pulmonary arterial hypertension ( pah ) is a group of diseases characterized by progressive increase in pulmonary vascular resistance ( pvr ) ( mean pulmonary arterial pressure [ pap ] > 25 mm hg at rest or > 30 mm hg with exercise , as confirmed by right heart catheterization ) , leading to right ventricular failure and premature death .
elevated pvr may result from multiple mechanisms , including vasoconstriction , proliferative and obstructive remodeling of pulmonary vessel wall , inflammation , and thrombosis .
pah is a rare disease with an incidence of only 5.9 cases per 1 million , and primary pah is an aggressive disease with a median survival of 2.8 years .
dasatinib is an oral multi - target tyrosine kinase inhibitor of bcr - abl , platelet - derived growth factor receptor ( pdgfr ) , src , discoidin domain receptor , and c - kit and has a ~300-fold greater potency in abl inhibition compared to imatinib in in vitro studies . in 2010 ,
dasatinib was approved by the food and drug administration for treatment of chronic myeloid leukemia ( cml ) as a frontline therapy and as a second - line treatment after imatinib failure .
however , previous case reports have identified several concerns over the development of pah in dasatinib - treated cml patients [ 3 - 8 ] . here , we describe two cml patients who developed pah while receiving dasatinib treatment , but were improved shortly after discontinuation of dasatinib .
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 ) . on 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 .
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 . on 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 fig .
he was initially treated with interferon - alpha and later received a daily regimen of 400 mg imatinib that was dose - adjusted over time because of aes .
because no cytogenetic response was achieved on imatinib , dasatinib was initiated at a dose of 140 mg daily from december 2 , 2005 and was initially well tolerated .
however , in february 2008 , the patient complained of intermittent nyha class ii dyspnea on effort , and his chest radiograph revealed right pe ; with sustained dasatinib treatment , the symptom progressed to nyha class iii on february 24 , 2009 . at that time ,
dasatinib was discontinued , and treatment with low dose sildenafil ( 25 mg / day ) was initiated .
however , a chest computed tomography scan revealed mild pulmonary congestion , and a transthoracic doppler echocardiogram showed an increased rvsp of 71 mm hg and a small amount of pericardial effusion .
laboratory tests for human immunodeficiency virus ( hiv ) and rheumatic diseases , including antinuclear antibodies , antibodies to double - stranded dna , and anti - scl-70 antibodies , were negative .
a careful review of concurrent medications or toxins suspected to play an essential role in the development of pah revealed no causative evidence .
after switching to nilotinib ( 800 mg / day ) in may 2009 , the patient s subjective dyspnea improved , and his rvsp decreased to 55 mm hg .
bnp levels returned to 28 pg / ml , and the 6-minute - walk test value improved from 480 m to 615 m. the patient intermittently discontinued nilotinib because of repeated hyperbilirubinemias and was transferred to our hospital in july 2009 .
eighteen months later , he lost cytogenetic response with an e292v mutation ; therefore , a daily dose of 100 mg dasatinib was reintroduced in december 2010 .
although the patient previously experienced dasatinib - associated pah , we chose to administer dasatinib in order to overcome the patient s mutation - related resistance .
the dose of dasatinib ( 40 - 60 mg / day ) was then adjusted according to the severity of dyspnea , and a major cytogenetic response on dasatinib was maintained .
after dasatinib administration , the patient again experienced a sustained nyha functional class ii dyspnea with serial elevation of left ventricular systolic pressure observed in a follow - up echocardiogram ( fig .
on april 11 , 2011 , a daily dose of 45 mg ponatinib was prescribed without improvement in pah while maintaining a complete cytogenetic response and a major molecular response . in august 2012
, the patient 's subjective dyspnea was improved to nyha functional class i. the changes in clinical course , cardiopulmonary parameters and treatment history are depicted in fig .
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 ) . on 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 .
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 . on 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 fig .
he was initially treated with interferon - alpha and later received a daily regimen of 400 mg imatinib that was dose - adjusted over time because of aes .
because no cytogenetic response was achieved on imatinib , dasatinib was initiated at a dose of 140 mg daily from december 2 , 2005 and was initially well tolerated .
however , in february 2008 , the patient complained of intermittent nyha class ii dyspnea on effort , and his chest radiograph revealed right pe ; with sustained dasatinib treatment , the symptom progressed to nyha class iii on february 24 , 2009 . at that time ,
dasatinib was discontinued , and treatment with low dose sildenafil ( 25 mg / day ) was initiated .
however , a chest computed tomography scan revealed mild pulmonary congestion , and a transthoracic doppler echocardiogram showed an increased rvsp of 71 mm hg and a small amount of pericardial effusion .
laboratory tests for human immunodeficiency virus ( hiv ) and rheumatic diseases , including antinuclear antibodies , antibodies to double - stranded dna , and anti - scl-70 antibodies , were negative .
a careful review of concurrent medications or toxins suspected to play an essential role in the development of pah revealed no causative evidence .
after switching to nilotinib ( 800 mg / day ) in may 2009 , the patient s subjective dyspnea improved , and his rvsp decreased to 55 mm hg .
bnp levels returned to 28 pg / ml , and the 6-minute - walk test value improved from 480 m to 615 m.
the patient intermittently discontinued nilotinib because of repeated hyperbilirubinemias and was transferred to our hospital in july 2009 .
