Biochemical markers and assessment of cardiotoxicity during preparative regimen and hematopoietic cell transplantation in acute leukemia
Introduction: Cardiotoxicity is a relatively frequent and potentially serious complication of antitumor treatment. Anthracyclines and other high-dose chemotherapy represent the greatest risk. The aim of the study was to assess cardiotoxicity during preparative regimen (PR) and hematopoietic cell tra...
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irk-123456789-1385502018-06-21T03:03:33Z Biochemical markers and assessment of cardiotoxicity during preparative regimen and hematopoietic cell transplantation in acute leukemia Horacek, J.M. Pudil, R. Tichy, M. Jebavy, L. Zak, P. Slovacek, L. Maly, J. Original contributions Introduction: Cardiotoxicity is a relatively frequent and potentially serious complication of antitumor treatment. Anthracyclines and other high-dose chemotherapy represent the greatest risk. The aim of the study was to assess cardiotoxicity during preparative regimen (PR) and hematopoietic cell transplantation (HCT) in acute leukemia (AL) with biochemical markers — “N-terminal pro brain natriuretic peptide” (NT-proBNP), cardiac troponin T (cTnT) and creatine kinase MB (CK-MB mass). Methods: Nineteen adult AL patients previously treated with anthracyclines — idarubicine, daunorubicine, mitoxantrone with standard doses for a cycle as 3 х 12 mg/m2, 3 х 50 mg/m2, 3 х 10 mg/m2 accordingly were studied. PR consisted of high-dose cyclophosphamide (HD-C) in combination with busulphan or total body irradiation (TBI). Plasma NT-proBNP, cTnT and CK-MB mass concentrations were measured the day before PR, the day after PR, the day after HCT and 14 days after HCT. Results: Before PR, mean plasma NT-proBNP value was 106.3 ± 55.7 ng/l. After PR, it increased to 426.1 ± 391.5 ng/l. After HCT, a further increase to 847.6 ± 780.6 ng/l was observed. Fourteen days after HCT, the mean NT-proBNP was 330.8±236.8 ng/l. The differences were statistically significant in comparison with the baseline values (p < 0.01). The NT-proBNP elevations were more pronounced in patients with cumulative doses (CD) of anthracyclines above 450 mg/m2 (p < 0.05), in patients with PR containing HD-C and TBI (p < 0.05). In all patients, plasma cTnT and CK-MB mass concentrations remained unchangable during PR and HCT. Conclusion: Our results suggest that administration of PR and HCT is in most AL patients associated with acute neurohumoral activation (significant rise in NT-proBNP). Persistent NT-proBNP elevations, in our study in 12 (63.2 %) patients, indicate subclinical cardiotoxicity (risk for development of heart failure) and require further follow-up. More pronounced NT-proBNP elevations in patients with higher CD of anthracyclines and in patients with PR containing combination of HD-C and TBI confirm that these therapeutic procedures seem to be more cardiotoxic and not very appropriate for patients with cumulation of risk factors for cardiotoxicity. Negative plasma cTnT and CK-MB mass concentrations show no detectable damage of cardiomyocyte structure during PR and HCT. Введение: кардиотоксические осложнения — это относительно частые и потенциально опасные последствия противоопухолевой терапии. Наибольшую кардиотоксичность отмечают при применении высоких доз химиопрепаратов, в частности антибиотиков антрациклинового ряда. Целью данного исследования была оценка кардиотоксичности при лекарственной подготовке пациентов с острым лейкозом (ОЛ) и проведении им трансплантации гематопоэтических стволовых клеток (ГСК), а также определение следующих биохимических маркеров – N-терминального промозгового натрийуретического пептида (NT-proBNP), сердечного тропонина T (cTnT) и креатинкиназы MB (CK-MB). Методы: обследованы 19 взрослых пациентов с ОЛ, прошедших предварительное лечение (ПЛ) с применением антрациклиновых антибиотиков (АА) – идарубицина, даунорубицина, митотриксантрона в дозах 3 х 12 мг/м2 , 3 х 50 мг/м2 , 3 х 10 мг/м2 соответственно. Кроме применения АА, ПЛ включало высокие дозы циклофосфамида (ВД-Ц) в сочетании с бусульфаном или радиолучевой терапией (РЛТ). Концентрацию NT-proBNP, cTnT и CK-MB определяли в плазме крови за день до и через день после проведения ПЛ, а также за день до и через 14 дней после трансплантации ГСК. Результаты: уровень NT-proBNP перед проведением ПЛ составил 106,3 ± 55,7 нг/л, а после повышался до 426,1 ± 391,5 нг/л. После трансплантации ГСК отмечали дальнейшее возрастание исследуемого показателя до 847,6 ± 780,6 нг/л. Через 14 дней после трансплантации ГСК концентрация NT-proBNP достигла 330,8 ± 236,8 нг/л, при этом разница была статистически достоверна по сравнению с исходными значениями (p < 0,01). Повышение уровня NT-proBNP в плазме крови более выражено у пациентов, получавших АА в суммарной дозе (СД) выше 450 мг/м2 (p < 0,05), а также у больных, получавших ВД-Ц и РЛТ (p < 0,05). Концентрация cTnT и CK-MB при проведении ПЛ и трансплантации ГСК не изменялась по отношению к исходному уровню. Выводы: показано, что применение ПЛ и трансплантация ГСК у большинства пациентов с ОЛ сопровождается острой нейрогуморальной активацией, что проявлялось в существенном повышении уровня NT-proBNP. Постоянно высокий уровень NTproBNP, отмеченный у 12 (63,2%) пациентов, свидетельствует о бессимптомной кардиотоксичности (риске развития сердечной недостаточности) и требует последующего врачебного наблюдения больных. Более выраженное повышение уровня NT-proBNP у пациентов с более высокой СД АА и у больных, получавших ВД-Ц и РЛТ, свидетельствует о том, что такое лечение является более кардиотоксичным и не рекомендовано для применения в случае наличия факторов риска проявления кардиотоксичности. 2007 Article Biochemical markers and assessment of cardiotoxicity during preparative regimen and hematopoietic cell transplantation in acute leukemia / J.M. Horacek, R. Pudil, M. Tichy, L. Jebavy, P. Zak, L. Slovacek, J. Maly // Experimental Oncology. — 2007. — Т. 29, № 3. — С. 243–247. — Бібліогр.: 26 назв. — англ. 1812-9269 http://dspace.nbuv.gov.ua/handle/123456789/138550 en Experimental Oncology Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
