Dasatinib-induced Pulmonary Arterial Hypertension Research Articles

Relationship between Dasatinib-induced Pulmonary Hypertension and Drug Dose

Objective Dasatinib, a second-generation tyrosine kinase inhibitor, is used for chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). It reportedly causes pulmonary arterial hypertension (PAH) and the dose-dependent induction of apoptosis in pulmonary endothelial cells. However, no report has yet discussed the relationship between dasatinib-induced PAH and drug dose. We therefore investigated the incidence of dasatinib-induced PAH and the relationship between dasatinib-PAH and drug dose in consecutive patients with CML and Ph+ ALL who took dasatinib. Methods The clinical data of 128 patients with CML (94 patients) and Ph+ ALL (34 patients) were retrospectively analyzed. Patients All patients (>17 years old) who received dasatinib from January 2009 to March 2020 at Jichi Medical University (Tochigi, Japan) were included. Patients who transferred within one month of starting dasatinib administration were excluded. Results Four (4.3%) and three (8.8%) patients developed pulmonary hypertension (PH), which was considered present when the transtricuspid pressure gradient was ≥40 mmHg, in the CML and ALL groups, respectively. No significant difference was observed between the PH onset and the administration period, cumulative dose, or daily dose of dasatinib. PH occurred in seven patients (5.5%), and the period from the start of dasatinib administration to the PH onset ranged from 7 to 39 (median: 28) months. No patients died from PH in either group. Conclusion Dasatinib-induced PAH does not occur time- or dose-dependently. When administering dasatinib, cardiovascular diagnostic modalities should be routinely checked, and PAH occurrence should be promptly detected.

Dasatinib-Induced Pulmonary Arterial Hypertension: A Case Report

Dasatinib-Induced Pulmonary Arterial Hypertension: A Case Report

Change of right ventricular systolic pressure can indicate dasatinib-induced pulmonary arterial hypertension in chronic myeloid leukemia.

BackgroundWe investigated the feasibility of the clinical application of non‐invasive transthoracic echocardiography for diagnosis of pulmonary arterial hypertension induced by dasatinib (D‐PAH) in chronic myeloid leukemia (CML).MethodsA total of 451 CML patients who were examined by 2D‐echocardiography at least once at baseline and/or during dasatinib therapy as frontline (n = 196) and subsequent line (n = 255) therapies were included in this study. D‐PAH was defined as right ventricular systolic pressure (RVSP) >40 mm Hg with relevant symptoms and the absence of other specific etiologies.ResultsA total of 847 echocardiographies were performed including at baseline (n = 255) and during dasatinib treatment (n = 592). During the median of 36.2 (0.1–181.8) months of dasatinib therapy, the level of RVSP gradually increased (Spearman's r = 0.2819, p < 0.001) and the mean RVSP was significantly increased after taking dasatinib therapy compared with baseline. During dasatinib therapy, 56 (12.4%) patients had RVSP >40 mm Hg without (asymptomatic, n = 27, 48.2%) or with symptoms (D‐PAH, n = 29, 51.8%). All asymptomatic patients maintained dasatinib therapy without further symptoms and the D‐PAH patients ultimately switched to other tyrosine kinase inhibitors. After dasatinib discontinuation, 13 (45%) and 15 (52%) patients showed RVSP normalization and gradual decrease, respectively.ConclusionsOur large cohort study demonstrated that the gradual increment of RVSP might be induced by dasatinib and non‐invasive echocardiography can be fast way for early diagnosis as well as for monitoring of D‐PAH.

