A case of worsening pulmonary arterial hypertension and pleural effusions by bosutinib after prior treatment with dasatinib

A 52-year-old man with a past medical history of chronic myeloid leukemia (CML) in remission developed progressive shortness of breath over a two-month period. He was initially treated with dasatinib for four years, until developing pulmonary arterial hypertension (PAH) with pleural effusions. His symptoms improved after stopping dasatinib. He was then switched to bosutinib for approximately one year, which was then stopped before admission due to worsening shortness of breath. His initial workup showed bilateral pleural effusions with severe PAH and cor pulmonale. He had symptomatic improvement with PAH-specific therapy following discontinuation of the bosutinib. The life expectancy of CML patients has increased in the era of the tyrosine kinase inhibitors (TKIs), and managing adverse events (AEs) of the TKIs and improving quality of life are becoming more important. Pulmonary hypertension (PH) and pleural effusions are rarely reported AEs of bosutinib. More reports with PH and pleural effusions arising after bosutinib use in patients previously treated with dasatinib is furthermore concerning. In this era with novel chemotherapeutic agents, physicians ought to be weary of the significant morbidity implicated by these agents in the lives of patients.

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Symptoms, impacts, and suitability of the Pulmonary Arterial Hypertension – Symptoms and Impact (PAH-SYMPACT™) questionnaire in patients with chronic thromboembolic pulmonary hypertension (CTEPH): a qualitative interview study

Journal of Patient-Reported Outcomes ◽

10.1186/s41687-021-00327-9 ◽

2021 ◽

Vol 5 (1) ◽

Author(s):

Brooke Currie ◽

Evan Davies ◽

Amélie Beaudet ◽

Larissa Stassek ◽

Leah Kleinman

Keyword(s):

Pulmonary Hypertension ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Chronic Thromboembolic Pulmonary Hypertension ◽

Shortness Of Breath ◽

Response Options ◽

Qualitative Interview Study ◽

Thromboembolic Pulmonary Hypertension ◽

Pulmonary Arterial ◽

The Impact

Abstract Background Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare form of pulmonary hypertension caused by blood clots and scar tissue in the blood vessels of the lungs. Health-related quality of life is often significantly impaired in patients with CTEPH. However, a better understanding of how CTEPH symptoms affect patients’ lives is needed to optimally assess the impact of the disease and treatment. Objectives This qualitative study aimed to better understand the symptoms of CTEPH and how they affect patients’ lives, as well as to determine the appropriateness of the Pulmonary Arterial Hypertension – Symptoms and Impact (PAH-SYMPACT™) questionnaire for use in this patient population. Methods Adults diagnosed with CTEPH, recruited from two clinical sites in the US, participated in one-to-one qualitative telephone interviews. They described their experience of CTEPH symptoms and the impact these symptoms have on their lives. They also provided feedback on the comprehensibility and relevance of the PAH-SYMPACT™‘s instructions, items, and response options. Results Participants (N = 12) had a mean age of 62.5 years. Two thirds were female and most (83%) had undergone pulmonary endarterectomy and/or balloon pulmonary angioplasty. The most frequently endorsed symptoms were shortness of breath (endorsed by all 12 participants), fatigue (11 participants), and lightheadedness (10 participants). All participants identified shortness of breath as an “extremely important” symptom, and seven participants rated fatigue as “extremely important.” The most frequent impacts of CTEPH were on ability to walk quickly (endorsed by all 12 participants), ability to walk up inclines or stairs (11 participants), and ability to carry things (11 participants). The PAH-SYMPACT™ items were relevant to most participants and reflected their experience of CTEPH. All participants indicated that no important CTEPH symptoms were missing from the PAH-SYMPACT™. Overall, the instructions, items, and response options of the PAH-SYMPACT™ were clear and easy to understand. Conclusions The symptoms and impacts experienced by patients with CTEPH align with items included in the PAH-SYMPACT™. The PAH-SYMPACT™ appears to be fit for purpose for assessing disease status in patients with CTEPH.