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Original contributions Original contributions Horacek, J.M. Pudil, R. Tichy, M. Jebavy, L. Zak, P. Slovacek, L. Maly, J. Biochemical markers and assessment of cardiotoxicity during preparative regimen and hematopoietic cell transplantation in acute leukemia Experimental Oncology |
| description |
Introduction: Cardiotoxicity is a relatively frequent and potentially serious complication of antitumor treatment. Anthracyclines and other high-dose chemotherapy represent the greatest risk. The aim of the study was to assess cardiotoxicity during preparative regimen (PR) and hematopoietic cell transplantation (HCT) in acute leukemia (AL) with biochemical markers — “N-terminal pro brain natriuretic peptide” (NT-proBNP), cardiac troponin T (cTnT) and creatine kinase MB (CK-MB mass). Methods: Nineteen adult AL patients previously treated with anthracyclines — idarubicine, daunorubicine, mitoxantrone with standard doses for a cycle as 3 х 12 mg/m2, 3 х 50 mg/m2, 3 х 10 mg/m2 accordingly were studied. PR consisted of high-dose cyclophosphamide (HD-C) in combination with busulphan or total body irradiation (TBI). Plasma NT-proBNP, cTnT and CK-MB mass concentrations were measured the day before PR, the day after PR, the day after HCT and 14 days after HCT. Results: Before PR, mean plasma NT-proBNP value was 106.3 ± 55.7 ng/l. After PR, it increased to 426.1 ± 391.5 ng/l. After HCT, a further increase to 847.6 ± 780.6 ng/l was observed. Fourteen days after HCT, the mean NT-proBNP was 330.8±236.8 ng/l. The differences were statistically significant in comparison with the baseline values (p < 0.01). The NT-proBNP elevations were more pronounced in patients with cumulative doses (CD) of anthracyclines above 450 mg/m2 (p < 0.05), in patients with PR containing HD-C and TBI (p < 0.05). In all patients, plasma cTnT and CK-MB mass concentrations remained unchangable during PR and HCT. Conclusion: Our results suggest that administration of PR and HCT is in most AL patients associated with acute neurohumoral activation (significant rise in NT-proBNP). Persistent NT-proBNP elevations, in our study in 12 (63.2 %) patients, indicate subclinical cardiotoxicity (risk for development of heart failure) and require further follow-up. More pronounced NT-proBNP elevations in patients with higher CD of anthracyclines and in patients with PR containing combination of HD-C and TBI confirm that these therapeutic procedures seem to be more cardiotoxic and not very appropriate for patients with cumulation of risk factors for cardiotoxicity. Negative plasma cTnT and CK-MB mass concentrations show no detectable damage of cardiomyocyte structure during PR and HCT. |
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Article |
| author |
Horacek, J.M. Pudil, R. Tichy, M. Jebavy, L. Zak, P. Slovacek, L. Maly, J. |
| author_facet |
Horacek, J.M. Pudil, R. Tichy, M. Jebavy, L. Zak, P. Slovacek, L. Maly, J. |
| author_sort |
Horacek, J.M. |
| title |
Biochemical markers and assessment of cardiotoxicity during preparative regimen and hematopoietic cell transplantation in acute leukemia |
| title_short |
Biochemical markers and assessment of cardiotoxicity during preparative regimen and hematopoietic cell transplantation in acute leukemia |
| title_full |
Biochemical markers and assessment of cardiotoxicity during preparative regimen and hematopoietic cell transplantation in acute leukemia |
| title_fullStr |
Biochemical markers and assessment of cardiotoxicity during preparative regimen and hematopoietic cell transplantation in acute leukemia |
| title_full_unstemmed |
Biochemical markers and assessment of cardiotoxicity during preparative regimen and hematopoietic cell transplantation in acute leukemia |
| title_sort |
biochemical markers and assessment of cardiotoxicity during preparative regimen and hematopoietic cell transplantation in acute leukemia |
| publisher |
Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
| publishDate |
2007 |
| topic_facet |
Original contributions |
| url |
http://dspace.nbuv.gov.ua/handle/123456789/138550 |
| citation_txt |
Biochemical markers and assessment of cardiotoxicity during preparative regimen and hematopoietic cell transplantation in acute leukemia / J.M. Horacek, R. Pudil, M. Tichy, L. Jebavy, P. Zak, L. Slovacek, J. Maly // Experimental Oncology. — 2007. — Т. 29, № 3. — С. 243–247. — Бібліогр.: 26 назв. — англ. |
| series |
Experimental Oncology |
| work_keys_str_mv |
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2025-07-10T06:02:07Z |
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2025-07-10T06:02:07Z |
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| fulltext |
Experimental Oncology ���� ��������� ���� ��eptem�er�� ������� ��������� ���� ��eptem�er�� ����eptem�er�� ����� ��� ���
Cardiotoxicity is a well-known and potentially serious
complication of antitumor treatment. The greatest risk for
development of carditoxicity represent anthracyclines [1]
and high-dose chemotherapy �HD-CT�� especially regi-
mens containing high-dose cyclophosphamide [��5].