OUT OF THE FRYING PAN AND INTO THE FIRE: A RARE CASE OF DASATINIB-INDUCED PULMONARY ARTERIAL HYPERTENSION

SESSION TITLE: Medical Student/Resident Pulmonary Vascular Disease Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Dasatinib is a tyrosine kinase inhibitor used to treat Ph+ acute lymphoblastic leukemia (ALL) and chronic myelogenous leukemia. Dasatinib inhibits SRC kinases involved with regulation of vasodilation and vascular proliferation. Rarely, it is associated with pulmonary arterial hypertension (PAH) in 0.45% of patients. We describe a case of new-onset PAH caused by maintenance dasatinib therapy for Ph+ B-cell ALL. CASE PRESENTATION: A 38 year old male with B-ALL status:post allogeneic stem cell transplantation on dasatinib for 15 months presented to the ER with worsening dyspnea, leg swelling and syncopal episodes for 2 months. He had no history of smoking, HIV, drug abuse, weight loss medications, clotting disorders, or sleep-disordered breathing. Labs showed BNP of 3700 and normal hematological, renal and liver function. Autoimmune testing including antinuclear, anti-mitochondrial, anti-citrullinated peptide and scleroderma antibodies was negative. Pulmonary function tests had isolated reduction in DLCO (49%). Echocardiogram (Echo) revealed severely dilated right ventricle (RV) with severely reduced right ventricular systolic function (RVSF), right ventricular systolic pressure (RVSP) 86 mmHg and normal left ventricular size and function. Echo was normal 1 year ago. CT angiogram was negative for pulmonary embolism with normal lung parenchyma. Right heart catheterization (RHC) showed mean pulmonary artery pressure (mPAP) of 45 mmHg, pulmonary capillary wedge pressure (PCWP) of 14 mmHg, cardiac output(CO) of 5.5 L/min, and pulmonary vascular resistance (PVR) of 5.6 Wood Units. Dasatinib was stopped and subcutaneous treprostinil and diuretic was initiated. Symptoms improved significantly and RHC in 3 months showed remarkable improvement with mPAP 6 mmHg, PCWP 5 mmHg, CO 5.85 L/min and PVR of 0.18. Echo improved with only mildly dilated RV, mildly decreased RVSF. Treprostinil was transitioned to oral macitentan and sildenafil. DISCUSSION: Dasatinib-induced PAH can be severe and irreversible in upto 37% of patients. Given that it can occur any time from 1 week to 75 months after starting therapy, a high index of suspicion is required to recognize this rare but potentially disastrous complication, regardless of duration of therapy. It can be challenging to identify PAH in a dyspneic patient with other, more common, pulmonary complications of dasatinib such as pleural effusion, which occurs in 35% of patients. CONCLUSIONS: Early recognition and treatment of dasatinib-induced PAH has implications for recovery and quality of life as discontinuation of the offending agent leads to resolution of PAH in the majority of patients. PAH specific therapy with pulmonary vasodilators may be warranted in severe disease with symptoms and RV dysfunction. Reference #1: El-Dabh A, Acharya D. Pulmonary hypertension with dasatinib and other tyrosine kinase inhibitors. Pulmonary Circulation. 2019;9(3):204589401986570. Reference #2: Montani D, Bergot E, Günther S et al. Pulmonary Arterial Hypertension in Patients Treated by Dasatinib. Circulation. 2012;125(17):2128-2137. Reference #3: Shah NP, Wallis N, Farber HW et al. Clinical features of pulmonary arterial hypertension in patients receiving dasatinib. American Journal of Hematology. 2015;90(11):1060-1064. DISCLOSURES: No relevant relationships by Abdul Khan, source=Web Response No relevant relationships by Nehan Sher, source=Web Response no disclosure on file for Ramachandra Sista; No relevant relationships by Daniel Yu, source=Web Response

Complete recovery from dasatinib-induced pulmonary arterial hypertension after successful discontinuation of tyrosine kinase inhibitor in a case of chronic myeloid leukemia

Complete recovery from dasatinib-induced pulmonary arterial hypertension after successful discontinuation of tyrosine kinase inhibitor in a case of chronic myeloid leukemia

Computed tomography-measured pulmonary artery to aorta ratio and EUTOS score for detecting dasatinib-induced pulmonary arterial hypertension.

