Reversible dasatinib-induced pulmonary arterial hypertension and right ventricle failure in a previously allografted CML patient

Mattei, Daniele; Feola, Mauro; Orzan, F; Mordini, Nicola; Rapezzi, Davide; Gallamini, Andrea

doi:10.1038/bmt.2008.415

Cited by 84 publications

(55 citation statements)

References 6 publications

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“…Dasatinib is a tyrosine and a serine-threonine kinase inhibitor that is 325 times as potent as imatinib in the inhibition of BCR-ABL kinase in vitro, and induces higher rates of cytogenic response in CML [33]. However, dasatinib potently inhibits the Src family, which is probably the single most prominent dasatinib-targeted family of protein kinases, including c-Src and Fyn, and it has been reported to cause PAH [8,34,35]. The PAH tends to resolve rapidly after discontinuation of dasatinib [34], suggesting that it may not be primarily due to marked cellular proliferation, but to chronic vasoconstriction.…”

Section: Discussionmentioning

confidence: 99%

Src tyrosine kinase is crucial for potassium channel function in human pulmonary arteries

et al. 2012

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The potassium channel TWIK-related acid sensitive potassium (TASK)-1 channel, together with other potassium channels, controls the low resting tone of pulmonary arteries. The Src family tyrosine kinase (SrcTK) may control potassium channel function in human pulmonary artery smooth muscle cells (hPASMCs) in response to changes in oxygen tension and the clinical use of a SrcTK inhibitor has resulted in partly reversible pulmonary hypertension.This study aimed to determine the role of SrcTK in hypoxia-induced inhibition of potassium channels in hPASMCs.We show that SrcTK is co-localised with the TASK-1 channel. Inhibition of SrcTK decreases potassium current density and results in considerable depolarisation, while activation of SrcTK increases potassium current in patch-clamp recordings. Moderate hypoxia and the SrcTK inhibitor decrease the tyrosine phosphorylation state of the TASK-1 channel. Hypoxia also decreases the level of phospho-SrcTK (tyr419) and reduces the co-localisation of the TASK-1 channel and phospho-SrcTK. Corresponding to this, hypoxia reduces TASK-1 currents before but not after SrcTK inhibition and, in the isolated perfused mouse lung, SrcTK inhibitors increase pulmonary arterial pressure.We propose that the SrcTK is a crucial factor controlling potassium channels, acting as a cofactor for setting a negative resting membrane potential in hPASMCs and a low resting pulmonary vascular tone.

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Section: Discussionmentioning

confidence: 99%

Src tyrosine kinase is crucial for potassium channel function in human pulmonary arteries

et al. 2012

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“…A search of the BMS pharmacovigilance database (including clinical trial data, cases spontaneously reported directly to BMS, case notifications from regulatory agencies, and published literature cases) identified the largest series reported to date, comprising 41 cases of RHC-confirmed PAH (Table II and Supplementary Table I), including 22 unpublished and 19 previously reported cases [4][5][6][7][8][9][10][11][23][24][25]. Most patients were treated for CML or Philadelphia chromosomepositive (Ph 1 ) acute lymphoblastic leukemia (ALL) per the approved indications for dasatinib, although 1 was treated for Ph 1 acute myeloid leukemia (AML).…”

Section: Rhc-confirmed Pah In Dasatinib-treated Patientsmentioning

confidence: 99%

“…Severe and potentially irreversible toxicities with the currently approved first-line BCR-ABL TKIs imatinib, dasatinib, and nilotinib are relatively rare and include hepatic failure, peripheral arterial occlusive disease, certain cardiac disorders, and sudden death [1][2][3]. Pulmonary hypertension (PH) and pulmonary arterial hypertension (PAH) have been reported as infrequent but significant adverse events (AEs) associated with dasatinib [4][5][6][7][8][9][10][11]. Consequently, a PAH warning is included in the product labeling for dasatinib, which states that if PAH is confirmed, dasatinib should be permanently discontinued [1].…”

Section: Introductionmentioning

confidence: 99%

Clinical features of pulmonary arterial hypertension in patients receiving dasatinib

et al. 2015

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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.

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“…Pulmonary complications, in particular pleural effusions, have been reported more frequently with dasatinib use compared with other TKIs [25]. In addition, isolated case reports have suggested that PAH may be a potential complication of dasatinib use [24,26,27]. On April 18, 2011, the French drug regulatory agency AFSSAPS revealed that 13 cases of pulmonary hypertension had been identified in dasatinib-treated patients in France [28].…”

mentioning

confidence: 99%

“…In a recent issue of the ERJ, DUMITRESCU et al [24] reported a case of PAH induced by dasatinib, a tyrosine kinase inhibitor (TKI) that has proven to be a life-saving treatment in patients with chronic myelogenous leukaemia. Although TKIs are usually well tolerated, these agents nonetheless exhibit systemic toxicity [24][25][26][27][28]. Pulmonary complications, in particular pleural effusions, have been reported more frequently with dasatinib use compared with other TKIs [25].…”

mentioning

confidence: 99%

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Simonneau²,

Dinh-Xuan³

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Eur Respir J

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Reversible dasatinib-induced pulmonary arterial hypertension and right ventricle failure in a previously allografted CML patient

Cited by 84 publications

References 6 publications

Src tyrosine kinase is crucial for potassium channel function in human pulmonary arteries

Src tyrosine kinase is crucial for potassium channel function in human pulmonary arteries

Clinical features of pulmonary arterial hypertension in patients receiving dasatinib

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