CASE REPORT

Elevation of pulmonary artery pressure as a complicationof nilotinib therapy for chronic myeloid leukemia

Dariusz Zakrzewski • Ilona Seferynska •

Krzysztof Warzocha • Tomasz Hryniewiecki

Received: 16 February 2012 / Revised: 8 May 2012 / Accepted: 11 May 2012 / Published online: 26 May 2012

� The Japanese Society of Hematology 2012

Abstract We present the case of a 72-year-old male with

chronic phase myeloid leukemia. Elevation of the pul-

monary artery pressure due to nilotinib therapy was noted.

This effect on pulmonary artery pressure was nilotinib dose

dependent.

Keywords Chronic myeloid leukemia � Nilotinib �Pulmonary artery pressure elevation

Nilotinib is a second-generation thyrosine kinase inhibitor

with 30-times greater potency against BCR-ABL fusion

gene than imatinib. Nilotinib is approved as a front-line

therapy in patient with chronic myeloid leukemia (CML)

and second-line in patient resistant or intolerant to imatinib

therapy. The QT interval prolongation and sudden deaths,

probably linked with ventricular repolarization abnormal-

ities, have been observed in patients treated with nilotinib

[1]. No other cardiac related adverse events have been

reported in the literature.

We present 72 years old male with chronic phase CML

diagnosed in June 2010. Patient had a history of arterial

hypertension, successfully treated with metoprolol succi-

nate, amlodipine and ramipril. There was no history of

coronary artery disease and conditions that increase the risk

of it, i.e., diabetes, renal failure, hypercholesterolemia and

tobacco smoking. Patient reported no additional conditions

that may be associated with pulmonary hypertension, i.e.,

lung disease, connective tissue disease, portal hyperten-

sion, HIV infection, congenital heart disease, history of

deep vein thrombosis and history of drugs and toxins

intake.

Front-line treatment for CML was imatinib 400 mg/day.

After 3 months of imatinib therapy complete hematologic

response was achieved but no cytogenetic response was

observed. Second-line treatment with nilotinib was started.

The clinical and echocardiographic evaluation of the

patient was performed prior to initiation of treatment with

nilotinib. Patient was asymptomatic. The blood pressure

was within normal limits. The echocardiographic study

revealed slightly dilated left ventricle and slightly hyper-

trophied walls with posterior wall and interventricular

septum diameters being 12 mm. The left atrium area was

22 cm2. The increased filling pressures was noted with E/

Ea = 16. The systolic function of left ventricle was normal.

The right chamber diameter was normal, with normal

systolic function (Table 1). The baseline plasma level of

N-terminal pro-B-type natriuretic peptide (NT-proBNP)

was 195 pg/ml (normal range 0–125 pg/ml). After 4 weeks

of treatment with nilotinib with standard dose of 800 mg/

day cardiological status of the patient was reassessed.

Patient complained of exercise dyspnoea. The echocar-

diographic study revealed dilated left ventricle with low

filling pressures with E/Ea being 1 and normal systolic

function. The pulmonary artery pressure reached

62 mmHg. The moderate tricuspid valve regurgitation and

dilatation of the right ventricle with its preserved systolic

function was noted (Table 1). The plasma level of NT-

proBNP reached 1269 pg/ml. The oral diuretic was

administered. Treatment with nilotinib was discontinued

because of cytopenia and diagnosis of coexistence of

multiple myeloma. Nine weeks after discontinuation of

D. Zakrzewski (&) � T. Hryniewiecki

Department of Heart Valve Diseases, Institute of Cardiology,

Warsaw, Poland

e-mail: dzakrzewski@ikard.pl

I. Seferynska � K. Warzocha

Department of Hematology, Institute of Hematology and

Transfusiology, Warsaw, Poland

123

Int J Hematol (2012) 96:132–135

DOI 10.1007/s12185-012-1103-0

nilotinib therapy cardiologic assessment of the patient

status was performed again. Patient complained of slight

exercise dyspnoea. The echocardiography showed the right

ventricular systolic pressure decrease to 42 mmHg, with

mild tricuspid regurgitation (Fig. 1). The left ventricle was

slightly dilated with normal systolic function. The E/Ea

index 7 indicated low filling pressures. The right chamber

basal diameter was normal, with normal systolic function

(Table 1). The plasma level of NT-proBNP decreased,

being 272 pg/ml.