Periodic echo-based screening to detect early stages of a rare complication of dasatinib, pulmonary arterial hypertension (PAH), is inefficient and weakens the potential benefit of dasatinib as a potent drug for chronic myelogenous leukemia (CML). This study aimed to identify the predisposing factors of DASA-PAH to stratify high-risk patients for dasatinib-induced PAH (DASA-PAH). Sixty consecutive adult patients who received dasatinib were enrolled in this case-control study. We defined DASA-PAH when at least one of the following four criteria was met: (1) recent electrocardiographic changes indicating right ventricular pressure overload, (2) estimated systolic pulmonary arterial pressure > 40mmHg measured by Doppler echocardiography; (3) computed tomography (CT)-measured pulmonary artery to aorta diameter (PaD/AoD) ratio > 1; and (4) mean pulmonary arterial pressure > 25mmHg and pulmonary artery wedge pressure < 15mmHg measured by right heart catheterization. We identified 13 patients with DASA-PAH among 59 patients analyzed. Baseline PaD/AoD ratios of patients who developed DASA-PAH (PH group) were significantly larger than those who did not (NPH group). A dramatic rise in PaD/AoD ratio after dasatinib treatment was observed. Interestingly, the EUTOS score and spleen size were significantly smaller in the PH than in the NPH group. High baseline PaD/AoD ratio and low EUTOS score were associated with DASA-PAH development. The spleen might play a protective role against DASA-PAH.

Dasatinib-induced pulmonary arterial hypertension.

Drug-induced (group 1) pulmonary hypertension (PH) is an important subgroup of PH involving dasatinib as a likely related agent, which is a second-generation tyrosine kinase inhibitor (TKI) used in the treatment of chronic myeloid leukaemia (CML). The mechanism of dasatinib-induced pulmonary arterial hypertension (PAH) is unclear. However, the occurrence of PAH with late onset in CML patients suggests a chronic pathological mechanism with an insidious onset rather than an acute inflammatory or cardiac aetiology. Dasatinib has a broader effect than other TKIs; the major known difference between dasatinib and other TKIs is the additional inhibition of Src family kinases. Therefore, Src inhibition was thought to play a role in the development of dasatinib-induced PAH. However, recently, it was also speculated that chronic dasatinib therapy may cause pulmonary endothelial damage, attenuate hypoxic pulmonary vasoconstriction responses and increase susceptibility to PAH independently of the Src family kinase-induced mechanism. Dasatinib-induced PAH usually seems to be reversible with the cessation of the drug, and sometimes with PAH-specific treatment strategies. Transthoracic echocardiography can be recommended as a routine screening prior to dasatinib initiation, and this non-invasive procedure can be utilized in patients having signs and symptoms attributable to PAH during dasatinib treatment.

Pulmonary arterial hypertension in a patient treated with dasatinib: a case report

BackgroundThere have been several reports on dasatinib-induced reversible pulmonary hypertension. This is the first reported case in Latvia; the patient did not discontinue the drug after the first adverse effects in the form of pleural effusions, which we speculate led only to partial reversion of the disease.Case presentationA 67-year-old white man with chronic myelogenous leukemia was treated with the dual Src and BCR-ABL tyrosine kinase inhibitor dasatinib. After treatment with dasatinib he had multiple pleural effusions which were suspected to be caused by congestive heart failure. Later a transthoracic Doppler echocardiography and right-sided heart catheterization revealed severe pulmonary hypertension with pulmonary vascular resistance of 12 Wood units and mean pulmonary artery pressure of 53 mmHg. Computed tomography ruled out a possible pulmonary embolism; laboratory specific tests for human immunodeficiency virus, rheumatoid factor, and anti-nuclear antibodies were negative, and dasatinib-induced pulmonary arterial hypertension was diagnosed.A follow-up right-sided heart catheterization and 6-minute walk test done a month after the discontinuation of dasatinib showed significant improvement: mean pulmonary artery pressure of 34 mmHg and pulmonary vascular resistance of 4 Wood units.ConclusionsPatients should always be closely monitored when using dasatinib for a prolonged time. Dasatinib-induced pulmonary hypertension may be fully reversible after the therapy is suspended, but the key factors involved are still unclear and need to be further studied.

Long-term outcomes of dasatinib-induced pulmonary arterial hypertension: a population-based study.