Myeloa�lative preparative regimen �PR�� in acute
leukemia �AL�� contains high-dose cyclophosphamide
in total dose of 1�� mg/kg �HD-C���� in some cases in
com�ination with fractionated total �ody irradiation �TBI��
1� Gy. This is followed �y hematopoietic cell transplanta-
tion �HCT��. Moreover�� these patients are pretreated with
conventional chemotherapy �CT�� containing anthracy-
clines in a relatively high cumulative dose �CD��. All of
these therapeutic procedures are potentially cardiotoxic
and require thorough monitoring of cardiac functions
during the treatment �acute cardiotoxicity�� and after its
completion �chronic and late cardiotoxicity��.
Various methods have �een recommended for
monitoring of cardiotoxicity [6�8]. In our conditions��
echocardiography and electrocardiography are rou-
tinely used. Recently�� �iochemical markers of cardiac
damage�� especially natriuretic peptides and cardiac
troponins�� are gaining ground in this field [�].
Natriuretic peptides � atrial natriuretic peptide �ANP����
�rain natriuretic peptide �BNP�� and N-terminal pro �rain
natriuretic peptide �NT-proBNP�� — are produced �y
myocardium in response to wall strain and pressure
overload [1�]. ANP is produced mainly in atria�� BNP/
NT-proBNP predominantly in ventricles. In cardiology��
natriuretic peptides are routinely used in diagnostics
of heart failure [11]. Normal plasma BNP/NT-proBNP
concentrations practically exclude heart failure due to
high negative predictive value of the test [1�].
Cardiac troponins — cardiac troponin T �cTnT���� car-
diac troponin I �cTnI�� — and myocardial izoenzyme of
BIOCHEMICAL MARKERS AND ASSESSMENT OF CARDIOTOXICITY
DURING PREPARATIVE REGIMEN AND HEMATOPOIETIC CELL
TRANSPLANTATION IN ACUTE LEUKEMIA
J.M. Horacek1, 4, *, R. Pudil2, M. Tichy3, 4, L. Jebavy1, 4, P. Zak1, L. Slovacek1, 4, J. Maly1
12nd Department of Medicine — Clinical Hematology, University Hospital and Charles University, Faculty
of Medicine in Hradec Kralove, Czech Republic
21st Department of Medicine, University Hospital and Charles University,
Faculty of Medicine in Hradec Kralove, Czech Republic
3Institute of Clinical Biochemistry and Diagnostics, University Hospital and Charles University,
Faculty of Medicine in Hradec Kralove, Czech Republic
4Department of Internal Medicine, University of Defence,
Faculty of Military Health Sciences in Hradec Kralove, Czech Republic
Introduction: Cardiotoxicity is a relatively frequent and potentially serious complication of antitumor treatment. Anthracyclines and other
high-dose chemotherapy represent the greatest risk. The aim of the study was to assess cardiotoxicity during preparative regimen (PR) and
hematopoietic cell transplantation (HCT) in acute leukemia (AL) with biochemical markers — “N-terminal pro brain natriuretic peptide”
(NT-proBNP), cardiac troponin T (cTnT) and creatine kinase MB (CK-MB mass). Methods: Nineteen adult AL patients previously
treated with anthracyclines — idarubicine, daunorubicine, mitoxantrone with standard doses for a cycle as 3 х 12 mg/m2, 3 х 50 mg/m2,
3 х 10 mg/m2 accordingly were studied. PR consisted of high-dose cyclophosphamide (HD-C) in combination with busulphan or total
body irradiation (TBI). Plasma NT-proBNP, cTnT and CK-MB mass concentrations were measured the day before PR, the day after
PR, the day after HCT and 14 days after HCT. Results: Before PR, mean plasma NT-proBNP value was 106.3 ± 55.7 ng/l. After PR, it
increased to 426.1 ± 391.5 ng/l. After HCT, a further increase to 847.6 ± 780.6 ng/l was observed. Fourteen days after HCT, the mean
NT-proBNP was 330.8±236.8 ng/l. The differences were statistically significant in comparison with the baseline values (p < 0.01). The
NT-proBNP elevations were more pronounced in patients with cumulative doses (CD) of anthracyclines above 450 mg/m2 (p < 0.05), in
patients with PR containing HD-C and TBI (p < 0.05). In all patients, plasma cTnT and CK-MB mass concentrations remained unchang-
able during PR and HCT. Conclusion: Our results suggest that administration of PR and HCT is in most AL patients associated with acute
neurohumoral activation (significant rise in NT-proBNP). Persistent NT-proBNP elevations, in our study in 12 (63.2 %) patients, indicate
subclinical cardiotoxicity (risk for development of heart failure) and require further follow-up. More pronounced NT-proBNP elevations in
patients with higher CD of anthracyclines and in patients with PR containing combination of HD-C and TBI confirm that these therapeutic
procedures seem to be more cardiotoxic and not very appropriate for patients with cumulation of risk factors for cardiotoxicity. Negative
plasma cTnT and CK-MB mass concentrations show no detectable damage of cardiomyocyte structure during PR and HCT.