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Idiopathic Pulmonary Arterial Hypertension Unmasked by Pregnancy

Acute Medicine Journal ◽

10.52964/amja.0833 ◽

2020 ◽

Vol 19 (4) ◽

pp. 240-243

Author(s):

Adam Maxwell ◽

◽

Thomas Holman ◽

Timea Novak ◽

◽

...

Keyword(s):

Pulmonary Hypertension ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Post Partum ◽

Right Heart Failure ◽

Idiopathic Pulmonary Arterial Hypertension ◽

Shortness Of Breath ◽

Acute Medical Unit ◽

Pulmonary Angiogram ◽

Pulmonary Arterial

A 31-year old woman presented to the acute medical unit 9 days post-partum with shortness of breath and peripheral oedema. Initially suspected to have either a pulmonary embolism or post-partum cardiomyopathy, she proceeded to have imaging including a CT Pulmonary angiogram and echocardiogram, which were suggestive of pulmonary hypertension and severe right heart failure. Her history and other investigations did not reveal any obvious cause for this. She was transferred to a specialist centre where she was diagnosed with Idiopathic Pulmonary Arterial Hypertension (IPAH), previously known as primary pulmonary hypertension. Shortness of breath during pregnancy and in the postpartum period is a relatively common acute medical presentation. Whilst IPAH is a rare diagnosis, it carries a high mortality rate, particularly in pregnancy, and requires prompt specialist investigation, diagnosis and management.

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Pulmonary complications of Bcr-Abl tyrosine kinase inhibitors

European Respiratory Journal ◽

10.1183/13993003.00279-2020 ◽

2020 ◽

Vol 56 (4) ◽

pp. 2000279 ◽

Cited By ~ 1

Author(s):

Jason Weatherald ◽

Louise Bondeelle ◽

Marie-Camille Chaumais ◽

Christophe Guignabert ◽

Laurent Savale ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Tyrosine Kinase ◽

Arterial Hypertension ◽

Tyrosine Kinase Inhibitors ◽

Kinase Inhibitors ◽

Chronic Myelogenous Leukaemia ◽

Pulmonary Complications ◽

Myelogenous Leukaemia ◽

Dependent Manner ◽

Pulmonary Arterial

Tyrosine kinase inhibitors (TKIs) targeting the Bcr-Abl oncoprotein revolutionised the treatment of chronic myelogenous leukaemia. Following the success of imatinib, second- and third-generation molecules were developed. Different profiles of kinase inhibition and off-target effects vary between TKIs, which leads to a broad spectrum of potential toxicities.Pulmonary complications are most frequently observed with dasatinib but all other Bcr-Abl TKIs have been implicated. Pleural effusions are the most frequent pulmonary complication of TKIs, usually associated with dasatinib and bosutinib. Pulmonary arterial hypertension is an uncommon but serious complication of dasatinib, which is often reversible upon discontinuation. Bosutinib and ponatinib have also been associated with pulmonary arterial hypertension, while imatinib has not. Rarely, interstitial lung disease has been associated with TKIs, predominantly with imatinib.Mechanistically, dasatinib affects maintenance of normal pulmonary endothelial integrity by generating mitochondrial oxidative stress, inducing endothelial apoptosis and impairing vascular permeability in a dose-dependent manner. The mechanisms underlying other TKI-related complications are largely unknown. Awareness and early diagnosis of the pulmonary complications of Bcr-Abl TKIs is essential given their seriousness, potential reversibility, and impact on future treatment options for the underlying chronic myelogenous leukaemia.

