Pulmonary Arterial Hypertension in Patients Treated by Dasatinib

Zalcman, Olivier Sitbon, Gérald Simonneau and Marc HumbertFrédéric Perros, Dermot S. O'Callaghan, Xavier Jaïs, Pascale Tubert-Bitter, Gérard Macro, Patrice Poubeau, Barbara Girerd, Delphine Natali, Christophe Guignabert,Arnaud Bourdin, Helene Bouvaist, Matthieu Canuet, Christophe Pison, Margareth David Montani, Emmanuel Bergot, Sven Günther, Laurent Savale, Anne Bergeron,

Pulmonary Arterial Hypertension in Patients Treated by Dasatinib

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Vascular Medicine

Pulmonary Arterial Hypertension in Patients Treatedby Dasatinib

David Montani, MD, PhD; Emmanuel Bergot, MD; Sven Gunther, MD; Laurent Savale, MD, PhD;Anne Bergeron, MD, PhD; Arnaud Bourdin, MD, PhD; Helene Bouvaist, MD; Matthieu Canuet, MD;

Christophe Pison, MD, PhD; Margareth Macro, MD; Patrice Poubeau, MD; Barbara Girerd, PhD;Delphine Natali, MD; Christophe Guignabert, PhD; Frederic Perros, PhD; Dermot S. O’Callaghan, MD;

Xavier Jaïs, MD; Pascale Tubert-Bitter, PhD; Gerard Zalcman, MD, PhD; Olivier Sitbon, MD, PhD;Gerald Simonneau, MD; Marc Humbert, MD, PhD

Background—The French pulmonary hypertension (PH) registry allows the survey of epidemiological trends. Isolatedcases of precapillary PH have been reported in patients who have chronic myelogenous leukemia treated with thetyrosine kinase inhibitor dasatinib.

Methods and Results—This study was designed to describe incident cases of dasatinib-associated PH reported in theFrench PH registry. From the approval of dasatinib (November 2006) to September 30, 2010, 9 incident cases treatedby dasatinib at the time of PH diagnosis were identified. At diagnosis, patients had moderate to severe precapillary PHwith functional and hemodynamic impairment. No other incident PH cases were exposed to other tyrosine kinaseinhibitors at the time of PH diagnosis. Clinical, functional, or hemodynamic improvements were observed within 4months of dasatinib discontinuation in all but 1 patient. Three patients required PH treatment with endothelin receptorantagonist (n�2) or calcium channel blocker (n�1). After a median follow-up of 9 months (min-max 3–36), themajority of patients did not demonstrate complete clinical and hemodynamic recovery, and no patients reached a normalvalue of mean pulmonary artery pressure (�20 mm Hg). Two patients (22%) died at follow-up (1 of unexplained suddendeath and 1 of cardiac failure in the context of septicemia, respectively, 8 and 12 months after dasatinib withdrawal).The lowest estimate of incident PH occurring in patients exposed to dasatinib in France was 0.45%.

Conclusions—Dasatinib may induce severe precapillary PH fulfilling the criteria of pulmonary arterial hypertension, thussuggesting a direct and specific effect of dasatinib on pulmonary vessels. Improvement is usually observed afterwithdrawal of dasatinib. (Circulation. 2012;125:2128-2137.)

Key Words: adverse drug events � pulmonary hypertension � vascular complications � chronic myeloid leukemia� dasatinib

Normal mean pulmonary artery pressure (mPAP) is14�3 mm Hg.1 Pulmonary hypertension (PH) is defined

by an increase in mPAP �25 mm Hg at rest.2 PH can beclassified into 5 groups according to pathomechanisms andclinical management. Group 1 (pulmonary arterial hyperten-sion, PAH) includes precapillary PH (with a normal pulmo-

nary capillary wedge pressure [PCWP] �15 mm Hg) that isidiopathic, heritable, drug-induced, or associated with variousconditions; group 2 corresponds to postcapillary PH; group 3corresponds to PH due to chronic lung diseases or hypox-emia; and group 4 corresponds to chronic thromboembolicPH. In contrast, group 5 consists of several forms of PH for

Received November 18, 2011; accepted March 9, 2012.From the Univ. Paris-Sud, Faculte de Medecine, Kremlin-Bicetre (D.M., S.G., L.S., B.G., D.N., C.G., F.P., D.S.O., X.J., O.S., G.S., M.H.); Assistance

Publique Hopitaux de Paris, DHU Thorax Innovation, Service de Pneumologie et Reanimation Respiratoire, Hopital Bicetre, Le Kremlin-Bicetre (D.M.,S.G., L.S., B.G., D.N., C.G., F.P., D.S.O., X.J., O.S., G.S., M.H.); INSERM U999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, LePlessis-Robinson (D.M., S.G., L.S., B.G., D.N., C.G., F.P., D.S.O., X.J., O.S., G.S., M.H.); Centre Hospitalier Universitaire de Caen, Service dePneumologie et Centre Regional de Competence de l’HTAP (E.B., G.Z.); ER3 INSERM, Universite de Caen, Caen (E.B., G.Z.); Universite Paris-Diderot,Service de Pneumologie, Hopital Saint-Louis, Paris (A. Bergeron); Service de Pneumologie, Hopital Arnaud de Villeneuve, Montpellier (A. Bourdin);Service de Cardiologie, Centre Hospitalier Universitaire, Grenoble (H.B.); Service de Pneumologie, Nouvel Hopital Civil, Strasbourg (M.C.); Service dePneumologie, Centre Hospitalier Universitaire, Grenoble, France (C.P.); Centre Hospitalier Universitaire de Caen, Service Hematologie Clinique, Caen(M.M.); Service de Pneumologie et Maladies Infectieuses, GHSR, Saint-Pierre, Reunion (P.P.); INSERM, CESP Centre de recherches en epidemiologieet sante des populations, U1018, Equipe biostatistique, F-94807 (P.T.-B.); Universite Paris-Sud, UMRS 1018, F-94807, Villejuif, France (P.T.-B.).

