Lorlatinib – Induced pulmonary arterial hypertension

Chabrol, A.; Mayenga, M.; Hamid, Abdul Momen; Friard, S.; Salvator, Hélène; Doubre, Hélèe; Fraboulet, S.; Métivier, Anne-Cécile; Catherinot, Émilie; Rivaud, Elisabeth; Chaumais, Marie-Camille; Montani, David; Couderc, Louis Jean; Tchérakian, Colas

doi:10.1016/j.lungcan.2018.03.023

Cited by 14 publications

(17 citation statements)

References 5 publications

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“…In our study, lapatinib showed a weak, nonsignificant disproportionality signal with a ROR of 1.13 (95% CI 0.61-2.10). Although not included in our study because of a lack of reported ICSRs in VigiBase, lorlatinib has recently been linked to PAH [7]. Further studies are needed to confirm these first reports.…”

Section: Discussionmentioning

confidence: 96%

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Pulmonary arterial hypertension associated with protein kinase inhibitors: a pharmacovigilance–pharmacodynamic study

et al. 2019

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The pathophysiology of pulmonary arterial hypertension (PAH) induced by protein kinase inhibitors (PKIs) remains unclear. To gain knowledge into this rare and severe pathology we performed a study combining a pharmacovigilance approach and the pharmacodynamic properties of PKIs.A disproportionality analysis on the World Health Organization pharmacovigilance database VigiBase using the reporting odds ratio (ROR) and 95% confidence interval was first performed. Then, we identified the most relevant cellular targets of interest through a systematic literature review and correlated the pharmacovigilance signals with the affinity for the different PKIs. We further performed a hierarchical cluster analysis to assess patterns of binding affinity.A positive disproportionality signal was found for dasatinib, bosutinib, ponatinib, ruxolitinib and nilotinib. Five non-receptor protein kinases significantly correlate with disproportionality signals: c-Src (r=0.79, p=0.00027), c-Yes (r=0.82, p=0.00015), Lck (r=0.81, p=0.00046) and Lyn (r=0.80, p=0.00036), all belonging to the Src protein kinase family, and TEC (r=0.85, p=0.00006). Kinases of the bone morphogenetic protein signalling pathway also seem to play a role in the pathophysiology of PKI-induced PAH. Interestingly, the dasatinib affinity profile seems to be different from that of other PKIs in the cluster analysis.The study highlights the potential role of the Src protein kinase family and TEC in PAH induced by PKIs. This approach combining pharmacovigilance and pharmacodynamics data allowed us to generate some hypotheses about the pathophysiology of the disease; however, the results have to be confirmed by further studies.

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Section: Discussionmentioning

confidence: 96%

“…Among drug-induced PAH, the multiple protein kinase inhibitor (PKI) dasatinib had been increasingly linked to PAH since 2009 [4,5]. More recently, several cases have reported potential association with or deterioration of pre-existing PAH with other PKIs such as bosutinib, ponatinib and lapatinib [6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Pulmonary arterial hypertension associated with protein kinase inhibitors: a pharmacovigilance–pharmacodynamic study

et al. 2019

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“…1 As other tyrosine kinase inhibitors (TKIs), ALKi efficacy is restrained by potential toxicities. 2,3 Their clinical manifestations must be accurately identified and distinguished from neoplastic process features, particularly in ALK-positive patient cases that may rapidly progress once become resistant to treatments.…”

Section: Pulmonary Arterial Hypertension In Alk Receptor Tyrosine Kinmentioning

confidence: 99%

Pulmonary Arterial Hypertension in ALK Receptor Tyrosine Kinase–Positive Lung Cancer Patient: Adverse Event or Disease Spread?

Tabbò

D’Aveni

Tota

et al. 2019

Journal of Thoracic Oncology

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“…The lorlatinib withdrawal associated with specific PAH treatment led to rapid clinical and hemodynamic improvement. 36…”

Section: Tki-induced Pah: Epidemiology and Clinical Presentationmentioning

confidence: 99%

Tyrosine Kinase Inhibitor–Induced Pulmonary Arterial Hypertension

Preda

Seferian

Jutant

et al. 2018

Advances in Pulmonary Hypertension

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The treatment of the malignant hematological diseases has been revolutionized by the use of tyrosine kinase inhibitors (TKI): for example, imatinib in patients with chronic myeloid leukemia. Dasatinib, a second-generation TKI, has been reported to induce severe pulmonary arterial hypertension (PAH). The mechanism of PAH development is presumed to be endothelial cell toxicity through the production of mitochondrial reactive oxygen species. There are other TKIs that are reported to cause PAH, such as: ponatinib, bosutinib, lapatinib, and lorlatinib. The management of PAH due to TKIs primarily involves stopping the TKI treatment, which can lead to clinical and hemodynamic normalization. A third of the patients who develop PAH can have persistent symptoms of dyspnea and right heart failure even after the interruption of the TKIs. For these patients, use of specific PAH treatment is indicated along with close follow-up. In rare cases, TKI-induced PAH can be fatal. Thus, early screening for PAH diagnosis and proper management is required.

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Lorlatinib – Induced pulmonary arterial hypertension

Cited by 14 publications

References 5 publications

Pulmonary arterial hypertension associated with protein kinase inhibitors: a pharmacovigilance–pharmacodynamic study

Pulmonary arterial hypertension associated with protein kinase inhibitors: a pharmacovigilance–pharmacodynamic study

Pulmonary Arterial Hypertension in ALK Receptor Tyrosine Kinase–Positive Lung Cancer Patient: Adverse Event or Disease Spread?

Tyrosine Kinase Inhibitor–Induced Pulmonary Arterial Hypertension

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