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 52-year-old male patient was diagnosed with CP CML in 2001. He was initially treated with interferon-alpha and later received a daily regimen of 400 mg imatinib that was dose-adjusted over time because of AEs. He had pleurisy of unknown origin during his teenage years. Because no cytogenetic response was achieved on imatinib, dasatinib was initiated at a dose of 140 mg daily from December 2, 2005 and was initially well tolerated.\nHowever, in February 2008, the patient complained of intermittent NYHA class II dyspnea on effort, and his chest radiograph revealed right PE; with sustained dasatinib treatment, the symptom progressed to NYHA class III on February 24, 2009. At that time, dasatinib was discontinued, and treatment with low dose sildenafil (25 mg/day) was initiated. One month after dasatinib discontinuation, a chest radiograph revealed a nearly resolved state. However, a chest computed tomography scan revealed mild pulmonary congestion, and a transthoracic Doppler echocardiogram showed an increased RVSP of 71 mm Hg and a small amount of pericardial effusion. BNP levels were elevated to 263 pg/mL. Laboratory tests for human immunodeficiency virus (HIV) and rheumatic diseases, including antinuclear antibodies, antibodies to double-stranded DNA, and anti-Scl-70 antibodies, were negative. A careful review of concurrent medications or toxins suspected to play an essential role in the development of PAH revealed no causative evidence.\nAfter switching to nilotinib (800 mg/day) in May 2009, the patient’s subjective dyspnea improved, and his RVSP decreased to 55 mm Hg. BNP levels returned to 28 pg/mL, and the 6-minute-walk test value improved from 480 m to 615 m. The patient intermittently discontinued nilotinib because of repeated hyperbilirubinemias and was transferred to our hospital in July 2009. Eighteen months later, he lost cytogenetic response with an E292V mutation; therefore, a daily dose of 100 mg dasatinib was reintroduced in December 2010. Although the patient previously experienced dasatinib-associated PAH, we chose to administer dasatinib in order to overcome the patient’s mutation-related resistance. The dose of dasatinib (40-60 mg/day) was then adjusted according to the severity of dyspnea, and a major cytogenetic response on dasatinib was maintained.\nAfter dasatinib administration, the patient again experienced a sustained NYHA functional class II dyspnea with serial elevation of left ventricular systolic pressure observed in a follow-up echocardiogram (). On April 11, 2011, a daily dose of 45 mg ponatinib was prescribed without improvement in PAH while maintaining a complete cytogenetic response and a major molecular response. In August 2012, the patient's subjective dyspnea was improved to NYHA functional class I. The changes in clinical course, cardiopulmonary parameters and treatment history are depicted in and .