Drs Montani and Bergot contributed equally to this work.The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.

111.079921/-/DC1.Correspondence to Marc Humbert, MD, PhD, Service de Pneumologie et Reanimation Respiratoire, Hopital Bicêtre, 78 rue du General Leclerc, 94270

Le Kremlin-Bicetre, France. E-mail [email protected]© 2012 American Heart Association, Inc.

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which the pathogenesis is unclear or multifactorial. Thisgroup includes chronic myeloproliferative disorders that cancause PH by various potential mechanisms, including highcardiac output, splenectomy, direct obstruction of pulmonaryarteries, chronic thromboembolism, portal hypertension, andcongestive heart failure.3,4

Editorial see p 2057Clinical Perspective on p 2137

Chronic myelogenous leukemia (CML) is a chronic my-eloproliferative disorder characterized by a translocationbetween chromosome 9 and 22, leading to a pathogenictyrosine kinase signal transduction protein, breakpoint clusterregion/Abelson (BCR/ABL). The prognosis of CML has beentransformed by tyrosine kinase inhibitors (TKIs), whichinhibit BCR/ABL kinase, such as imatinib. However, up to20% of CML patients treated by imatinib do not achievecomplete cytogenetic response. Data suggest that 2 novelTKIs, dasatinib and nilotinib, are associated with higher ratesof complete cytogenetic response in imatinib-resistant andnewly diagnosed chronic-phase CML.5,6 It is noteworthy thatdasatinib shows greater inhibition of BCR/ABL kinase incomparison with imatinib (�300 times in vitro) and alsoinhibits several other kinases, including the Src family.7,8

Until recently, dasatinib was proposed as a second-linetherapy for patients with CML with resistant disease or whowere unable to tolerate imatinib. A randomized, controlledtrial has recently demonstrated that first-line dasatinib mayinduce significantly higher and faster rates of completecytogenetic response in newly diagnosed CML in comparisonwith imatinib, suggesting that dasatinib may become morewidely used in the treatment of CML in the future.5 Inaddition, dasatinib is currently being tested in other malignantdisorders, such as melanoma and breast, head and neck,ovarian, and non–small-cell lung cancers.9

Although TKIs are usually well tolerated, these agents arenonetheless characterized by systemic toxicity. Importantside effects of imatinib include edema, musculoskeletal pains,diarrhea, nausea, rash, abdominal pain, fatigue, headache,leucopenia, neutropenia, thrombocytopenia, anemia, and ele-vated liver enzymes, as well. It is noteworthy that imatinibmay also induce cardiac toxicity, with an estimated preva-lence of congestive heart failure of 0 � 6%.10 Pulmonarycomplications, and specifically pleural effusions, have beenreported more frequently with dasatinib use compared withother TKIs.11–13 In addition, some case reports have suggestedthat PH may be a potential specific complication of dasatinibuse.14–19 By contrast, clinical and hemodynamic improve-ments have been reported with imatinib therapy in 2 patientswith CML and coexistent severe precapillary PH.20 It wassuggested that this effect could be due to inhibition oftyrosine kinase targets of imatinib such as platelet-derivedgrowth factor receptors and c-kit.21–23 A recent randomizedcontrolled trial has shown that PAH patients treated byimatinib demonstrate hemodynamic improvements. How-ever, further studies are needed to better evaluate the overallrisk-benefit ratio of TKIs in PAH.24

The French PH Registry involves a network of specializedpulmonary vascular centers and has facilitated the study of

trends in PH at a national level.25–27 Since 2009, cases ofsevere precapillary PH occurring in CML patients treatedwith dasatinib have been reported to the Agence Francaise deSecurite Sanitaire des Produits de Sante, the French pharma-covigilance agency, and included in the French PH Registry.This finding prompted us to assess for a potential causal link.The present report summarizes the clinical characteristics andoutcomes of incident cases of dasatinib-associated PH iden-tified from the French Registry.

MethodsWe first reviewed all incident cases from the French PH Registry ofconfirmed precapillary PH among patients in whom a diagnosis ofCML was made or who had received treatment with dasatinib,imatinib, or nilotinib. This Registry was established in accordancewith French bioethics laws (Commission Nationale del’Informatique et des Libertes), and all patients gave their informedconsent. Diagnosis of precapillary PH, defined as mPAP�25 mm Hg with a normal PCWP �15 mm Hg, was confirmed inall patients by right heart catheterization. Right atrial pressure,mPAP, PCWP, and mixed venous oxygen saturation (SvO2) wererecorded. Cardiac output (CO) was measured by the standardthermodilution technique. Cardiac index was calculated as CO/bodysurface area. Pulmonary vascular resistance (PVR) were calculatedas (mPAP-PCWP)/CO, expressed in mm Hg/L per min. Acutevasodilator testing was performed during right heart catheterizationby the use of inhaled nitric oxide.28 Routine evaluation at baselineincluded medical history, physical examination, echocardiography,contrast-enhanced computed tomography of the chest, ventilation/perfusion lung scan, abdominal ultrasound, autoimmunity screening,and HIV serology. Age at diagnosis and clinical status as assessed bymodified New York Heart Association (NYHA) functional classwere recorded at diagnosis. A nonencouraged 6-minute walk testaccording to the American Thoracic Society recommendations wasperformed. Point mutations and large rearrangements in BMPR2gene were searched as previously described29 in 7 patients (patients1, 2, 3, 4, 5, 6, and 8) after they underwent genetic counseling andsigned written informed consent.

