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 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.