Key Words: cardiotoxicity, biochemical markers, transplantation, acute leukemia.
Received: July 2, 2007.
*Correspondence: E-mail: jan.hor@post.cz
Abbreviations: AL – acute leukemia; ANP – atrial natriuretic
peptide; BNP – brain natriuretic peptide; CD – cumulative
dose; CK-MB mass – creatine kinase MB; CT – chemotherapy;
cTnI – cardiac troponin I; cTnT – cardiac troponin T; DT – decele-
ration time; ECHO – echocardiography; EF – ejection fraction;
HCT – hematopoietic cell transplantation; HD-C – high-dose
cyclophosphamide; HD-CT – high-dose chemotherapy; LV – left
ventricular; NT-proBNP – N-terminal pro brain natriuretic peptide;
PR – preparative regimen; TBI – total body irradiation.
Exp Oncol ����
���� ��� �������
��� Experimental Oncology ���� ��������� ���� ��eptem�er��
creatine kinase �CK-MB�� are cardiospecific markers that
show structural damage of cardiomyocytes from various
causes�� including cardiotoxic effect of CT [1�].
Assessment of cardiotoxicity of HD-CT with �io-
chemical markers of structural or functional myocardial
damage was the aim of only a few studies from recent
time. In some studies�� cardiac troponins [1��16] and
natriuretic peptides [1��1�] were suggested as predic-
tors of late cardiac dysfunction after HD-CT and HCT.
In these studies�� different types of HD-CT were used in
various�� not only hematological malignancies. Accord-
ing to availa�le literature�� monitoring and comparison
of acute cardiotoxicity of PR used in AL was not the
su�ject of any study so far.
The aim of the presented study was to assess
cardiotoxicity during PR and HCT in AL with �iochemi-
cal markers � NT-proBNP�� cTnT�� CK-MB mass — and
echocardiography �ECHO��. We compared cardiotoxici-
ty of two myeloa�lative PR used in AL. We assessed
the impact of prior anthracycline treatment on plasma
concentrations of �iochemical markers of cardiac
damage in the peritransplant period.
METHODS
Patients. Nineteen consecutive adult patients with
AL were studied. The patients consisted of 1� males and
6 females with the mean age of ��.8 ± 1�.� years �range:
���56��. Four of the patients were treated for arterial hy-
pertension�� the other patients had no known pre-existing
cardiovascular disease. Renal and liver functions were nor-
mal in all patients. The patients were treated with conven-
tional CT containing anthracyclines in total CD of ��6.� ±
�1.6 mg/m� �range: ����6����. To calculate the total CD
of anthracyclines�� we applied conversion factors derived
from the maximum recommended cumulative doses for
individual agents used �idaru�icine�� daunoru�icine and
mitoxantrone��. The standard doses for a cycle of chemo-
therapy were: idaru�icine � x 1� mg/m��� daunoru�icine � x
5� mg/m��� mitoxantrone � x 1� mg/m�. In all patients�� PR
consisted of intravenous Cyclophosphamide in total dose
of 1�� mg/kg �HD-C���� in 1� patients in com�ination with
peroral Busulphan 16 mg/kg �Bu/HD-C�� and in 6 patients
in com�ination with fractionated total �ody irradiation
1� Gy �TBI/HD-C��. In all cases�� cryopreserved peripheral
�lood stem cells were used as the source for HCT. Ten
patients were given allogeneic grafts and � autologous
grafts. The study was approved �y the local ethical com-
mittee. All patients gave a written consent �efore they were
included in the study.
Biochemistry. �erial measurements of plasma
NT-proBNP�� cTnT and CK-MB mass concentrations
were performed the day �efore PR�� the day after PR��
the day after HCT and 1� days after HCT�� i. e. at the
time of �one marrow recovery.
Venous �lood samples were o�tained from an indwell-
ing catheter after �� min of rest in supine position. The
�lood samples were withdrawn into chilled tu�es contain-
ing EDTA. The whole �lood was immediately centrifuged��
the plasma was decanted�� frozen and stored at ��� °C until
assayed. Plasma concentrations of �iochemical markers
were measured �y electrochemiluminescence immuno-
assay on Elecsys 1�1� analyzer �Roche Diagnostics��.
Based on a num�er of studies�� NT-proBNP values
�ellow 1�� ng/l for male�� 15� ng/l for female are con-
sidered normal and allow to rule out heart failure due
to high negative predictive value of the test [1��� ��].
We used these cut-off values for cardiac dysfunction.
Values a�ove cut-off respecting gender �1�� ng/l for
male�� 15� ng/l for female�� were considered elevated��
NT-proBNP concentrations a�ove 5�� ng/l were conside-
red markedly elevated. Elevated NT-proBNP concentra-
tions in association with the given treatment show func-
tional myocardial damage and are a sign of toxic effect
of the treatment on myocardium. CTnT concentrations
a�ove �.�1 µg/l and CK-MB mass concentrations a�ove
�.�� µg/l were taken as elevated and showing structural
damage of cardiomyocytes caused �y the treatment.
Echocardiography. ECHO was performed �efore PR
and in the early period after HCT �within � days after HCT��.
The ECHO evaluation was done with Hewlett Packard Im-
age Point ultrasound �y an experienced echocardiogra-
phist. Parameters of systolic and diastolic left ventricular
�LV�� function and presence of pericardial effusion were as-
sessed. In the study�� systolic LV dysfunction was defined as
ejection fraction �EF�� �ellow 55%. Diastolic LV dysfunction
was defined as E/A inversion and deceleration time �DT��
a�ove ��� ms on the transmitral Doppler curve �impaired
relaxation��. Pericardial effusion was defined as separation
of pericardial leaves at least � mm in systole.