We then estimated the total number of patients treated withimatinib, dasatinib, and nilotinib in France during the period 2006 to2010 using data from the French pharmacovigilance agency, and thepharmaceutical companies that market dasatinib (Bristol-Myers-Squib, Princeton, NJ) and imatinib and nilotinib (Novartis, Basel,Switzerland).

ResultsDescription of Patients Treated With Imatinib,Dasatinib, and Nilotinib for HematologicMalignancy Identified in the French PH RegistryFrom the approval of dasatinib (November 2006) to Septem-ber 30, 2010, 9 incident PH patients with either a diagnosis ofCML or treatment with dasatinib were identified. All 9patients were receiving dasatinib therapy at the time of PHdiagnosis. Characteristics of these 9 dasatinib-treated patientsare shown in Table 1. Eight of the patients were females, andmedian age was 51 years (min-max 17–74). Chronic throm-boembolic PH was excluded on the basis of ventilation/perfusion lung scan and contrast-enhanced computed tomog-raphy of the chest. Conditions associated with PAH, such asportal hypertension, HIV infection, connective tissue dis-eases, or congenital heart diseases were excluded. No patienthad a family history of PAH, and no other drug and toxicexposure known to induce PAH were identified. No patienthad a history of left heart disease or chronic respiratory

Montani et al Dasatinib-Induced PAH 2129



disease and/or hypoxia. Cardiovascular risk factors orcomorbidities, including systemic hypertension, diabetesmellitus, dyslipidemia, arrhythmia, and coronary arterydisease, were absent in our patients, with the exception ofmild systemic hypertension and coronary artery disease in1 patient (patient 9).

None of the 7 patients tested for BMPR2 point mutationsand large rearrangements carried a deleterious mutation. Ofnote, patient 4 had a BMPR2 gene variant in exon 12(c.1607G�T, pArg536Leu). This variant was not previouslyreported in PAH patients and concerned an amino acidconserved in interspecies comparisons. However, in silicoanalysis (Polyphen, Sift) were not in favor of a pathogeniceffect of this polymorphism. Thus, in the current state ofknowledge, it is not possible to make a conclusion on theimplication of this BMPR2 variant in the development ofPAH.

In 8 of the 9 patients, second-line therapy with dasatinibwas initiated because of resistance or intolerance to first-lineimatinib therapy. In 1 patient, the indication for dasatinib wasacute lymphoblastic leukemia with coexisting BCR/ABLtranslocation. No patient had clinical evidence of PH beforeinitiation of dasatinib therapy. Of note, 6 patients had normalresults on a previous Doppler echocardiography before initi-ation of dasatinib, and 2 of these patients had normalechocardiography results between imatinib withdrawal anddasatinib initiation. All patients were considered to havesatisfactory disease control with dasatinib therapy at time ofPH diagnosis. Median delay between initiation of dasatiniband PH diagnosis was 34 months (min-max 8–48). At thetime of diagnosis, the dose of dasatinib ranged from 70 to 140mg/d (median 100 mg/d). Concomitant treatments includedanagrelide in 1 patient. Before initiation of dasatinib, previ-ous therapies included interferon �2B in 6 patients, hydroxy-carbamide in 6 patients, cytarabine in 3 patients, and imatinibin 8 patients (Table 1).

Evaluation of Pulmonary Hypertensionat DiagnosisAt PH diagnosis, all patients presented with recent andprogressive dyspnea on exertion and had marked functional

impairment (NYHA functional class II, III, and IV in 2, 4, and3 patients, respectively). Median 6-minute walk test was242 m (min-max 0–508). Right heart catheterization con-firmed precapillary PH in all patients (median PCWP10 mm Hg, min-max 3–13) with severe hemodynamic im-pairment (Table 2). Median mPAP was 46 mm Hg (min-max30–59), median CO was 6 L/min (min-max 3.3–8.9), andmedian PVR was 5.9 mm Hg/L per min (min-max 3.3–12.4).At diagnosis, median transpulmonary gradient was markedlyincreased to 34 mm Hg (min-max 22–48). Acute vasodilatortesting was performed in 7 patients. One patient showing adecrease in mPAP from 47 to 36 mm Hg associated withnormal CO was considered to have an acute vasodilatorresponse.28 At the time of right heart catheterization, hemo-globin level was normal or moderately reduced in themajority of patients (median hemoglobin 12.3 g/dL, min-max77–160). Circulating brain natriuretic peptide or N-terminalpro-B-type natriuretic peptide levels were measured in 8patients and were increased in all cases. Diffusion lungcapacity for carbon monoxide was measured in 4 patients andrevealed significantly reduced values in all cases with amedian value of 53% of predicted (min-max 44–63). At thetime of PH diagnosis, contrast-enhanced computed tomogra-phy of the chest showed bilateral pleural effusions in 6 of 9patients; echocardiography confirmed mild pericardial effu-sion in 3 patients (Table 3).

