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 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 .