Statistical analysis was performed with the “�ta-
tistica for Windows�� Version 5.�” program. Analysis
of variance �ANOVA���� paired two tailed t-tests and
McNemar tests were used. Correlations were evaluated
with normal and �pearman correlation tests. The values
are expressed as mean ± �D. Pro�a�ility values < �.�1
and < �.�5 were considered statistically significant.
RESULTS AND DISCUSSION
�ignificance of NT-proBNP for evaluation of cardio-
toxicity. The day �efore PR�� mean plasma NT-proBNP
concentration was 1�6.� ± 55.� ng/l �slightly elevated
in � patients��. The mean NT-proBNP concentration in-
creased to ��6.1 ± ��1.5 ng/l �elevated in 1� patients��
markedly elevated in 5 patients�� after completion of
PR. After HCT�� a further increase to 8��.6 ± �8�.6 ng/l
�elevated in 1� patients�� markedly elevated in � patients��
was o�served. At the time of �one marrow recovery
�1� days after HCT���� the mean NT-proBNP concentra-
tion was ���.8 ± ��6.8 ng/l. Values remained elevated
in 1� �6�.�%�� patients�� markedly elevated in 5 ��6.� %��
patients. The differences were statistically significant
in comparison with the �aseline NT-proBNP value �p <
�.�1�� Fig. 1��. The NT-proBNP elevations were more
pronounced in patients with CD of anthracyclines a�ove
�5� mg/m� �p < �.�5���� in patients with PR containing
TBI and HD-C �p < �.�5�� Fig. � and ���. The changes in
NT-proBNP concentrations were not significantly dif-
ferent after infusion of allogeneic or autologous grafts.
Associations �etween changes in NT-proBNP concentra-
Experimental Oncology ���� ��������� ���� ��eptem�er�� ��5���� ��������� ���� ��eptem�er�� ��5�eptem�er�� ��5�� ��5 ��5
tions and gender�� age or history of arterial hypertension
were not significant.
Fig. 1. Plasma NT-proBNP concentrations in the peritransplant
period in AL patients. *p < �.�1 vs �efore PR.
Fig. 2. Plasma NT-proBNP concentrations in the peritransplant
period according to CD of anthracyclines. �p < �.�5��
Fig. 3. Plasma NT-proBNP concentrations in the peritransplant
period according to PR. �p < �.�5��
Explanatory notes to Fig. 1��: �efore PR — the day �efore initia-
tion of preparative regimen�� after PR — the day after completion
of preparative regimen�� after HCT — the day after hematopoietic
cell transplantation �graft infusion���� day + 1� — 1� days after
hematopoietic cell transplantation ��one marrow recovery��.
�lightly elevated NT-proBNP concentrations �efore
PR were in � ��1.1%�� patients. These elevations were likely
caused �y prior anthracycline-�ased CT. More pronounced
NT-proBNP elevations in patients with higher CD of anthra-
cyclines and in patients with PR containing com�ination of
HD-CT and radiotherapy suggest that these therapeutic
procedures are associated with higher myocardial strain��
and thus seem to �e more cardiotoxic. In our previously
pu�lished study�� we proved that solely intravenous hydra-
tion in AL patients does not lead to significant increase in
NT-proBNP concentrations [�1]. In the study of �nowden
et al.�� administration of PR containing HD-C was associated
with higher NT-proBNP elevation than other PR [1�]. �o far��
there are no other studies comparing acute cardiotoxicity
of different PR �y means of natriuretic peptides.
Three studies from recent time have dealt with the
assessment of cardiotoxicity of HD-CT and HCT [1��1�].
In these studies�� most patients had significant elevations
in BNP/NT-proBNP after HD-CT and HCT. Persistent NT-
proBNP elevations were o�served in �����% patients.
During follow-up�� the patients with persistent BNP/
NT-proBNP elevations had more often cardiac dysfunction
than the other patients. The results show that monitoring
of BNP/NT-proBNP could identify patients at risk for deve-
lopment of cardiac dysfunction after HD-CT and HCT.
In our patients�� elevated NT-proBNP concentrations
1� days after HCT were found in a higher percentage of
patients than in the study of Niwa et al — 6�.�% versus
�5.6% [18]. This difference could �e explained �y rela-
tively high CD of anthracyclines in our patients — even
�efore PR �1.1% patients had a slightly elevated
NT-proBNP. The results can �e influenced �y the num-
�er of patients took that part in the study.
In the peritransplant period�� one �5.�%�� of the
patients developed manifestation of cardiotoxicity —
clinical signs of heart failure�� mild systolic dysfunc-
tion �EF 5�%���� NT-proBNP concentrations 65�.� ng/l
�after PR�� and ���8.� ng/l �after HCT��. In this patient��
�aseline NT-proBNP was �1�.� ng/l�� which was �y far
the highest value in the group. This patient had CD of
anthracyclines a�ove the maximum recommended CD
�55� mg/m����� PR contained com�ination of TBI and
HD-C and allogeneic HCT was performed.
Cardiospecific markers �cTnT and CK-MB mass��. There
were no differences in plasma level of cTnT and CK-MB mass
during the PR and HCT�� which earlier considered as showing
no detecta�le damage of cardiomyocyte structure �Ta�le 1��.
However�� cTnT is pro�a�ly not the most sensitive marker for
cardiac damage caused �y oncology treatment.
