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.
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).