Clinical, Functional, and Hemodynamic EvolutionAfter Withdrawal of DasatinibA potential causal relationship between dasatinib exposureand development of precapillary PH was suspected. Dasatinibwas therefore discontinued in all patients following confir-mation of the diagnosis of PH, and treatment was substitutedby nilotinib in 6 patients and by hydroxycarbamide in 2others. In addition, treatment with the endothelin receptorantagonist bosentan was initiated in 2 patients. High-dosecalcium channel blocker therapy was commenced for thepatient with an acute vasodilator response (patient 1). In theremaining 6 patients, treatment with specific PAH therapywas not deemed necessary.

Table 1. Characteristics of Patients With Dasatinib-Associated PH

Age atDiagnosis, y

Sex,M/F

HematologicMalignancy

Delay BetweenInitiation of

Dasatinib andDiagnosis of PH, mo

Dose ofDasatinib at

Diagnosis, mg/d

ConcomitantTreatment at

Diagnosis of PH Previous Therapy for CML

1 74 F CML 33 100 . . . IFN�2B, HCM, imatinib

2 51 F CML 30 100 Anagrelide IFN�2B, HCM, mercaptopurine, imatinib

3 64 F CML 28 140 . . . Imatinib

4 28 F CML 45 100 . . . IFN�2B, cytarabine, imatinib


6 29 F CML 36 100 . . . IFN�2B, HCM, vincristine, mercaptopurine,methotrexate, cytarabine, imatinib

7 17 F ALL 8 100 . . . Vincristine, methotrexate, Adriamycin,cytarabine


9 68 M CML 48 80 . . . HCM, imatinib

ALL indicates acute lymphoblastic leukemia; CML, chronic myeloid leukemia; HCM, hydroxycarbamide; IFN, interferon; and PH, pulmonary hypertension.

2130 Circulation May 1, 2012



All but 1 patient showed clinical, functional, and/or hemo-dynamic improvements following dasatinib discontinuationwith a median follow-up of 15 months (min-max 8–36months). NYHA functional class improved and, at the lastevaluation, 6 patients were in functional class I, 2 patients inclass II, and 1 patient in class III (Figure 1A). Evolution of6-minute walk test (Figure 1B) was available in 6 patients andshowed significant improvement (478 m, min–max 278–635) in comparison with baseline values of these patients(242 m, min-max 0–429).

Even if hemodynamic improvement was usually observed,no patient demonstrated complete normalization of pulmo-nary hemodynamic indices (Table 4). An invasive hemody-namic evaluation at distance of withdrawal of dasatinib wasavailable for 8 patients after a median follow-up of 5 months(min-max 3–18). One patient (patient 8) died before hemo-dynamic evaluation. The last right heart catheterizationshowed a significant hemodynamic improvement (Figure 1Cand 1D) with a decrease of mPAP from 47 mm Hg (min-max30–59) to 28 mm Hg (min-max 25–50) and a decrease of

PVR from 6.1 mm Hg/L per min (min-max 3.3–12.4) to2.9 mm Hg/L per min (min-max 1.6–5.0). Importantly, noneof our patients reached a normal hemodynamic status, andmPAP remained elevated (�25 mm Hg) in all patients,consistent with a diagnosis of persistent PH.

In some patients with long-term follow-up and sequentialevaluations, there was evidence of continuing improvementin clinical and hemodynamic parameters several months afterdasatinib discontinuation, even among those patients inwhom specific PAH therapy had not been introduced (Table4). Nevertheless, patient 3 who did not present initial im-provement had no secondary improvement either, and died at12 months after PH diagnosis.

Outcomes of Patients With Dasatinib-Induced PHTwo patients (22%) died at follow-up (patients 3 and 9).Survival of patients with dasatinib-induced PH is presented inonline-only Data Supplement Figure I. Patient 3 died ofcardiac failure in the context of septicemia due to Candidaalbicans, 12 months after diagnosis of dasatinib-induced PH.

Table 2. Hemodynamic Parameters at the Time of PH Diagnosis

mPAP,mm Hg

RAP,mm Hg

PCWP,mm Hg

CO,L/min

CI, L/minper m2

PVR, mm Hg/Lper min SvO2, %

Acute VasodilatorResponse*

1 47 14 13 5.6 2.9 6.1 66 Yes (mPAP: 36, CI: 2.9)

2 59 13 11 6.5 4.0 7.4 63 No (mPAP: 59, CI: 6.4)

3† 30 5 8 6.7 4.7 3.3 72 No (mPAP: 27, CI: 6.9)

4‡

5 49 6 10 8.9 4.8 4.4 65 No (mPAP: 50, CI: 5.1)

6 49 24 8 3.3 1.8 12.4 55 No (mPAP: 47, CI: 2.0)

7 38 6 11 4.8 3.2 5.6 72 No (mPAP: 31, CI: 2.7)

8 37 6 3 3.3 1.9 10.3 54 No (mPAP: 39, CI: 2.4)

9 45 4 10 6.4 4.0 5.4 74 No (mPAP: 38)

mPAP indicates mean pulmonary artery pressure; RAP, right atrial pressure; PCWP, pulmonary capillary wedge pressure; CO, cardiac output; CI, cardiac index; PVR,pulmonary vascular resistance; SvO2, mixed venous oxygen saturation.

*Acute vasodilator response was defined as a decrease in mPAP of �10 mm Hg to reach an absolute value of �40 mm Hg, associated with no change or anincrease in CO.28

†Severe clinical and hemodynamic impairment necessitated initial management in an intensive care unit with catecholamines; right heart catheterization wasperformed after successful weaning of catecholamines 2 weeks after withdrawal of dasatinib.