Table 1. Plasma concentrations of cardiospecific markers in the peritrans-
plant period in AL patients
Cardiospecific markers Before PR After PR After HCT Day +14 p
cTnT [µg/l] < 0.01 < 0.01 < 0.01 < 0.01 NS
CK-MB mass [µg/l] 1.094 ±
0.511
1.218 ±
0.418
1.183 ±
0.346
1.117 ±
0.472
NS
Measurement of cardiac troponins is a very sensitive
method that is a�le to detect a minimal damage of cardio-
myocytes after HD-CT [15�� ��]. In the recently pu�lished
study �y Cardinale et al.�� cTnI positivity �≥ �.�8 µg/l��
within �� h after HD-CT was seen in nearly ��% of on-
cology patients. CTnI positivity was associated with a
significantly higher decrease in LV EF and other cardiac
events during �-year follow-up [16].
Assessment of cTnT and cTnI is for clinical use
equivalent. However�� only assessment of cTnT is stan-
dardized at present [��]. According to the results of
Cardinale et al.�� we would expect at least low positivity of
cTnT in a�out 5 patients. Despite using a highly sensitive
assay on cTnT with sensitivity of �.�1 µg/l�� we did not find
cTnT positivity in any of our patients after PR and HCT.
This finding is in concordance with the study of Auner
et al.�� in which administration of HD-C and TBI 1� Gy did
not lead to elevation of cTnT in any of �� hematooncolo-
gy patients [��]. Either in the study of Benvenuto et al.��
administration of HD-C caused no elevation in cTnI [�5].
At present�� routine use of cardiac troponins for monitor-
��6 Experimental Oncology ���� ��������� ���� ��eptem�er��
ing of cardiotoxicity of antitumorous treatment cannot
�e esta�lished to clinical practice due to disunity of the
availa�le assays �lack of standardization�� and inconsis-
tence of results. The timing of sample collection and
determination of cut-off value for treatment-related
cardiotoxicity may play an important role.
Echocardiography. Changes in ECHO parameters
during the peritransplant period are shown in Ta�le �.
Correlations �etween plasma NT-proBNP concentra-
tions and ECHO parameters did not reach statistical sig-
nificance.In the early period after PR and HCT�� we found
a decrease in systolic LV function �LV EF 6�.� ± 1.�%
vs 61.� ± �.5%���� which was statistically significant �p <
�.�5��. In 1 �5.�%�� of the patients�� a decrease in LV EF
function more than 1�% with symptoms of heart failure
developed. In the other patients�� LV EF remained within
normal range �a�ove 55%��. After PR and HCT�� diastolic
LV dysfunction newly appeared in � patients and small
pericardial effusion in � patients. These changes in
ECHO parameters are caused �y com�ination of acute
impact of PR and HCT and influence of the prior anthra-
cycline treatment. Newly developed pericardial effusion
after PR and HCT in � �1�.5%�� patients and presence
of pericardial effusion altogether in 6 ��1.6%�� is lower
than pu�lished in the literature. After PR containing
HD-C�� pericardial effusion has �een reported in up to
�� % of patients [�6].
Table 2. Abnormal ECHO findings in the peritransplant period in AL patients
Abnormal ECHO findings Before PR and HCT After PR and HCT p
Systolic LV dysfunction 0 1 (5.3%) NS
Diastolic LV dysfunction 3 (15.8%) 6 (31.6%) NS
Pericardial effusion 4 (21.1%) 6 (31.6%) NS
We are aware that our results are partially limited �y
the num�er of patients participating in the study and a
relatively short period of the follow-up. These findings
require a further prospective follow-up and confirming in
further studies in a larger num�er of patients. Long-term
cardiology follow-up is warranted in all oncology patients
treated with anthracyclines and HD-CT followed �y HCT.
Our results show that administration of PR and HCT
is in most AL patients associated with acute neurohu-
moral activation �significant rise in NT-proBNP��. In our
study�� NT-proBNP remained elevated in 1� �6�.�%��
patients at the time of �one marrow recovery. These
persistent NT-proBNP elevations indicate su�clinical
cardiotoxicity �risk for development of heart failure�� and
require further follow-up. NT-proBNP elevations were
significantly more pronounced in patients with higher
CD of anthracyclines and in patients with PR containing
com�ination of radiotherapy and HD-CT. Thus�� these
therapeutic procedures seem to �e more cardiotoxic
and not very appropriate for patients with cumulation of
risk factors for cardiotoxicity. Predictive value of these
changes is not clear and must �e yet determined.
Administration of PR and HCT may lead to manifes-
tation of cardiotoxicity — in our study in 1 �5.�%�� of the
patients. Development of acute heart failure in the patient
with the highest �aseline NT-proBNP concentration sug-
gests that implementation of NT-proBNP to commonly
performed pretransplant cardiac examinations could
�e useful in the identification of patients at high risk for
development of cardiotoxicity in terms of heart failure and
in the early diagnostics of cardiac dysfunction in the peri-
transplant period. Relatively high price of this assay and
necessity of repeated measurements remains the limita-
tion for implementation to routine clinical practice.
In our study�� negative plasma cTnT and CK-MB mass
concentration show no detecta�le damage of cardio-
myocyte structure during PR and HCT. Thus�� routine
measurement of these cardiospecific markers in the
peritransplant period in asymptomatic patients does not
seem to �e of value in the detection of cardiotoxicity.
However�� further studies using more sensitive markers
of cardiac damage �such as ischemia modified al�umin��
fatty acid �inding protein�� glycogen phosphorylase BB��
could �ring a new view on this issue.
