Elevation of pulmonary artery pressure as a complication of nilotinib therapy for chronic myeloid...
Transcript of Elevation of pulmonary artery pressure as a complication of nilotinib therapy for chronic myeloid...
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: [email protected]
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
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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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