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Primary alveolar hypoventilation and XXXXY chromosopathy

Monaldi Archives for Chest Disease ◽

10.4081/monaldi.2006.564 ◽

2016 ◽

Vol 65 (3) ◽

Author(s):

D. Samolski ◽

A. Antón ◽

M. Mayos ◽

M. Subirana ◽

R. Güell

Keyword(s):

Respiratory Failure ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Positive Pressure Ventilation ◽

Cor Pulmonale ◽

Positive Pressure ◽

Hypercapnic Respiratory Failure ◽

Non Invasive ◽

Alveolar Hypoventilation ◽

Pulmonary Arterial

The association of primary alveolar hypoventilation (PAH) and chromosomic diseases has not been described previously. A 19 year-old man with Fraccaro’s syndrome (XXXXY karyotype) was admitted to evaluate chronic hypercapnic respiratory failure, pulmonary arterial hypertension and cor pulmonale. PAH was diagnosed. As effective treatment, such as non-invasive positive pressure ventilation (NIPPV), is available for this disorder we should intensify the search for PAH in patients with chromosome disease.

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

European Respiratory Journal ◽

10.1183/13993003.02472-2018 ◽

2019 ◽

Vol 53 (5) ◽

pp. 1802472 ◽

Cited By ~ 11

Author(s):

Lucie Cornet ◽

Charles Khouri ◽

Matthieu Roustit ◽

Christophe Guignabert ◽

Marie-Camille Chaumais ◽

...

Keyword(s):

Cluster Analysis ◽

Pulmonary Arterial Hypertension ◽

Protein Kinase ◽

Arterial Hypertension ◽

Kinase Inhibitors ◽

Protein Kinase Inhibitors ◽

World Health ◽

Protein Kinase Family ◽

Kinase Family ◽

Pulmonary Arterial

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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Development of Rho kinase inhibitors for pulmonary arterial hypertension

Folia Pharmacologica Japonica ◽

10.1254/fpj.139.251 ◽

2012 ◽

Vol 139 (6) ◽

pp. 251-255

Author(s):

Minoru Seto

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Kinase Inhibitors ◽

Rho Kinase ◽

Rho Kinase Inhibitors ◽

Pulmonary Arterial

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Is hyponatremia associated with mortality in pulmonary arterial hypertension?

Pulmonary Circulation ◽

10.1177/2045894018776888 ◽

2018 ◽

Vol 8 (2) ◽

pp. 204589401877688 ◽

Cited By ~ 1

Author(s):

Anastasiia A. Rudkovskaia ◽

Adriano R. Tonelli ◽

Youlan Rao ◽

Jeffrey P. Hammel ◽

Gregory K. Buller ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Sodium Level ◽

Continuous Variable ◽

Functional Class ◽

Right Atrial ◽

Left Heart Failure ◽

Tertiary Referral Center ◽

Pulmonary Arterial ◽

One Year

Hyponatremia is associated with poor prognosis in left heart failure and liver disease. Its prognostic role in pulmonary arterial hypertension (PAH) is not well defined. We investigated the association between hyponatremia and one-year mortality in two large cohorts of PAH. This study is a secondary analysis evaluating the association between hyponatremia and one-year mortality in patients treated with subcutaneous treprostinil (cohort 1). The results are validated using a PAH registry at a tertiary referral center (cohort 2). Eight-hundred and twenty patients were enrolled in cohort 1 (mean age = 47 ± 14 years) and 791 in cohort 2 (mean age = 55 ± 15 years). Sodium level is negatively correlated with mean right atrial pressure (r = −0.09, P = 0.018; r = −0.089, P = 0.015 in cohorts 1 and 2, respectively). In unadjusted analyses of cohort 1, the sodium level (as a continuous variable) is associated with one-year mortality (hazard ratio = 0.94; P = 0.035). Hyponatremia loses its significance (as a continuous variable and when dichotomized at ≤ 137 mmol/L; P = 0.12) when adjusted for functional class (FC), which is identified as the variable whose presence turns the effect of sodium level into non-significant. Secondary analyses using a cut-off value of < 135 mmol/L showed similar results. These results are validated in cohort 2. Although the sample size for patients with sodium < 130 mmol/L is small (n = 31), severe hyponatremia is associated with higher overall mortality (47% versus 23%; P = 0.01), even when adjusting for age, FC, and baseline 6-min walk distance ( P < 0.001). Although baseline hyponatremia is associated with one-year mortality, it loses its significance when adjusted for FC.