Cardiotoxicity of oncology treatment develops
mainly in the com�ination of more potentially cardiotoxic
procedures�� as in case of AL treatment. Cardiotoxicity
is a serious interdisciplinary pro�lem that requires co-
operation of an oncologist with a cardiologist.
ACKNOWLEDGEMENTS
The work was supported �y research projects
MO �FVZ ����5�� �Czech Ministry of Defence�� and
M�M ���16��81� �Czech Ministry of Education��.
REFERENCES
1. Shan K, Lincoff AM, Young JB. Anthracycline-induced
cardiotoxicity. Ann Intern Med 1996; 125: 47–58.
2. Gottdiener JS, Appelbaum FR, Ferrans VJ, Deisseroth A,
Ziegler J. Cardiotoxicity associated with high dose cyclophos-
phamide therapy. Arch Intern Med 1981; 141: 758–63.
3. Goldberg MA, Antin JH, Guinan EC, Rappeport JM.
Cyclophosphamide cardiotoxicity: an analysis of dosing as a
risk factor. Blood 1986; 68: 1114–8.
4. Morandi P, Ruffini PA, Benvenuto GM, Raimondi R,
Fosser V. Cardiac toxicity of high-dose chemotherapy. Bone
Marrow Transplant 2005; 35: 323–34.
5. Yeh ET, Tong AT, Lenihan DJ, Yusuf SW, Swafford J,
Champion C, Durand JB, Gibbs H, Zafarmand AA, Ewer MS.
Cardiovascular complications of cancer therapy: diagnosis, patho-
genesis and management. Circulation 2004; 109: 3122–31.
6. Ganz WI, Sridhar KS, Ganz SS, Gonzalez R, Chakko S,
Serafini A. Review of tests for monitoring doxorubicin-induced
cardiomyopathy. Oncology 1996; 53: 461–70.
7. Meinardi MT, van der Graaf WT, van Veldhuisen DJ, Gie-
tema JA, de Vries EG, Sleijfer DT. Detection of anthracycline-
induced cardiotoxicity. Cancer Treat Rev 1999; 25: 237–47.
8. Elbl L, Vasova I, Kral Z, Tomaskova I, Smardova L, Wag-
nerova B, Jedlicka F, Vorlicek J. Evaluation of acute and early car-
diotoxicity in survivors of Hodgkin’s disease treated with ABVD
or BEACOPP regimens. J Chemother 2006; 18: 199–208.
9. Sparano JA, Brown DL, Wolff AC. Predicting cancer
therapy-induced cardiotoxicity. The role of troponins and
other markers. Drug Saf 2002; 25: 301–11.
10. Yasue H, Yoshimura M, Sumida H, Kikuta K, Kugiya-
ma K, Jougasaki M, Ogawa H, Okumura K, Mukoyama M,
Nakao K. Localization and mechanism of secretion of B-type
natriuretic peptide in comparison with those of A-type natri-
uretic peptide in normal subjects and patients with heart failure.
Circulation 1994; 90: 195–203.
11. Remme WJ, Swedberg K. Guidelines for the diagnosis
and treatment of chronic heart failure. Eur Heart J 2001;
22: 1527–60.
Experimental Oncology ���� ��������� ���� ��eptem�er�� ������� ��������� ���� ��eptem�er�� ����eptem�er�� ����� ��� ���
12. Cowie MR, Jourdain P, Maisel A, Dahlstrom U, Follath F,
Isnard R, Luchner A, McDonagh T, Mair J, Nieminen M, Fran-
cis G. Clinical application of B-type natriuretic peptide (BNP)
testing. Eur Heart J 2003; 24: 1710–8.
13. De Lemos JA, Morrow DA. Combining natriuretic pep-
tides and necrosis markers in the assessment of acute coronary
syndromes. Rev Cardiovasc Med 2003; 4 (Suppl 4): 37–46.
14. Cardinale D, Sandri MT, Martinoni A, Tricca A, Civelli M,
Lamantia G, Cinieri S, Martinelli G, Cipolla CM, Fiorentini C. Left
ventricular dysfunction predicted by early troponin I release after
high-dose chemotherapy. J Am Coll Cardiol 2000; 36: 517–22.
15. Sandri MT, Cardinale D, Zorzino L, Passerini R, Lentati P,
Martinoni A, Martinelli G, Cipolla CM. Minor increases in plasma
troponin I predict decreased left ventricular ejection fraction after
high-dose chemotherapy. Clin Chem 2003; 49: 248–52.
16. Cardinale D, Sandri MT, Colombo A, Colombo N,
Boeri M, Lamantia G, Civelli M, Peccatori F, Martinelli G,
Fiorentini C, Cipolla CM. Prognostic value of troponin I in
cardiac risk stratification of cancer patients undergoing high-
dose chemotherapy. Circulation 2004; 109: 2749–54.
17. Snowden JA, Hill GR, Hunt P, Carnoutsos S, Spear-
ing RL, Espiner E, Hart DN. Assessment of cardiotoxicity during
haemopoietic stem cell transplantation with plasma brain natriu-
retic peptide. Bone Marrow Transplant 2000; 26: 309–13.
18. Niwa N, Watanabe E, Hamaguchi M, Kodera Y, Miya-
zaki H, Kodama I, Ohono M. Early and late elevation of plasma
atrial and brain natriuretic peptides in patients after bone mar-
row transplantation. Ann Hematol 2001; 80: 460–5.
