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 70-year old male with chronic phase CML diagnosed in 1996 was changed to dasatinib therapy due to subsequent haematological progress under hydroxyurea combined with interferon alpha (1996-2002) and imatinib (2002-2004: 400 mg/day, 2004-2005: 800 mg/d). Dasatinib treatment with a dose of 70 mg bid was applied for 32 months. Side effects during this period were minor as the medication was generally tolerated well.\nHowever, suddenly the patient developed tachy-dyspnea (25/min), transsudative, non-malignant pleural effusions (glucose 116 mg/dl; lactate dehydrogenase 188 IU/ml of effusions, serum lactate dehydrogenase 1073 IU/ml; protein content of effusions 31 g/l, serum protein content 67 g/l) and fatigue increasing within a few weeks.\nEchocardiography showed highly increased right ventricular systolic pressure (RVSP) of 73 mm Hg. Invasive haemodynamic evaluation confirmed severe pre-capillary PH with consecutive right heart failure (details on prognostic factors and haemodynamics listed in Table ). Clinically, the patient was assigned to WHO/NYHA functional class IV.\nAs other underlying pathophysiological reasons were ruled out by serological tests, chest CT, scintigraphy of the lung and abdominal ultrasound, dasatinib was consequently discontinued. Normal wedge pressures at right heart catheterisation also excluded tyrosine kinase inhibitor-induced cardiomyopathy or other left heart diseases as possible underlying pathologies.\nAfter discontinuation of dasatinib medication low-dose PAH-specific therapy with vasodilative phosphodiesterase-V inhibitor sildenafil (3 × 20 mg) was initiated. Acute symptoms relieved within days.\nDuring the following 10 months prognostic parameters such as the N-terminal fragment of pro brain-natriuretic peptide (NT-proBNP), 6-minute walking distance (6MWD), RVSP, pulmonary artery mean pressure (PAPmean) and pulmonary vascular resistance (PVR) improved significantly (see Table ). Additionally, the patient's subjective well-being advanced decisively which was also reflected by a functional class improvement to NYHA II (Figure ).\nPulmonary complications of dasatinib therapy have been reported ranging from pleural effusions to lung parenchymal affections []. In particular, pleural effusions caused by dasatinib, which are mostly exsudative due to clonal expansion of natural killer T cells, are well recognised and have been documented in various studies [,,]. In addition to the EMEA data set [], in a retrospective analysis of 138 patients receiving dasatinib in once or twice daily treatment schedules, pleural effusions of any grade were detected in 35% of the complete study population comprising chronic phase, accelerated phase and blast crisis [].\nStatistically significant, dose-dependent increase in RVSP was reported in a subgroup of 18 patients and dasatinib cessation led to normalisation of RVSP in 10 patients []. Dyspnoea, nausea, fatigue and oedema - unspecific yet classical symptoms found in PH - are among the most frequently observed unwanted dasatinib effects. Up to now, the extent of dasatinib-associated pre-capillary PH in contribution to these symptoms remains illusive since data regarding haemodynamics are lacking. However, all three detailed cases with dasatinib-related pre-capillary PH developed after a 2-year period of treatment (Figure ).\nOur findings in combination with the two other published cases suggest a yet unknown association of pre-capillary PH with dasatinib []. Therefore, our patient was categorised into Dana Point class 1.3 that resembles drug-induced pulmonary arterial hypertension (PAH, []). Dana Point I represents the only class where PAH-specific drugs are labelled for. Hence PAH-specific therapy with low-dose sildenafil was started.\nDana Point class V, on the other side, combines all multifactorial or uncertain causes of PH and it explicitly includes chronic myeloproliferative diseases. Nevertheless, in this case connection of PH with myeloproliferative disease is also unlikely since, firstly, the CML was stable under dasatinib therapy for almost three years without acceleration until the end of dasatinib therapy. Secondly, a recent report showed a preferential association of myeloproliferative disease-associated PH with chronic thromboembolism [], which was ruled out in our patient by CT scans and V/Q scintigraphy. In such case the use of sildenafil would have been off-label.\nTaking into consideration that pleural effusions are found rarely in pre-capillary pulmonary hypertension another differential diagnosis has to be mentioned: pulmonary veno-occlusive disease (PVOD). PVOD, again, seems to be unlikely since it typically presents as non-responsive PH []. However, symptoms and RVSP of our patient rapidly improved after discontinuation of dasatinib and initiation of sildenafil therapy. Additionally, typical signs of PVOD such as ground glass opacity and septal thickening in CT scans or crackles and clubbing on examination [] were absent in the presented case.\nMost interestingly, although dasatinib also inhibits the platelet-derived growth factor receptor (PDGFR) pathway there may be a contrary effect on proliferative aspects of PAH compared to imatinib which has been shown to be an effective treatment improving PAH and animal survival as well as reversing pulmonary remodelling in rodent model systems, a series of case reports and a phase II trial [-]. Hence, a prospective randomised safety and efficacy trial is currently ongoing (IMPRES, ClinicalTrials.gov: NCT00902174).\nAs key mechanisms, imatinib reversed overexpression and increased phosphorylation of PDGFRβ in pulmonary arteries from rat models of pulmonary hypertension, inhibited PDGFR-related ERK1/2 activation in lungs of these animals thereby suppressing rat pulmonary artery smooth muscle cell (PA-SMC) proliferation and inducing PA-SMC apoptosis [].\nWhile dasatinib inhibits Bcr-Abl at significantly lower inhibitory concentrations (IC50) as compared to imatinib, its effect on c-kit and PDGFR are rather similar. In addition, however, and different from imatinib, dasatinib also inhibits the SRC family of kinases []. Whether this aspect of the compound is causally related to PH development remains unclear.