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Pulmonary vasculature

10.1093/med/9780199657742.003.0017 ◽

2017 ◽

Author(s):

Sophie Vergnaud ◽

David Dobarro ◽

John Wort

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Treatment Strategies ◽

Symptomatic Improvement ◽

Pulmonary Vasculature ◽

History Of ◽

Diffuse Cutaneous Systemic Sclerosis ◽

Pulmonary Arterial ◽

Phosphodiesterase 5 ◽

Haemodynamic Improvement

A 16-year-old girl with a diagnosis of diffuse cutaneous systemic sclerosis is referred to a specialist pulmonary hypertension centre with a history of progressive breathlessness, reduced exercise tolerance, and raised pulmonary pressures on transthoracic echocardiogram. She is found to have pulmonary arterial hypertension on right cardiac catheterization and is started on sildenafil, a phosphodiesterase-5 inhibitor, which stabilizes her condition. An endothelin receptor antagonist is added, which provides some initial symptomatic improvement. She continues to deteriorate over a period of 5 years, ultimately requiring intravenous prostanoids, the only treatment to provide a real symptomatic and haemodynamic improvement. This chapter explores the physiology and pathophysiology of pulmonary arterial hypertension, its classification, the means of investigation and diagnosis, who to refer to specialist centres, and the concepts behind current and future treatment strategies.

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Long-term study of oral treprostinil to treat pulmonary arterial hypertension: dosing, tolerability, and pharmacokinetics

Pulmonary Circulation ◽

10.1177/2045894019866335 ◽

2020 ◽

Vol 10 (4) ◽

pp. 204589401986633 ◽

Cited By ~ 1

Author(s):

R. James White ◽

Keyur Parikh ◽

Roblee Allen ◽

Jeremy Feldman ◽

Carlos Jerjez-Sanchez ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Adverse Events ◽

Arterial Hypertension ◽

Total Daily Dose ◽

Walk Distance ◽

Long Term Study ◽

Pulmonary Arterial ◽

One Year ◽

Minute Walk Distance ◽

Minute Walk

Oral treprostinil may be an option for low- and intermediate-risk patients with pulmonary arterial hypertension, a rare lung vascular disease. This open-label extension study collected data on participants who completed previously reported, placebo-controlled oral treprostinil studies. Eligible participants had completed the prospective parent studies and took increasing doses of oral treprostinil twice daily; some later transitioned to three times daily dosing. Investigators measured 6-minute walk distance at Month 12 as the sole efficacy measure but collected adverse events throughout the study. A single center measured pharmacokinetics in 13 subjects who changed dosing from twice daily to three times daily. Eight hundred and ninety-four participants enrolled and 71% completed one year of therapy, with a median total daily dose of 7 mg and a median 6-minute walk distance increase of 22 m (interquartile range, −14 to 67 m). Subjects achieving higher doses had larger increases in 6-minute walk distance; 42% of participants completed three years of therapy. Adverse events were typical for prostacyclin class therapy, but prostacyclin-type adverse events may have been better tolerated with three times daily dosing in 105 participants. In 13 participants transitioned to three times daily dosing with pharmacokinetic measurements before and after, trough drug levels were higher with three times daily dosing. Oral treprostinil is associated with modest but durable, dose-responsive effects on exercise tolerance for those who remained on therapy at one year in this prospective, uncontrolled study. Three times daily dosing was associated with higher trough levels and better tolerability. The recently completed Freedom-EV study will provide further insights into the utility of oral treprostinil ( https://clinicaltrials.gov/show/NCT01560624 ).

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