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 .
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 .