This study aimed to describe the long-term outcomes of pulmonary arterial hypertension (PAH) induced by dasatinib.21 incident, right heart catheterisation-confirmed cases of dasatinib-induced PAH were identified from the French Pulmonary Hypertension Registry. Clinical and haemodynamic variables were compared from baseline to last follow-up (median (range) 24 (1-81) months).Median age was 52 years and 15 patients were female (71%). 19 patients received dasatinib for chronic myelogenous leukaemia for a median (range) duration of 42 (8-74) months before PAH diagnosis. No bone morphogenic protein receptor-2 (BMPR2) mutations were found in the 10 patients tested. Dasatinib was uniformly discontinued and 11 patients received PAH medications. Four patients died during follow-up. NewYork Heart Association functional class improved from 76% in class III/IV to 90% in class I/II (p<0.01). Median (range) 6-min walk distance improved from 306 (0-660) to 430 (165-635) m (p<0.01). Median (range) mean pulmonary arterial pressure improved from 45 (30-70) to 26 (17-50) mmHg (p<0.01) and pulmonary vascular resistance from 6.1 (3.2-27.3) to 2.6 (1.2-5.9) Wood units (p<0.01). Patients treated with PAH medications had worse baseline haemodynamics but similar long-term outcomes to untreated patients. PAH persisted in 37% of patients.Dasatinib-induced PAH frequently improves after discontinuation but persisted in over one-third of patients, therefore systematic follow-up is essential.

In vitro and in vivo evaluation of dasatinib and imatinib on physiological parameters of pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) results from occlusion or vasoconstriction of pulmonary vessels, leading to progressive right ventricular failure. Dasatinib, a BCR-ABL1 tyrosine kinase inhibitor (TKI) approved for the treatment of chronic myelogenous leukemia, has been associated with PAH. In contrast, the BCR-ABL1 TKI imatinib has demonstrated anti-vasoproliferative properties and has been investigated as a potential treatment for PAH. Here we describe studies evaluating the effects of dasatinib and imatinib on cardiovascular and pulmonary functions to understand the reported differential consequences of the two TKIs in a clinical setting. The direct effects of dasatinib and imatinib were explored in vivo to investigate possible mechanisms of dasatinib-induced PAH. In addition, effects of dasatinib and imatinib on PAH-related mediators were evaluated in vitro. In rats, both TKIs increased plasma nitric oxide (NO), did not induce PAH-related structural or molecular changes in PA or lungs, and did not alter hemodynamic lung function compared with positive controls. Similarly, in the pulmonary artery endothelial cells and smooth muscle cells co-culture model, imatinib and dasatinib increased NO and decreased endothelin-1 protein and mRNA. The results of these studies indicated that dasatinib did not induce physiological changes or molecular signatures consistent with PAH when compared to positive controls. Instead, dasatinib induced changes consistent with imatinib. Both dasatinib and imatinib induced biochemical and structural changes consistent with a protective effect for PAH. These data suggest that other factors of unclear etiology contributed to the development of PAH in patients treated with dasatinib.

Reversible Pulmonary Arterial Hypertension Induced by Dasatinib in a Patient With Chronic Myeloid Leukemia

A case study is provided of dasatinib-induced pulmonary arterial hypertension (PAH) in a patient with chronic myeloid leukemia. This condition resolved completely within 2 months of drug discontinuation. Transthoracic echocardiography (TTE) data were obtained throughout the recovery process. After 30 months of dasatinib treatment, a woman in her 30s developed orthopnea and signs of right heart failure (leg edema, hepatomegaly, and weight gain). Transthoracic echocardiography indicated elevated mean pulmonary artery pressure, severely impaired systolic and diastolic right ventricular functions, and dilation of the right ventricle and atrium. Once dasatinib was discontinued, clinical symptoms improved rapidly, and follow-up TTE 2 months later showed normal right heart function. Treatment with an alternative tyrosine kinase inhibitor was initiated and has continued without recurrence of PAH. This case suggests that dasatinib, which inhibits a broad spectrum of tyrosine kinases, could cause reversible PAH; therefore, careful cardiopulmonary evaluation by TTE is necessary.