‡PH was screened by echocardiography and confirmed by right heart catheterization 6 weeks after withdrawal of dasatinib.

Table 3. Clinical and Functional Evaluation at the Time of PH Diagnosis

NYHA FC,I–IV

PleuralEffusions

PericardialEffusions 6-MWT, m BNP,* ng/L

PaO2,kPa

DLCO,% theo

1 III Bilateral No 300 168 8.9 . . .

2 III Minimal and bilateral Minimal 345 424 8.9 44

3 IV No Minimal 0 1635 . . . . . .

4 III No No . . . . . . 13.2 59

5 III Bilateral No 183 128 . . . . . .

6 IV Bilateral No 0 Increase of NT-proBNP 9.9 . . .

7 II Bilateral No 429 432 9.9 46

8 IV Bilateral Minimal 0 603 7.6 . . .

9 II No No 630 163 10.6 63

BNP indicates brain natriuretic peptide; DLCO, diffusion lung capacity for carbon monoxide; NYHA FC, New York Heart Association functional class; PaO2, partialpressure of arterial oxygen; 6-MWT, 6-minute walk test; NT-proBNP, N-terminal pro-B-type natriuretic peptide; % Theo, percentage of predicted theoretical value.

*Normal values of BNP are �100 ng/L.




Of note, this patient was the only case in our series who didnot show improvements after withdrawal of dasatinib and hadthe most severe hemodynamic compromise at diagnosisrequiring management in intensive care unit with catechol-amines (Table 4). At last evaluation (9 months after dasatinibwithdrawal), the patient was still in NYHA functional classIII with signs of right heart failure, and brain natriureticpeptide levels were elevated (2134 ng/L, normal value �100ng/L). No right heart catheterization was performed, butDoppler echocardiography showed right ventricular dilata-tion, paradoxical septum, and estimated systolic PAP was70 mm Hg. Even if the cause of death was not directly relatedto pulmonary vascular disease, the presence of severe PHand progressive right heart failure could be at least in partinvolved in the fatal outcome in this patient. Eight monthsafter dasatinib withdrawal, the second patient (patient 9)experienced sudden death a few days after long-distanceairplane flight, a situation at risk in PH patients.2 At 1month after dasatinib withdrawal, this patient had a clini-cal improvement (NYHA functional class I), but no hemo-dynamic evaluation was performed, suggesting that mildlysymptomatic precapillary PH could have been still presentin a patient who presented initially with a mean PAP of45 mm Hg. Because death occurred in a foreign country,no autopsy was performed, and the cause of sudden deathremains uncertain.

Estimates of the Numbers of Patients Exposed toImatinib, Dasatinib, and Nilotinib inFrance (2006–2010)CML is a rare disease with an incidence ranging between 1and 1.5 cases/100 000 per year and an estimated prevalenceof 1/17 000 in France. Imatinib, dasatinib, and nilotinib havebeen available for use in France since February 2002,November 2006, and February 2008, respectively. The pres-ent data were discussed with the Agence Francaise deSecurite Sanitaire des Produits de Sante in November 2010and estimates of TKIs prescription in France between No-vember 1, 2006 and September 30, 2010 were provided byNovartis France and Bristol-Myers-Squibb France (both inRueil Malmaison, France). The numbers of patients treatedby imatinib, dasatinib, and nilotinib in France during thisperiod were 8750 (69.7% of the total number of patientsexposed to one of these TKIs in France), 2900 (23.1%), and900 (7.2%), respectively. All patients with incident PH in ourcase series were receiving dasatinib. Importantly, 13 PHcases (including our 9 cases) were reported to the Frenchpharmacovigilance agency during the same period (online-only Data Supplement Figure II). Thus, the lowest estimate ofincident PH occurring in patients exposed to dasatinib inFrance was 13 of 2900 (0.45%). In contrast, no incident casesof PH associated with imatinib or nilotinib use were reported

Figure 1. Evolution of clinical, functional,and hemodynamic parameters afterdasatinib discontinuation. A, After amedian delay of 15 months (min-max8–36 months) after dasatinib discontinu-ation, improvement of NYHA functionalclass was observed; however, 3 patientsremained symptomatic with functionalclass II or III symptoms at the last evalu-ation and 2 patients died duringfollow-up (after 8 and 12 months). B,Evolution of 6-minute walk distance wasavailable in 6 patients and showed sig-nificant improvement in comparison withbaseline values (P�0.05). C and D, Aninvasive hemodynamic evaluation afterwithdrawal of dasatinib was available for8 patients after a median follow-up of 5months (min-max 3–18). mPAP and PVRsignificantly decreased after dasatinibwithdrawal (P�0.05). Of note, none ofour patients reached a normal hemody-namic status, and mPAP remains ele-vated (�25 mm Hg) in all patients at thelast hemodynamic evaluation. E repre-sent spontaneous evolution of 6-MWDand hemodynamic parameters afterdasatinib withdrawal; F, the 2 patientstreated with endothelin receptor antago-nists; Œ, the patient treated with calciumchannel blockers. NYHA indicates NewYork Heart Association; 6-MWD,6-minute walk distance; mPAP, meanpulmonary artery pressure; PVR, pulmo-nary vascular resistance; ERA, endothe-lin receptor antagonists; CCB, calciumchannel blockers.




during the same period. Concomitantly, 51 PH cases havebeen reported to the pharmacovigilance of Bristol-Myers-Squibb (including 12 cases with right heart catheterization).Based on this information, the French, European, and USdrug agencies have published warnings on the risk of PH inpatients treated with dasatinib in March, July, and October2011, respectively.30–32

DiscussionSince 2008, the French PH Registry has identified 9 incidentcases of symptomatic precapillary PH in patients with hema-tologic malignancies treated with dasatinib. In these patients,no other causes or risk factors for PH were identified andthere was no clinical evidence of PH when dasatinib wasinitiated. However most patients had severe symptoms andmarked hemodynamic compromise at time of PH diagnosis.