The treatment with reduced dose of nilotinib, i.e.,

400 mg/day was restarted after normalization of blood

count. Therapy with thalidomide was also initiated due to

coexistence of multiple myeloma. Enoxaparin was

administered as a prophylaxis of thromboembolic compli-

cations. Patient status was rechecked after 6 weeks of

therapy. Patient presented with moderate exercise dysp-

noea. The echocardiographic study revealed that the pul-

monary artery systolic pressure increased to 50 mmHg,

with more than mild tricuspid regurgitation. The dimension

of the left ventricle was slightly increased and its systolic

function was within normal limits. There was a decrease of

filling pressures with E/Ea index being 1. The right ven-

tricle was slightly dilated with normal systolic function

(Table 1). The plasma level of NT-proBNP reached

460 pg/ml.

The pulmonary hypertension is defined as a detection of

mean pulmonary arterial pressure C25 mmHg at rest dur-

ing right heart catheterization according to European

Society of Cardiology guidelines. The echocardiographic

assessment of pulmonary artery systolic pressure is based

on estimated right atrial pressure and peak tricuspid

regurgitation velocity. However this latter parameter can-

not reliably define the pulmonary pressure as overestima-

tions by[10 mmHg are common in patients with less than

severe tricuspid regurgitation. Therefore, the echocardiog-

raphy is able to establish only the possibility of the pul-

monary hypertension, which is based on arbitrary criteria

of tricuspid regurgitation velocity. Pulmonary hypertension

Table 1 Echocardiographic parameters at baseline, after treatment with nilotinib with normal dose and half dose and after discontinuation of the

drug

Baseline After 4 weeks of treatment

with nilotinib (800 mg/day)

After discontinuation

of nilotinib

After 6 weeks of treatment

with nilotinib (400 mg/day)

LV EDd (mm) 63 64 61 61

LV ESd (mm) 33 48 36 38

MPI 0.33 0.08 0.22 0.20

E/Ea 16 1 7 1

RV basal diameter (mm) 41 43 32 43

TAPSE (mm) 32 23 27 32

Tricuspid regurgitation velocity (m/s) 2.39 3.7 2.9 3.2

PA systolic pressure (mmHg) 26 65 42 50

NYHA class I III II II

NT-proBNP (pg/ml) 195 1269 272 460

LV left ventricle, RV right ventricle, EDd end-diastolic diameter, ESd end-systolic diameter, MPI myocardial performance index of the left

ventricle, E peak early transmitral velocity, Ea Doppler tissue myocardial velocity in early diastole of the mitral annulus, PA pulmonary artery,

TAPSE tricuspid annular plane systolic excursion, NYHA New York Heart Association Functional Classification

Fig. 1 Serial transthoracic echocardiograms show a reduction in

peak tricuspid regurgitation velocity from 3.7 m/s on 800 mg/day of

nilotinib to 2.9 m/s 9 weeks after discontinuation of nilotinib therapy

Elevation of pulmonary artery pressure 133

123

diagnosis is likely if tricuspid regurgitation exceeds 3.4 m/s,

whereas the diagnosis is possible if tricuspid regurgitation

velocity ranges from 2.9 to 3.4 m/s. Nevertheless echo-

cardiographic study allows to serial, non-invasive moni-

toring of pulmonary artery pressure.

This is a first report of the elevation of the pulmonary

artery pressure in patient treated with nilotinib due to

CML. In presented case the right heart catheterization was

not performed and, therefore, the diagnosis of pulmonary

hypertension cannot be established. However the increase

of peak tricuspid regurgitation velocity from baseline 2.3 to

3.7 m/s after 4 weeks of full dose of nilotinib was noted in

echocardiographic study. The discontinuation of nilotinib

resulted in decrease of peak tricuspid regurgitation veloc-

ity to 2.9 m/s that further increased to 3.2 m/s after rein-

troduction of half dose of nilotinib. On the basis of

echocardiographic findings the diagnosis of pulmonary

hypertension is likely in presented case. The baseline

echocardiographic characteristics of the patient showed left

ventricle diastolic dysfunction grade I established on the

basis of decreased Ea \ 10 cm/s, increased left atrium

volume, E/A being 0.8 and deceleration time 262 ms.

