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).
A 43-year-old male patient without comorbidity was diagnosed with chronic phase (CP) CML in 1999. He had been treated with imatinib until hematological progression; this patient was subsequently treated with a daily regimen of 140 mg dasatinib beginning from July 15, 2005. After several adjusted doses were administered because of repeated thrombocytopenia, the final dasatinib dose was restored in June 2010 to 140 mg daily and was maintained without additional adverse events (AEs).\nOn April 15, 2011, 69 months after initial dasatinib administration, the patient presented with New York Heart Association (NYHA) functional class II dyspnea. A chest radiograph revealed that the patient had grade 2 pleural effusion (PE). Furosemide (40 mg/day) and prednisolone (30 mg/day) were administered for 3 weeks. Although PE improved with this treatment, the patient’s dyspnea persisted to the same degree. Electrocardiography showed slight right ventricular hypertrophy. A transthoracic Doppler echocardiogram revealed a highly increased right ventricular systolic pressure (RVSP) of 92 mm Hg, an enlarged right heart cavity (right atrial area of 37.8 cm2, basal right ventricular end-diastolic diameter of 44.5 mm), and a small amount of pericardial effusion. The left heart chambers and left ventricular ejection fraction were normal. The systolic PAP was estimated at 90 mm Hg, and right ventricular function was impaired, as assessed by a reduced tricuspid annular plane systolic excursion of 15.6 mm. Other potential causes of PAH (such as congenital heart disease, pulmonary embolism, and parenchymal lung disease []) were ruled out by chest contrast-enhanced 3-dimensional computed tomography. B-type natriuretic peptide (BNP) levels were elevated to 353.33 pg/mL. No causative medication had been taken.\nOn May 9, 2011, dasatinib was discontinued, and a regimen of sildenafil, a calcium channel blocker, and diuretics was initiated. One month later, subjective symptoms improved to NYHA functional class I. Follow-up echocardiography revealed an improved RVSP of 79 mm Hg and an estimated systolic PAP of 80 mm Hg. Re-evaluation revealed a significant improvement, with RVSP decreased to 57 mm Hg and PE completely absent 2 months after dasatinib discontinuation. On July 4, 2011, the patient started ponatinib at a dose of 45 mg once daily, and this treatment has been continued without any AEs. The changes in clinical course, cardiopulmonary parameters and treatment history are depicted in and and .