As discussed in the updated PH classification, PH withunclear or multiple causes may develop in patients withCML.3,4 One hypothesis is that PH develops merely as aconsequence of the underlying hematologic disorder. How-ever, information from the French PH Registry from 2008 to2010 showed that all incident PH cases reported in CMLpatients and/or patients treated by TKIs occurred only inindividuals receiving dasatinib, which was, in most cases,introduced as a second-line treatment. Another argument infavor of a potential link between PH and dasatinib therapy isthe clinical and hemodynamic improvement usually observedafter dasatinib was replaced by either nilotinib or hydroxy-

carbamide. In the majority of cases, these improvementsoccurred in the absence of specific PAH therapy. The lack ofCML relapse or hemodynamic deterioration following intro-duction of nilotinib therapy, coupled with the lack of cases ofincident PH among CML patients not treated by dasatinib(�75% of CML patients in that period) is highly suggestiveof a causal link between dasatinib and PH. Given theavailability of alternative CML therapeutic strategies and thefact that there was evidence of at least mild persistent PH inall patients, reintroduction of dasatinib was not attempted inany of our patients.

Recent case reports have described the occurrence of PH indasatinib-treated CML patients.14–18 The strength of ourreport is the availability of both a large prospective PHdatabase that allows surveillance of national trends for PHand invasive pulmonary hemodynamic data at baseline andfollowing dasatinib withdrawal. In recent years, this databasehas facilitated the study of PAH occurring in patients exposedto fenfluramine or fenfluramine derivatives such as dexfen-fluramine and benfluorex.33–35 The number of patients inFrance treated by dasatinib was relatively small at the time ofour report (�3000). Thus, the occurrence of 9 incident casesof severe precapillary PH in dasatinib-exposed individualsbetween 2008 and 2010 in our registry plus 4 additional casesreported at the French pharmacovigilance level indicated thatthis complication may affect at least 0.45% of chronicallydasatinib-exposed individuals. Our data indicate that PH

Table 4. Management and Outcomes

PAH TherapyCurrent Therapy for

Hematologic MalignancyShort-Term (�4-mo) Evaluation After

Discontinuation of DasatinibLong-Term (�4 mo) Evaluation After

Discontinuation of Dasatinib

1 6 mo of CCBthen stopped

Nilotinib After 3 mo, NYHA FC I, 6-MWT: 320, mPAP: 42,PVR: 4.6, BNP: 30

After 15 mo, NYHA FC II, 6-MWT: 360, mPAP:30, PVR: 2.6

After 36 mo, NYHA FC II, normalechocardiography

2 No Hydroxycarbamide After 1 mo, NYHA FC II, 6-MWT: 453, mPAP: 31,PVR: 5.9, BNP: 21

After 18 mo, NYHA FC II, 6-MWT: 525, mPAP:28, PVR: 3.5, BNP: 10

3 No Nilotinib After 3 mo, NYHA FC III, mPAP: 35, PVR: 3.9,BNP: 715

After 9 mo, NYHA FC III, echocardiography:right ventricular dilatation, paradoxical, septum,

sPAP: 70, BNP: 2134

Death after 12 mo

4 No Nilotinib After 6 wk, NYHA FC II, 6-MWT: 508, mPAP: 25,PVR: 3.2, BNP �100

After 4 mo, NYHA FC I, 6-MWT: 580, BNP: 30

After 24 mo, NYHA FC I

5 No Hydroxycarbamide After 3 mo, NYHA FC II, 6-MWT: 265, mPAP: 26,PVR: 2.5

After 15 mo, NYHA FC I, 6-MWT: 278, BNP:11, normal echocardiography

6 ERA Nilotinib After 2 mo, NYHA FC III After 6-mo, NYHA FC II, 6-MWT: 430, mPAP:50, PVR: 5


7 No Nilotinib After 1 mo, NYHA FC I, 6-MWT: 544, BNP:36 After 5 mo,NYHA FC I, 6-MWT: 528, mPAP: 25,PVR: 2.9, BNP: 16


8 ERA None After 1 mo, NYHA FC IAfter 12 mo, NYHA FC IAfter 3 mo, NYHA FC I, 6-MWT: 635, mPAP: 25,

PVR: 1.6

9 No Nilotinib After 1 mo, NYHA FC I Sudden death after 8 mo

BNP was expressed as nanograms per liter. BNP indicates brain natriuretic peptide; CCB, calcium channel blocker; ERA, endothelin receptor antagonist; mPAP,mean pulmonary artery pressure; sPAP, systolic pulmonary artery pressure; NYHA FC, New York Heart Association functional class; and 6-MWT, 6-minute walk test.




