A 61-year-old woman with no past history of cardiopulmonary disease was diagnosed with chronic myeloid leukemia (CML) and initially started on Imatinib therapy. Four years later, a bone marrow biopsy showed progression of CML to precursor B-cell acute lymphoblastic leukemia (ALL) and the patient was switched to therapy with Dasatinib at a dose of 140 mg daily due to disease progression on Imatinib. At this time, the patient also received two cycles of chemotherapy with Cyclophosphamide, Vincristine, Adriamycin, and Dexamethasone. Following this, a repeat bone marrow aspirate showed complete hematologic, cytogenetic, and molecular remission and the patient was continued on Dasatinib therapy. However, 26 months later, the patient developed a persistent dry cough and severe dyspnea on exertion. Initial laboratory testing showed a white blood cell count of 3700, with 46% neutrophils and 45% lymphocytes. Blood cultures were negative for infection, and the patient did not produce adequate sputum for culture. A chest X-ray showed bilateral pleural effusions with cardiomegaly, suggestive of right ventricular failure (). A CT scan was performed, which noted an enlarged central pulmonary artery and bilateral pleural effusions; no other abnormalities concerning the lung parenchyma, pulmonary veins, or interstitium were reported. No pulmonary embolism was seen. An echocardiogram confirmed the presence of a dilated and hypokinetic right ventricle and a dilated right atrium ( and ). Other potential causes of pulmonary hypertension (PH) were excluded by a negative V/Q scan and a review of past records showing normal echocardiographic testing one year prior. A right heart catheterization (RHC) was performed with a mean pulmonary artery pressure (mPAP) of 54 mmHg, pulmonary capillary wedge pressure (PCWP) of 11 mmHg, and pulmonary vascular resistance (PVR) of 18.22 Woods Units, yielding a diagnosis of pulmonary arterial hypertension (PAH). The right atrial (RA) pressure was 19 mmHg, and the cardiac output (CO) by the Fick method was 2.36 L/min (Cardiac index of 1.46 L/min/m2). Vasoreactivity testing was not performed. In clinic follow-up one month after diagnosis, a D-dimer test was done and found to be elevated at 1.73 mg/L (reference = 0–0.5 mg/L); however, a polymerase chain reaction (PCR) test for the BCR-ABL gene was < 0.001% at that time, consistent with her levels while in remission. A complete autoantibody screen was also done and found to be negative (antinuclear antibody, anti-double strand DNA, anti-Smith, ANCA, ribonucleoprotein, anti-histone, SCL-70, chromatin, centromere, SSA/SSB). Her BNP was noted to be 560 pg/mL (reference = 0–100 pg/mL), her 6-minute walk test (6MWT) was 250 m using 2 L oxygen via nasal cannula with a nadir pulse oximetry saturation of 96%, and her functional class was WHO-FC III. Dasatinib was suspected to be the precipitating factor for the patient’s new PAH given the temporal association with the patient’s symptoms and exclusion of other etiologies, and was promptly replaced with Nilotinib (a related second-generation tyrosine kinase inhibitor with a lower rate of drug-induced PAH compared with Dasatinib) to continue therapy for CML. Given the severity of the patient’s symptoms and RHC data, the patient was also started on combination therapy with a phosphodiesterase-5 inhibitor, Tadalafil, at 20 mg daily and an endothelin receptor antagonist, Ambrisentan, at 5 mg daily. The patient was also started on furosemide at 10 mg daily and was not started on systemic anticoagulation. The Tadalafil was up-titrated over a period of four weeks to 40 mg daily, followed by an up-titration of Ambrisentan to 10 mg daily over the following four weeks. The patient experienced marked symptomatic improvement, and repeat chest X-ray () and echocardiogram four months after beginning therapy showed complete resolution of the PH with a normal right ventricular size and function ( and ). A repeat RHC performed at the same time showed full resolution of PAH, with mPAP of 18 mmHg, PCWP of 9 mmHg, and PVR of 1.96 Woods Units. The RA pressure was 5 mmHg and the CO by the Fick method was 4.59 L/min (cardiac index of 2.51 L/min/m2). Her BNP was measured in clinic at this time and had decreased to 18 pg/mL, her 6MWT had improved to 425 m on room air with a nadir pulse oximetry saturation of 96%, and her functional class was WHO-FC I. Given the marked improvement both symptomatically and hemodynamically, Ambrisentan and furosemide were discontinued and Tadalafil was weaned sequentially over the following four months. Despite the cessation of her pulmonary vasodilator therapy, the patient did not have a return of her dyspnea or exercise intolerance. She continues to remain symptom-free after five months without targeted PH therapy.
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 .