eighteen months later , he lost cytogenetic response with an e292v mutation ; therefore , a daily dose of 100 mg dasatinib was reintroduced in december 2010 .
although the patient previously experienced dasatinib - associated pah , we chose to administer dasatinib in order to overcome the patient s mutation - related resistance .
the dose of dasatinib ( 40 - 60 mg / day ) was then adjusted according to the severity of dyspnea , and a major cytogenetic response on dasatinib was maintained .
after dasatinib administration , the patient again experienced a sustained nyha functional class ii dyspnea with serial elevation of left ventricular systolic pressure observed in a follow - up echocardiogram ( fig .
on april 11 , 2011 , a daily dose of 45 mg ponatinib was prescribed without improvement in pah while maintaining a complete cytogenetic response and a major molecular response . in august 2012 ,
the patient 's subjective dyspnea was improved to nyha functional class i. the changes in clinical course , cardiopulmonary parameters and treatment history are depicted in fig .
the cause of pah can be classified as idiopathic , hereditary , or associated with congenital heart disease , connective tissue disease , hiv infection , portal hypertension , drugs and toxins , and hemoglobinopathies .
although right heart catheterization was not performed to establish a diagnosis of pah in our two patients , they had an estimated systolic pap of over 30 mm hg in echocardiogram .
these patients did not have any possible causes of pah such as family history of pah , congenital heart disease , infection , rheumatologic disease or hiv .
pah in our patients continued to worsen during administration of dasatinib but became normalized after switching to another tyrosine kinase inhibitor . according to french reports ,
the lowest estimated incidence of pah occurring in patients exposed to dasatinib was 13 of 2,900 ( 0.45% ) .
preclinical findings have suggested that an imbalance in pdgfr expression contributes to excessive smooth muscle proliferation observed in ovine perinatal pulmonary hypertension .
another study found that platelet - derived growth factor ( pdgf ) and pdgfr mrna are overexpressed in pulmonary arterial smooth muscle cells and endothelial cells from the pulmonary arteries of patients displaying severe pah ; in addition , immunostaining of these tissues confirms high protein levels of pdgf / pdgfr .
the ability to inhibit pdgfr signaling suggests that both imatinib and dasatinib have similar effects on pulmonary vascular remodeling ; furthermore , imatinib was effective for the treatment of pah through blockade of pdgfr phosphorylation in several studies . therefore , a unique mechanism of dasatinib - associated pah may exist independent of effects on pdgf / pdgfr signaling .
the main difference in the kinase profile between dasatinib and imatinib is the inhibition of src family kinases .
preclinical findings suggest that src kinase activity is related to hypoxic vasoconstriction in the rat pulmonary artery
. therefore , src activity may be one of the main mechanisms of dasatinibrelated pah .
the patients presented in this report and other patients in some previously published cases have several common characteristics ( table 2 ) .
first , dasatinib had been given for a long period of time ( 19 - 52 months ) before clinical manifestations of pah developed .
the occurrence of pah at a late onset suggests a chronic pathological mechanism with an insidious , as opposed to acute , inflammatory , or cardiac etiology .
in our case , the first patient developed dyspnea after approximately 69 months on dasatinib , and the second patient developed dyspnea after 38 months in the first instance and almost immediately after starting dasatinib in the second instance .
for the second patient , during the second administration of dasatinib , we observed a short time interval between the initiation of dasatinib and diagnosis of pah . given that this was a re - trial of dasatinib and his baseline rvsp was already elevated to 55 mm hg at the time of restarting dasatinib , the short interval between initiation of dasatinib and manifestation of pah symptoms can be explained .
second , these patients demonstrated rapid symptomatic and hemodynamic improvement ( within several days to 4 months ) after discontinuation of dasatinib .
this reversibility is remarkable because normalization of pulmonary hemodynamics is not usually achieved in pah with usual medical treatments .
third , a majority of patients have had a history of pe with pericardial effusion .
it was previously reported that pe occurred in 17%-54% of patients on dasatinib , which suggests a similar mechanism of development for dasatinib - associated pah and pe . given these common characteristics , we suggest that dasatinib is the primary cause of pah in our two cases . in conclusion ,
long - term treatment with dasatinib may contribute to pah , which may improve spontaneously after discontinuation .
routine cardiopulmonary evaluation before and during treatment with dasatinib will be needed in patients with clinical manifestations .
 we describe two cases of pulmonary arterial hypertension ( pah ) that occurred under dasatinib treatment and were resolved after dasatinib discontinuation . 
 two patients with chronic phase chronic myeloid leukemia ( cml ) were switched to dasatinib therapy because of hematological progress while receiving imatinib . 
 these patients had new york heart association ( nyha ) functional class ii dyspnea with elevated right ventricular systolic pressure ( rvsp ) , which progressed under dasatinib treatment . 
 after dasatinib treatment was discontinued , subjective symptoms were improved to nyha functional class i and the follow - up transthoracic doppler echocardiography showed improved rvsp . 
 treatment with an alternate tyrosine kinase inhibitor was initiated and had been continued without development of dyspnea or elevation of rvsp . 
 this report suggests that dasatinib can cause the reversible pah , therefore , routine cardiopulmonary evaluation before and during treatment with dasatinib may be needed in cml patients with clinical manifestations . 
Introduction
Case Reports
1. Case 1
2. Case 2
Discussion