Dasatinib induces lung vascular toxicity and predisposes to pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is a life-threatening disease that can be induced by dasatinib, a dual Src and BCR-ABL tyrosine kinase inhibitor that is used to treat chronic myelogenous leukemia (CML). Today, key questions remain regarding the mechanisms involved in the long-term development of dasatinib-induced PAH. Here, we demonstrated that chronic dasatinib therapy causes pulmonary endothelial damage in humans and rodents. We found that dasatinib treatment attenuated hypoxic pulmonary vasoconstriction responses and increased susceptibility to experimental pulmonary hypertension (PH) in rats, but these effects were absent in rats treated with imatinib, another BCR-ABL tyrosine kinase inhibitor. Furthermore, dasatinib treatment induced pulmonary endothelial cell apoptosis in a dose-dependent manner, while imatinib did not. Dasatinib treatment mediated endothelial cell dysfunction via increased production of ROS that was independent of Src family kinases. Consistent with these findings, we observed elevations in markers of endothelial dysfunction and vascular damage in the serum of CML patients who were treated with dasatinib, compared with CML patients treated with imatinib. Taken together, our findings indicate that dasatinib causes pulmonary vascular damage, induction of ER stress, and mitochondrial ROS production, which leads to increased susceptibility to PH development.

Dasatinib causes pulmonary endothelial damage and aggravates pulmonary hypertension

Background Pulmonary arterial hypertension (PAH) is a life-threatening disease that can be induced by dasatinib, an orally bioavailable dual Src/Bcr-Abl tyrosine kinase inhibitor (TKI) used in the treatment of chronic myelogenous leukaemia (CML). Today, key questions remain regarding the long-term evolution of dasatinib-induced PAH and the mechanism(s) involved. Methods and results Here, we report major improvements and some cases of complete normalization of clinical, functional, and hemodynamic status 4–54 months after dasatinib withdrawal–and PAH therapy in some cases–in a well-characterized cohort of 18 incident cases of dasatinib-induced PAH. In contrast to chronic imatinib treatment, we demonstrate that chronic dasatinib therapy causes pulmonary endothelial damage in humans and rodents. We found that rats pretreated with dasatinib, but not with imatinib, exhibit increased susceptibility to experimental pulmonary hypertension (PH). Furthermore, we found significant elevations of markers of endothelial dysfunction or damage in the serum of CML patients treated with dasatinib when compared with CML patients treated with imatinib. These in vivo observations were replicated in vitro, with a dose-dependent induction of pulmonary endothelial cell apoptosis of cultured pulmonary endothelial cells with dasatinib, but not with imatinib, a phenomenon mediated through production of reactive oxygen species (ROS) and induction of endoplasmic reticulum (ER) stress and not dependent of Src kinase inhibition. Conclusions Collectively, we show that dasatinib causes pulmonary endothelial damage and aggravates PH through production of ROS and induction of chronic ER stress.

Real-Life Data and a Single Center Experience on Dasatinib-Induced Pulmonary Arterial Hypertension in Patients with Philadelphia Chromosome-Positive Leukemias

