A 70-year old male with chronic phase CML diagnosed in 1996 was changed to dasatinib therapy due to subsequent haematological progress under hydroxyurea combined with interferon alpha (1996-2002) and imatinib (2002-2004: 400 mg/day, 2004-2005: 800 mg/d). Dasatinib treatment with a dose of 70 mg bid was applied for 32 months. Side effects during this period were minor as the medication was generally tolerated well.\nHowever, suddenly the patient developed tachy-dyspnea (25/min), transsudative, non-malignant pleural effusions (glucose 116 mg/dl; lactate dehydrogenase 188 IU/ml of effusions, serum lactate dehydrogenase 1073 IU/ml; protein content of effusions 31 g/l, serum protein content 67 g/l) and fatigue increasing within a few weeks.\nEchocardiography showed highly increased right ventricular systolic pressure (RVSP) of 73 mm Hg. Invasive haemodynamic evaluation confirmed severe pre-capillary PH with consecutive right heart failure (details on prognostic factors and haemodynamics listed in Table ). Clinically, the patient was assigned to WHO/NYHA functional class IV.\nAs other underlying pathophysiological reasons were ruled out by serological tests, chest CT, scintigraphy of the lung and abdominal ultrasound, dasatinib was consequently discontinued. Normal wedge pressures at right heart catheterisation also excluded tyrosine kinase inhibitor-induced cardiomyopathy or other left heart diseases as possible underlying pathologies.\nAfter discontinuation of dasatinib medication low-dose PAH-specific therapy with vasodilative phosphodiesterase-V inhibitor sildenafil (3 × 20 mg) was initiated. Acute symptoms relieved within days.\nDuring the following 10 months prognostic parameters such as the N-terminal fragment of pro brain-natriuretic peptide (NT-proBNP), 6-minute walking distance (6MWD), RVSP, pulmonary artery mean pressure (PAPmean) and pulmonary vascular resistance (PVR) improved significantly (see Table ). Additionally, the patient's subjective well-being advanced decisively which was also reflected by a functional class improvement to NYHA II (Figure ).\nPulmonary complications of dasatinib therapy have been reported ranging from pleural effusions to lung parenchymal affections []. In particular, pleural effusions caused by dasatinib, which are mostly exsudative due to clonal expansion of natural killer T cells, are well recognised and have been documented in various studies [,,]. In addition to the EMEA data set [], in a retrospective analysis of 138 patients receiving dasatinib in once or twice daily treatment schedules, pleural effusions of any grade were detected in 35% of the complete study population comprising chronic phase, accelerated phase and blast crisis [].\nStatistically significant, dose-dependent increase in RVSP was reported in a subgroup of 18 patients and dasatinib cessation led to normalisation of RVSP in 10 patients []. Dyspnoea, nausea, fatigue and oedema - unspecific yet classical symptoms found in PH - are among the most frequently observed unwanted dasatinib effects. Up to now, the extent of dasatinib-associated pre-capillary PH in contribution to these symptoms remains illusive since data regarding haemodynamics are lacking. However, all three detailed cases with dasatinib-related pre-capillary PH developed after a 2-year period of treatment (Figure ).\nOur findings in combination with the two other published cases suggest a yet unknown association of pre-capillary PH with dasatinib []. Therefore, our patient was categorised into Dana Point class 1.3 that resembles drug-induced pulmonary arterial hypertension (PAH, []). Dana Point I represents the only class where PAH-specific drugs are labelled for. Hence PAH-specific therapy with low-dose sildenafil was started.\nDana Point class V, on the other side, combines all multifactorial or uncertain causes of PH and it explicitly includes chronic myeloproliferative diseases. Nevertheless, in this case connection of PH with myeloproliferative disease is also unlikely since, firstly, the CML was stable under dasatinib therapy for almost three years without acceleration until the end of dasatinib therapy. Secondly, a recent report showed a preferential association of myeloproliferative disease-associated PH with chronic thromboembolism [], which was ruled out in our patient by CT scans and V/Q scintigraphy. In such case the use of sildenafil would have been off-label.\nTaking into consideration that pleural effusions are found rarely in pre-capillary pulmonary hypertension another differential diagnosis has to be mentioned: pulmonary veno-occlusive disease (PVOD). PVOD, again, seems to be unlikely since it typically presents as non-responsive PH []. However, symptoms and RVSP of our patient rapidly improved after discontinuation of dasatinib and initiation of sildenafil therapy. Additionally, typical signs of PVOD such as ground glass opacity and septal thickening in CT scans or crackles and clubbing on examination [] were absent in the presented case.\nMost interestingly, although dasatinib also inhibits the platelet-derived growth factor receptor (PDGFR) pathway there may be a contrary effect on proliferative aspects of PAH compared to imatinib which has been shown to be an effective treatment improving PAH and animal survival as well as reversing pulmonary remodelling in rodent model systems, a series of case reports and a phase II trial [-]. Hence, a prospective randomised safety and efficacy trial is currently ongoing (IMPRES, ClinicalTrials.gov: NCT00902174).\nAs key mechanisms, imatinib reversed overexpression and increased phosphorylation of PDGFRβ in pulmonary arteries from rat models of pulmonary hypertension, inhibited PDGFR-related ERK1/2 activation in lungs of these animals thereby suppressing rat pulmonary artery smooth muscle cell (PA-SMC) proliferation and inducing PA-SMC apoptosis [].\nWhile dasatinib inhibits Bcr-Abl at significantly lower inhibitory concentrations (IC50) as compared to imatinib, its effect on c-kit and PDGFR are rather similar. In addition, however, and different from imatinib, dasatinib also inhibits the SRC family of kinases []. Whether this aspect of the compound is causally related to PH development remains unclear.
