A 63-year-old man presented to our department with exertional dyspnoea. He had a 2-year history of dyspnoea that had worsened over the previous 6 months. He had also been diagnosed with CML at the age of 55, for which a first-generation TKI, imatinib (400 mg daily), was prescribed as his first-line therapy. However, since this caused facial oedema and massive pleural effusion, a second-generation TKI, dasatinib (100 mg daily), was chosen as his second-line therapy 5 years before presentation. Concomitant pleural effusion and anaemia was thought to have caused the dyspnoea 2 years prior to presentation; subsequently, an additional dose of diuretics and a reduced dose of dasatinib (50 mg daily) resulted in a transient improvement of dyspnoea following a decrease in the amount of pleural effusion and a slight increase in haemoglobin without further evaluation.\nElectrocardiography (Figure ) and transthoracic echocardiography (TTE) (Figure , Table ) on admission indicated severe right ventricular pressure overload. Physical examination showed jugular vein dilatation. His lung sounds were normal, but cardiac auscultation revealed increased intensity of the P2 sound. The liver was slightly enlarged, but splenomegaly was unclear. Laboratory data showed markedly elevated brain natriuretic peptide (442 pg/mL; normal reference value, <18.4 pg/mL), and anti-nuclear and anti-centromere antibody positivity (1280X and 166X, respectively). Contrast-enhanced chest computed tomography showed no evidence of pulmonary embolism, and perfusion-ventilation scintigraphy showed no evidence of segmental mismatch. Neither abdominal ultrasonography nor upper endoscopy showed clear evidence of portal hypertension. Right heart catheterization (RHC) confirmed markedly increased mean pulmonary artery pressure (MPAP; 67 mmHg; normal reference value, ≤20 mmHg) and pulmonary vascular resistance [PVR; 23.5 wood units (WU); normal reference value, ≤3 WU3] on room air (Table ). Because the patient presented with Raynaud’s phenomenon and nail fold bleeding, a skin biopsy was performed. Pathological findings included increased collagen fibres in subcutaneous adipose tissue and the dermis, increased mucin deposits between collagen fibres, and infiltration of inflammatory cells (mainly lymphocytes) around vessels, supporting a diagnosis of scleroderma. Neither DASA-PAH nor scleroderma-associated PAH (SSc-PAH) could be defined as the primary cause of PAH.\nBased on these findings, we simultaneously discontinued dasatinib and started initial combination therapy with the pulmonary vasodilators, tadalafil (40 mg daily), macitentan (10 mg daily), and selexipag (1.2 mg twice daily). RHC 1 month later showed improvement of the patient’s MPAP and PVR to 35 mmHg and 5.7 WU, respectively (Table ), with his 6-min walk distance also improving from 20 m to 490 m. RHC at 3 months demonstrated further improvement of MPAP and PVR to 33 mmHg and 3.9 WU, respectively. Serial TTEs performed at 1 and 3 months also revealed improved right ventricular pressure overload (Figure and C, Table ). At 4 months, as the Philadelphia chromosome became detectable, TKI administration with imatinib (300 mg daily) was resumed at a lower dose than previously prescribed. At 1 year, MPAP and PVR improved to reasonable values of 18 mmHg and 1.3 WU, respectively. We then withdrew selexipag from the treatment regimen without any evidence of clinical worsening.
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 .