▪Background: Drug-induced pulmonary arterial hypertension (PAH) can be observed as an adverse event (AE) during the administration of dasatinib (DAS), which is a second generation tyrosine kinase inhibitor (TKI), used in the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). The occurence of DAS-induced PAH at a late onset in most of the cases suggests a chronic pathological mechanism rather than an acute inflammatory or cardiac etiology. The treatment strategies of DAS-induced PAH include the cessation of the drug and PAH-specific therapies.Aim: The aim of the study was to evaluate the frequency, clinical features, management strategies and outcomes of patients with DAS-induced PAH among a cohort consisted of CML and Ph+ ALL patients who had received DAS as a salvage treatment after imatinib (IM) failure or intolerance.Patients and Methods: Forty patients with Ph+ leukemias who received second-line DAS were enrolled. Patients' demographics, Sokal risk scores, molecular and cytogenetic responses, comorbidities [including preexisting cardiac disease, renal insufficiency, hypertension and chronic obstructive pulmonary disease (COPD)], DAS dose, dosing intervals and treatment durations, durations of IM therapy prior to DAS, and if any, treatments prior to IM (interferon (IFN), cytarabine (Ara-C), and hydroxyurea (HU)) and follow-up periods were noted retrospectively. TKI response criteria were based on the recommendations of European LeukemiaNet, and the definitions of the CML phases and responses were as described elsewhere.Results: Twenty-four patients were male, and the median age was 45 years (range, 18-81 years). There were 39 patients with CML and one with Ph+ ALL. Among the thirty-nine CML patients, 3 were in accelerated phase (CML-AP), two with blast crisis (CML-BC), and the rest were in chronic phase (CML-CP). The percentanges of low, intermediate, and high Sokal risk scores were 46%, 33%, and 21%, respectively. Thirteen patients received only IM prior to DAS, whereas the others had used HU, IFN and Ara-C prior to IM. After a median duration of 41.5 months (range, 1-93 months) of IM, the reason for switching to DAS were IM failure and intolerance in 37 and 3 patients, respectively. DAS was administered with a median of 50 months (range, 2-78 months). During DAS treatment hematological AEs were observed in 6 patients, whereas in twenty-one pulmonary complications including exacerbation of COPD and pneumonia (n=1), pleuro/pericaridal effusions (n=19), PAH (n=5) and gastrointestinal bleeding (n=1) were detected. DAS therapy was ceased in 13 patients, of which ten were switched to nilotinib (NIL) due to AEs (n=7) and failure (n=3). Also, two patients received cytotoxic treatment due to BC and one had allogeneic hematopoietic stem cell transplantation (allo-HSCT).Five patients (12.5%) had DAS-induced PAH (Table 1). Four of them were in CML-CP at diagnosis, and one was in CML-AP. All cases received DAS due to IM failure. At the time of DAS initiation, 4 cases were in CML-CP and one in CML-BC. PAH was diagnosed by transthoracic echocardiography (TTE) in 3 patients, and by right heart catheterization (RHC) in 2, and it was observed after a median of 8 months (range, 2-25 months) of DAS. Three patients had accompanying pleuro/pericardial effusions. All patients with DAS-induced PAH were alive at the time of the analysis, and the management of PAH included dose reduction in two, and DAS was switched to NIL in 2 cases and allo-HSCT was performed in one.Conclusion: DAS-induced PAH seems to be reversible with the cessation and/or modification of DAS ± PAH-specific treatments. As pulmonary vascular toxicity related to DAS is thought to be molecule-related rather than class-related, it seems reasonable to switch to another TKI. The patients in our cohort had good responses to dose modification and drug cessation and none received PAH-specific therapy. Although DAS-induced PAH is mainly defined as a late complication, we detected that PAH can be observed even after 2 months of drug exposure.PAH can be observed during DAS treatment and physicians should be aware of this AE. Routine cardiopulmonary evaluation prior to and/or during DAS may be beneficial. Mechanisms under this pathological condition, preceding and prognostic factors, and treatment strategies are needed to be evaluated with prospective trials. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Long-Term Assessment of Dasatinib-Induced Pulmonary Arterial Hypertension in Chronic Myeloid Leukemia