Our patient is a 67-year-old white man, who works as a teacher in a small city. He does not smoke tobacco; he has a history of arterial hypertension grade I to II and coronary heart disease. His mother died from myocardial infarction due to occlusive coronary artery disease. He was diagnosed as having CML in 2006. The treatment was initially started with imatinib (Glivec, Novartis) 400 mg administered orally once daily. Imatinib 400 to 800 mg per day was taken for 53 months. He lost major molecular response (MMR) and imatinib therapy was replaced with dasatinib 100 mg orally administered once daily and after 6 months MMR was achieved. He was also using torasemide 20 mg orally administered once daily and metoprolol succinate 50 mg orally administered once daily. In April 2015 he developed increasing dyspnea on exertion, fatigue, and peripheral edema. He consulted his family physician, and a chest X-ray was done, confirming pleural effusion. On admission his heart rate was 97 beats per minute and blood pressure was 143/90 mmHg. Fever was not present. He presented with peripheral edema and diminished breath sounds. Pleural friction rub was present. Deformity of the spine accompanied by lower back pain was noted during neurological check-up. The pleural fluid was drawn out several times via thoracentesis (1.5 to 2 liters of exudate in total) but cytological analysis excluded malignancy, a GeneXpert® tuberculosis test of a bronchial smear was also negative, therefore, the pleural effusion was suspected to be caused by congestive heart failure. A complete blood count was normal, but his creatinine levels were elevated (Tables and ). Over the course of the next 4 months his general condition deteriorated as he experienced multiple recurrences of pleural effusion requiring drainage of the built-up fluid (Table ). Dasatinib therapy was stopped in September 2015 after 42 months of treatment. A coronarography was done in September 2015; it did not reveal any hemodynamically important stenosis in his coronary arteries, thereby excluding coronary artery disease. An echocardiogram showed right ventricular dilation, estimated right ventricle systolic pressure of 125 mmHg, and severe tricuspid regurgitation suggesting PH.\nRHC performed on 12 October 2015 revealed severe PAH with mPAP of 53 mmHg and normal left ventricle diastolic pressure (Table ). A computed tomography scan confirmed the absence of pulmonary embolism; laboratory specific tests for HIV, rheumatoid factor, and anti-nuclear antibodies (ANA) were negative and dasatinib-induced PAH was diagnosed. The 6-minute walk test (6MWT) distance was limited to 165 m (Table ). He started PAH-targeted treatment with sildenafil 20 mg × 3 orally administered and restarted CML therapy with imatinib 400 mg orally administered daily on 19 October 2015.\nHis condition rapidly improved, a check-up RHC done a month later showed mPAP of 34 mmHg, decreased pulmonary vascular resistance, and increased cardiac output values (Table ). His 6MWT score was 2.1 times higher (Table ). Echocardiography done in February 2016 revealed right ventricle systolic pressure of 50 mmHg; a complete blood count and biochemistry showed no abnormalities (Tables and ). He has been asymptomatic since, but treatment for PAH with sildenafil is still necessary. The last hematological check-up was in January 2017, he was still on imatinib 400 mg daily and had normal complete blood count and MMR (BRA-ABL was negative).