BCR-ABL tyrosine kinase inhibitors (TKIs) is favorable, and a more precise understanding of serious and potentially irreversible treatment-related toxicities is essential to properly inform treatment choice. Few cases of pulmonary arterial hypertension (PAH) have been reported in patients with leukemia treated with dasatinib, a second-generation BCR-ABL TKI. To better understand characteristics and outcomes of dasatinib-treated patients with PAH, all clinical cases of PAH confirmed by right-heart catheterization in the Bristol-Myers Squibb pharmacovigilance database (N 5 41), including 22 previously unpublished cases, were examined for previous treatments for leukemia, patient characteristics, time to PAH onset, and outcomes. Our analysis shows that compared with PAH due to other etiologies, dasatinib-related PAH is atypical, in that it is associated with partial to complete reversibility upon treatment discontinuation. The incidence of dasatinib-related PAH appears to be low. Most PAH cases were observed in patients who had received prior treatments for leukemia. No specific patient attributes appear to be associated with an increased risk of developing PAH while receiving dasatinib. Symptoms of PAH in dasatinib-treated leukemia patients should prompt a thorough workup, including consideration of confirmatory right-heart catheterization. In cases of confirmed PAH, dasatinib should be discontinued.

Pulmonary hypertension associated with ponatinib therapy

“…Over 50 drugs, including anorexigens, abused substances and recently the tyrosine kinase inhibitor (TKI) dasatinib, have been temporally and/or mechanistically related to the development of pulmonary arterial hypertension (PAH) in humans (where the evidence base for causality is wide ranging) and in animal models [1][2][3]. The TKIs imatinib, dasatinib, nilotinib and bosutinib are available to treat chronic myelogenous leukaemia (CML) and acute lymphoblastic leukaemia.…”

“…The respective roles of dasatinib and ponatinib have to be discussed as regards the vascular complications including PAH in our patient. To date, dasatinib has been associated with the development of PAH in 49 cases overall [1,4,11], including 27 previously published and 22 unpublished cases [3]. In all 27 published cases, dasatinib was discontinued.…”

“…PAH-targeted therapy was given to 14 cases [4]. Among the 22 unpublished cases [3], dasatinib was stopped in 19 and PAH-targeted therapy was given to eight [3]. Partial or complete improvement was seen in 38 (77.6%) out of the 49 cases.…”

Insights into etiological factors of pulmonary hypertension in cancer patients

“…Follow-up of patients showed reversibility of PH with discontinuation or reducing the dose of dasatinib. However, complete recovery may not be possible in every affected patient after all [44].…”

“…However, the underlying pathophysiological mechanism is unknown, and some suggest a secondary immune reaction or possibly uncontrolled proliferation of vascular endothelium and smooth muscles caused by inhibition of the regulatory SCR kinase [41]. The incidence of PH in patients receiving dasatinib varied from (0.45% to 12%) [42][43][44] and it can be detected early up to 2 months or late about 48 months after initiation of dasatinib [42,43]. Follow-up of patients showed reversibility of PH with discontinuation or reducing the dose of dasatinib.…”