▪Background: To explore a real incidence of dasatinib-induced pulmonary arterial hypertension (D-PAH) in clinical practice, we investigated 82 imatinib or other 2G tyrosine kinase inhibitor (TKI)-failed chronic myeloid leukemia (CML) patients who received dasatinib as a second-line therapy.Methods: Routine chest X-ray and Doppler echocardiography were regularly evaluated in all patients and additional tests were performed if dyspnea developed on treatment.Results: Median age at the time of starting dasatinib was 48 (16-82) years. Of 82 patients, 8 patients (9.8%) showed an elevation of right ventricular systolic pressure (RVSP>35mmHg) by Doppler echocardiography. Among them, 7 patients (8.5%) were considered D-PAH with a median dasatinib treatment duration of 32.6 (10.3-108.7) months. They underwent follow-up Doppler echocardiography median 5 (2-9) times.Five patients showed severe D-PAH (RVSP >70mmHg), 1 was moderate (RVSP 46mmHg), and 1 was mild (RVSP 41mmHg). Advanced studies such as pulmonary angiographic catheterization (patient 1 and 2) or pulmonary arterial computed tomography (patient 3 and 4) were performed for confirming D-PAH or ruling out PAH due to pulmonary vascular abnormality. Six patients had bilateral pleural effusion and 1 had unilateral pleural effusion. With sildenafil (n=5) + dose reduction (n=1) + switch to other TKI (n=6), all of patients improved dyspnea, and RVSP level was completely resolved in 3 patients. In addition, previous nilotinib therapy and concomitant pleural effusion were significant contributing factors for D-PAH.Conclusion: Regardless of complete resolution of pleural effusion, a patient with sustained dyspnea on dasatinib treatment should be carefully evaluated by Doppler echocardiography and a regular monitoring will be needed for early intervention.Abstract 5535. Table 1Characteristics of patients with dasatinib-induced PAHCohortAge at PAH diagnosis (year)SexTreatment duration before dasatinib (month)Previous therapy for CMLDuration between initiation of dasatinib and diagnosis of PAH (month)Daily mean dose of dasatinib (mg/d)Duration between diagnosis of D-PAH and last follow up (month)Treatment of D-PAHSwitch to other TKIOutcome153M54.4Interferon, Hydroxyurea, Imatinib, nilotinib26.412373.5Sildenafilnilotinib and ponatinibpartial250M36.6Interferon, Hydroxyurea, Imatinib, dasatinib, nilotinib50.311255.2Sildenafilnilotinib and radotinibpartial337F31.7Imatinib, nilotinib21.78839.7SildenafilDose de-escalationradotinibpartial445M70.9Hydroxyurea, Imatinib69.810135.2SildenafilDose de-escalationponatinibcomplete559F107.4Interferon, Hydroxyurea, Imatinib83.69214.3noneradotinibpartial646F12.6Imatinib29.17613.0Steroid, Sildenafilradotinibcomplete738F30.2Imatinib33.19810.2Dose reductionNAcomplete DisclosuresNo relevant conflicts of interest to declare.

Dasatinib-induced pulmonary arterial hypertension unresponsive to PDE-5 inhibition

Our experimental work was aimed at the influence of red-wine polyphenolic compound (RWPc, Provinol) on defence airways reflexes (cough, bronchoconstriction, mucociliary clearance) and on inflammation during experimentally induced allergic asthma. We studied the effects of RWPc and combinations of RWPc with clinically used antiasthmatics (budesonide and theophylline). The allergic inflammation of the airways was induced in guinea pigs by 21-day ovalbumin (OVA) sensitization. During ovalbumin (OVA) sensitization experimental animals were treated with RWPc (20 mg/kg/day p.o.), budesonide (1 mM by inhalation), theophylline (10 mg/kg/ day i.p.) or with half-dose combinations of these substances. Our result showed that 21 days administration of RWPc caused a significant decrease in bronchial hyperreactivity (to bronchoconstricting mediators) and decrease in parameters of cough reflex. RWPc adjusted ciliary movement frequency on physiological values. The bronchodilatory, antitussive of RWPc was comparable to theophylline and budesonide. Furthermore, the half-dose combinations of RWPc with theophylline or budesonide exceeded an above-mentioned effects of substances used as monotherapy. Our results demonstrated the antiinflammatory effect of RWPc (decrease of IL-4, IL-5 level in BALF, decrease of eosinophilia). In conclusion, we can summarize that RWPc possesses efficient antiasthmatic activity. This work was supported by Centre of Experimental and Clinical Respirology II. ‘‘Project co-financed from EU sources’’ and by Grant VEGA 1/0020/11 .

Reversible dasatinib-induced pulmonary arterial hypertension and right ventricle failure in a previously allografted CML patient

Reversible dasatinib-induced pulmonary arterial hypertension and right ventricle failure in a previously allografted CML patient