Additionally, the left ventricle diameter was mildly

increased with normal myocardial performance index

(MPI) that indicated preserved systolic function. Never-

theless NT-proBNP level above normal limit and increased

filling pressures at baseline may indicate the mild left

ventricle dysfunction. This may result from arterial

hypertension. The influence of the previous imatinib ther-

apy should be also taken into consideration. The incidence

of heart failure due to imatinib therapy varies from 1.7 to

3.8% [2, 3] The mechanism of cardiotoxicity after thyro-

sine kinase inhibitor is related to altered kinase and other

signaling pathways influencing the mitochondrial electron

transport chain and inhibition of AMP-activated protein

kinase that results in ATP depletion [4].

The serial echocardiographic assessment of the filling

pressures showed the significant decrease after nilotinib

therapy with E/Ea ratio being 1. The E/Ea ratio below 8 is

typically seen in patients with pulmonary hypertension

related to pulmonary parenchymal or vascular disease,

whereas increased E/Ea ratio indicates pulmonary hyper-

tension that results from left ventricle dysfunction. Addi-

tionally the echocardiographic study did not show the

deterioration of the left ventricular function on nilotinib

therapy. This is in agreement with previous animal study

that showed no influence of nilotinib on left ventricular

ejection fraction [5]. The dilatation of the left ventricle was

noted in presented case, which may indicate the slight

cardiotoxic effect of the nilotinib normal dose, i.e.,

800 mg/day. This finding was not supported by animal

study that showed no effect of nilotinib on left ventricular

volume and end-diastolic diameter [5]. Nevertheless the

elevation of the pulmonary artery pressure apparently was

not a consequence of a passive response to raised left

ventricular end-diastolic pressure because of the decrease

of filling pressure. The possibility of pulmonary embolism

as a reason of pulmonary artery pressure increase is rather

slight, considering the concomitant, prophylactic anti-

thrombotic treatment with enoxaparin during thalidomide

therapy. The change of pulmonary artery pressure was

nilotinib dose dependent. The highest pulmonary artery

pressure was noted on normal dose of nilotinib, whereas

half of the dose resulted in the intermediate pulmonary

artery pressure. The lowest pulmonary artery pressure after

cessation of nilotinib therapy was observed. Nilotinib

seems to exert the direct influence on pulmonary

circulation.

The pulmonary arterial hypertension and elevation of

brain natriuretic peptide were observed in patients treated

with dasatinib multi-targeted kinase inhibitor of BCR-

ABL. This phenomenon was observed in patient after long-

term treatment with dasatinib [6, 7]. However, the long-

term therapy with reduced dose of dasatinib was also

related to pulmonary arterial hypertension [8, 9] .The res-

olution of pulmonary arterial hypertension was noted sev-

eral weeks after discontinuation of dasatinib and in some

cases after introduction of sildenafil therapy. Dasatinib

inhibits more than 30 kinases and has a less specific target

profile in comparison with nilotinib. However the patho-

physiology of pulmonary arterial hypertension is unclear

[6–9]. The confounding finding is the clinical efficacy of

imatinib in patients with pulmonary arterial hypertension

that was showed in recent study. The significant decrease in

pulmonary vascular resistance (PVR) was noted in imatinib

recipients in comparison with control group [10]. This

phenomenon is linked with the inhibition of platelet-

derived growth factor receptor (PDGFR). PDGF and

PDGFR activate smooth muscle hyperplasia in pulmonary

vessels, therefore may play the significant role in patho-

genesis of pulmonary hypertension. However both nilotinib

and dasatinib boast their ability of PDGFR inhibition.

Therefore, there must be an alternative pathophysiological

path that may promote pulmonary hypertension in some

individuals treated with novel thyrosine kinase inhibitors.

The previous studies showed the link between NT-

proBNP levels and right ventricular function in patients

with pulmonary arterial hypertension [11]. Increases in

NT-proBNP plasma level were linked with the worse

prognosis, whereas the decreasing plasma level indicates

successful pulmonary hypertension management [12]. In

presented case NT-proBNP plasma levels correlated with

pulmonary artery pressure and may be a marker of its

elevation in patient presenting with dyspnoea on nilotnib

therapy. Further studies are required to address this com-

plication in patients treated with nilotinib due to CML.

134 D. Zakrzewski et al.

123

Nevertheless the echocardiographic study should be con-

sidered in patients who present with exercise dyspnoea that

occurred on nilotinib therapy.

Conflict of interest None.

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