arises as a late complication of dasatinib therapy, occurringafter 8 to 48 months of exposure, in accordance with previousreports.14–18 One of the common nonhematologic side effectsof dasatinib is fluid retention and pleural effusions, but theunderlying mechanisms remain unclear.11–13 Interestingly, weobserved bilateral pleural effusions in 6 patients; however,severe precapillary PH persisted even after resolution ofpleural effusions. Although PH remains a rare complication,it is important to note that, at this time, dasatinib was licensedonly as a second-line therapy. Recent data suggest thatdasatinib may be used as first-line therapy in CML. There-fore, this agent is likely to become increasingly prescribed inthe future, and the number of cases of dasatinib-induced PHmay increase, particularly with extended duration of therapy.We therefore recommend to screen routinely for PH byechocardiography before commencing dasatinib and to per-form additional diagnostic testing in patients receiving thistherapy who develop dyspnea or other symptoms suggestiveof PH. Where these investigations indicate possible PH, aright heart catheterization is mandatory to confirm the diag-nosis of PH.2

In series reporting dasatinib-associated pleural effusion,sex ratio was consistent with the known sex distribution ofCML (55% of cases occurring in females).11,13 In our series,dasatinib-associated PH, we observed a female predominance(8 females and 1 male), that is in keeping with the femalepredominance characteristic of PAH.36 Estrogen metabolism,which has been potentially implicated in the pathogenesis ofPAH,37 may also be relevant in dasatinib-induced PH. Nev-ertheless, because only a minority of patients exposed todasatinib will develop PH, it is likely that other cofactors arerequired for the development of overt disease. Multiple hitsare indeed likely to trigger the onset of PH, even amongpatients with an obvious predisposing condition, such asBMPR2 mutations.29,38 We screened for BMPR2 mutation in7 patients, and only 1 BMPR2 variant of unknown signifi-cance was found. In the context of cardiotoxicity induced byTKIs, preexisting cardiac conditions predispose to cardiotox-icity.10,39,40 In our series, common cardiovascular risk factorsare not associated with dasatinib-induced PH, and furtherstudies are needed to identify the potential predisposingfactors that could identify patients at high risk of dasatinib-induced PH. Interestingly, clinical, functional, and hemody-namic improvements were generally observed after dasatinibwithdrawal. However, 1 patient died in the context ofrefractory right heart failure and another unexplained suddendeath was reported in our case series. In addition, all subjectsremained at least mildly symptomatic and had a persistentlyabnormal hemodynamic pattern at last follow-up. It is note-worthy that other reports that have suggested a completereversibility of PH have no invasive hemodynamic evaluationat follow-up.14–18 Therefore, longer-term follow-up will berequired to characterize the natural history and outcomes ofdasatinib-induced PH.

Imatinib, dasatinib, and nilotinib are used for the treatmentof CML because of their ability to inhibit the deregulatedBRC-ABL tyrosine kinase.41,42 However, the kinase targetprofiles of these 3 drugs are markedly different (Table 5).43

Recently, the kinase and nonkinase targets of these 3 TKIs

have been characterized showing that dasatinib displayed aless specific target profile than imatinib or nilotinib.44 SeveralTKIs or multiple kinase inhibitors, including imatinib,sorafenib, and sunitinib exhibit cardiotoxicity both in exper-imental models and in humans.39,40,45 Kerkela et al40 demon-strated that the cardiotoxicity of TKIs was an unanticipatedside effect of inhibition of c-Abl, a common characteristics ofTKIs used in the treatment of CML. In addition, Chintalgattuet al46 reported that cardiomyocyte platelet-derived growthfactor receptor-beta is a regulator of the compensatory car-diac response to pressure overload-induced stress, suggestingthat inhibition of platelet-derived growth factor pathway maybe at least in part responsible for cardiotoxicity due to TKIs.Accumulated evidence indicates that receptors of tyrosinekinases (RTKs) play an important role in the pathogenesis ofPAH, and inhibition of some specific RTK signaling mayrepresent an attractive treatment for the disease. RTKs bind totheir ligands with high affinity, and several members of thesecell surface receptors, including receptors of platelet-derivedgrowth factor,21,22 fibroblast growth factor-2,47,48 c-kit,23 andepidermal growth factor,49,50 are involved in the pathogenesisof human and experimental PH. A proof-of-concept 24-weekrandomized, double-blind, placebo-controlled pilot studyshowed that, although imatinib was not associated withsignificant change in the primary end point (6-minute walktest), treatment conferred significant hemodynamic improve-ments.24 It is noteworthy that neither imatinib nor nilotinibhave been associated with incident cases of PH to date, andthe association with dasatinib appears unique and paradoxicalbecause it also acts as a potent RTK inhibitor. Whenanalyzing the complex history of our patients, one cannotexclude that previous exposure to several drugs, such asinterferon �2B, hydroxycarbamide, imatinib, and other che-

Table 5. Targets of Tyrosine Kinases Inhibitors Approved inthe Treatment of CML: Imatinib, Nilotinib, and Dasatinib

Imatinib, Nilotinib Dasatinib

ABL ABL TXK LIMK2

ARG ARG DDR1 MYT1

BCR-ABL BCR-ABL DDR2 PTK6/Brk

KIT KIT ACK QIK

PDGFR PDGFR ACTR2B QSK

DDR1 SRC ACVR2 RAF1

NQO2 YES BRAF RET

FYN EGFR/ERBB1 RIPK2

LYN EPHA2 SLK

HCK EPHA3 STK36/ULK

LCK EPHA4 SYK

FGR EPHA5 TA03

BLK FAK TESK2

FRK GAK TYK2

CSK GCK ZAK

BTK HH498/TNNI3K

TEC ILK

BMX LIMK1

Adapted from Swords et al.43




motherapies, could have played a part in the subsequentdevelopment of PH. However, the previous drug regimen ofour patients did not include the same agents before dasatinibinitiation (Table 1). The rapid relief of symptoms andhemodynamic improvements after withdrawal of dasatinibare consistent with a reversible component. Nevertheless, theabsence of complete resolution observed after dasatinibdiscontinuation suggests some degree of associated pulmo-nary vascular remodeling may develop. In contrast to ima-tinib and nilotinib, dasatinib is a potent inhibitor of additionalimportant families of RTKs, including the Src and the Ephreceptors/ephrin tyrosine kinases (Table 5).43 c-Src tyrosinekinase is abundantly expressed in vascular tissue, and activa-tion of Src appears to play a critical role for smooth musclecell proliferation and vasoconstriction.51 Mounting evidencesuggests a crucial role of c-Src tyrosine kinase in vascularhomeostasis and its direct involvement in PH (Figure 2).51,52

Thus, it would be of interest to investigate the effect onpulmonary vasculature of the inhibition of Src and on the Ephreceptors/ephrin tyrosine kinases, as well, by dasatinib.

In conclusion, we report cases of severe precapillary PHfulfilling the criteria of drug-induced PAH, confirmed bycomplete invasive hemodynamic evaluation, that suggest adirect and specific effect of dasatinib on the pulmonaryvasculature. Although clinical improvement was generallyobserved after withdrawal of dasatinib, some patients re-mained symptomatic and showed persistent hemodynamicimpairment several months after discontinuation of this agent.Even if PH is a rare complication in patients treated withdasatinib, the increased use of dasatinib in the treatment of

CML will certainly increase the number of patients at risk ofdeveloping PH. Physicians need to be aware of this compli-cation to appropriately monitor and manage thesepatients.30–32

AcknowledgmentsThe authors thank Universite Paris-Sud, Assistance Publique-Hopitaux de Paris, and Institut National de la Sante et de laRecherche Medicale (INSERM).

Sources of FundingUniversite Paris-Sud, AP-HP, and INSERM had no direct involve-ment in study design, in the collection, analysis, and interpretation ofdata; in the writing of the report; and in the decision to submit thepaper for publication. All authors had full access to study data andhad final responsibility for the decision to submit for publication.

DisclosuresDrs Montani, Savale, Jaïs, and Sitbon have received speaker fees orhonoraria for consultations from Actelion, Bayer, GSK, Lilly,Novartis, Pfizer and United Therapeutics. Drs Simonneau andHumbert have received speaker fees or honoraria for consultationsfrom Actelion, Bayer, Bristol-Myers-Squib, GSK, Lilly, Novartis,Pfizer and United Therapeutics GZ received reimbursement fromActelion and Lilly for attending French and international meetingsand fees from Bristol-Myers-Squib and Lilly for participating toadvisory boards.

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CLINICAL PERSPECTIVEThe prognosis of chronic myelogenous leukemia has been transformed by tyrosine kinase inhibitors that inhibit BCR/ABLkinase, such as imatinib, dasatinib, and nilotinib. The present report summarizes the clinical characteristics and outcomesof 9 incident cases of severe precapillary pulmonary hypertension (PH) fulfilling the criteria of pulmonary arterialhypertension induced by dasatinib use identified from the French PH registry. PH occurred after 8 to 48 months of dasatinibexposure. Most patients had severe symptoms and marked hemodynamic compromise at time of PH diagnosis. Based onour registry and data from the national pharmacovigilance agency, the lowest estimate of incident PH occurring in patientsexposed to dasatinib in France was 0.45%. Of note, clinical, functional, and hemodynamic improvements were generallyobserved after dasatinib withdrawal. Nevertheless, all subjects remained at least mildly symptomatic and had persistentabnormal hemodynamics. Even if PH is a rare complication in patients treated with dasatinib, the increased use of this agentin the treatment of chronic myelogenous leukemia may result in higher numbers of patients at risk of developingdrug-induced pulmonary arterial hypertension. Physicians need to be aware of this complication to appropriately monitorand manage these patients. We therefore recommend screening routinely for PH by echocardiography before commencingdasatinib and performing additional diagnostic testing in patients developing dyspnea or other symptoms suggestive of PH.Where these investigations indicate possible PH, a right heart catheterization is mandatory to confirm the diagnosis andmechanisms of PH.




1

SUPPLEMENTARY MATERIALS

Supplementary Figure 1. Survival from dasatinib discontinuation of patients with

dasatinib-induced PH.

Two patients (22%) died at follow-up (patients 3 and 9). Patient 3 died of cardiac failure in

the context of septicaemia due to Candida Albicans, 12 months after diagnosis of dasatinib-

induced PH. Of note, this patient was the only case of our series that did not show

improvements after withdrawal of dasatinib and had the most severe hemodynamic

compromise at diagnosis requiring management in intensive care unit with catecholamines.

Eight months after dasatinib withdrawal, patient 9 experienced sudden death several days

after long-distance airplane flight.

Supplementary Figure 2. Occurrence of incident cases of pre-capillary pulmonary

hypertension in subjects treated with tyrosine kinase inhibitors in the French Registry

(2002-2010)

From the approval of dasatinib (November 2006) to 30th September 2010, 9 cases from the

French PH Registry were reported to the French pharmacovigilance agency. Four additional

cases were reported, thus the lowest estimate of incident pre-capillary PH occurring in

patients exposed to dasatinib in France was 13/2,900 (0•45%). Of note, neither imatinib nor

nilotinib have been associated with incident cases of PH to date.



2

Supplementary Figure 1.

Supplementary Figure 2.



Pulmonary Arterial Hypertension in Patients Treated by Dasatinib

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