19. Sandri MT, Salvatici M, Cardinale D, Zorzino L,
Passerini R, Lentati P, Leon M, Civelli M, Martinelli G,
Cipolla CM. N-terminal pro-B-type natriuretic peptide after
high-dose chemotherapy: a marker predictive of cardiac dys-
function? Clin Chem 2005; 51: 1405–10.
20. Hess G, Runkel S, Zdunek D, Hitzler WE. N-terminal
pro-brain natriuretic peptide (NT-proBNP) in healthy blood
donors and in patients from general practitioners with and with-
out a diagnosis of cardiac disease. Clin Lab 2005; 51: 167–72.
21. Horacek JM, Pudil R, Jebavy L, Strasová A, Praus R, Zák P,
Malý J. The use of biochemical markers in cardiotoxicity monitor-
ing in patients treated for leukemia. Neoplasma 2005; 52: 430–4.
22. Adamcova M, Sterba M, Simunek T, Potacova A,
Popelova O, Mazurova Y, Gersl V. Troponin as a marker of
myocardiac damage in drug-induced cardiotoxicity. Expert
Opin Drug Saf 2005; 4: 457–72.
23. Panteghini M. The measurement of cardiac markers:
where should we focus? Am J Clin Pathol 2002; 118: 354–61.
24. Auner HW, Tinchon C, Brezinschek RI, Eibl M,
Sormann S, Maizen C, Linkesch W, Schmon-Kampel R,
Quehenberger F, Tiran A, Sill H. Monitoring of cardiac function
by serum cardiac troponin T levels, ventricular repolarization
indices, and echocardiography after conditioning with fractiona-
ted total body irradiation and high-dose cyclophosphamide. Eur
J Haematol 2002; 69: 1–6.
25. Benvenuto GM, La Vecchia L, Morandi P, Ruffini P,
Mezzena G. Assessment of cardiotoxicity of high dose cyclo-
phosphamide with electrocardiographic, echocardiographic,
and troponin I monitoring in patients with breast tumors. Ital
Heart J Suppl 2000; 1: 1457–63.
26. Petersen FB, Bearman SI. Preparative regimens and
their toxicity. In: Forman SJ, Blume KG, Thomas ED, eds.
Bone marrow transplantation. Boston: Blackwell Scientific
Publications, 1994: 79–83.
БИОХИМИЧЕСКИЕ МАРКЕРЫ И ОЦЕНКА КАРДИОТОКСИЧНОСТИ
В ТЕЧЕНИЕ ПРЕДВАРИТЕЛЬНОЙ ТЕРАПИИ ПАЦИЕНТОВ
С ОСТРЫМ ЛЕЙКОЗОМ С ПОСЛЕДУЮЩЕЙ ТРАНСПЛАНТАЦИЕЙ
СТВОЛОВЫХ ГЕМАТОПОЭТИЧЕСКИХ КЛЕТОК
Введение: кардиотоксические осложнения — это относительно частые и потенциально опасные последствия противоопухолевой
терапии. Наибольшую кардиотоксичность отмечают при применении высоких доз химиопрепаратов, в частности антибиотиков
антрациклинового ряда. Целью данного исследования была оценка кардиотоксичности при лекарственной подготовке пациентов
с острым лейкозом (ОЛ) и проведении им трансплантации гематопоэтических стволовых клеток (ГСК), а также определение
следующих биохимических маркеров – N-терминального промозгового натрийуретического пептида (NT-proBNP), сердечного
тропонина T (cTnT) и креатинкиназы MB (CK-MB). Методы: обследованы 19 взрослых пациентов с ОЛ, прошедших предварительное
лечение (ПЛ) с применением антрациклиновых антибиотиков (АА) – идарубицина, даунорубицина, митотриксантрона в дозах 3
х 12 мг/м2, 3 х 50 мг/м2, 3 х 10 мг/м2 соответственно. Кроме применения АА, ПЛ включало высокие дозы циклофосфамида
(ВД-Ц) в сочетании с бусульфаном или радиолучевой терапией (РЛТ). Концентрацию NT-proBNP, cTnT и CK-MB определяли
в плазме крови за день до и через день после проведения ПЛ, а также за день до и через 14 дней после трансплантации ГСК.
Результаты: уровень NT-proBNP перед проведением ПЛ составил 106,3 ± 55,7 нг/л, а после повышался до 426,1 ± 391,5 нг/л.
После трансплантации ГСК отмечали дальнейшее возрастание исследуемого показателя до 847,6 ± 780,6 нг/л. Через 14 дней
после трансплантации ГСК концентрация NT-proBNP достигла 330,8 ± 236,8 нг/л, при этом разница была статистически
достоверна по сравнению с исходными значениями (p < 0,01). Повышение уровня NT-proBNP в плазме крови более выражено
у пациентов, получавших АА в суммарной дозе (СД) выше 450 мг/м2 (p < 0,05), а также у больных, получавших ВД-Ц и РЛТ (p
< 0,05). Концентрация cTnT и CK-MB при проведении ПЛ и трансплантации ГСК не изменялась по отношению к исходному
уровню. Выводы: показано, что применение ПЛ и трансплантация ГСК у большинства пациентов с ОЛ сопровождается острой
нейрогуморальной активацией, что проявлялось в существенном повышении уровня NT-proBNP. Постоянно высокий уровень NT-
proBNP, отмеченный у 12 (63,2%) пациентов, свидетельствует о бессимптомной кардиотоксичности (риске развития сердечной
недостаточности) и требует последующего врачебного наблюдения больных. Более выраженное повышение уровня NT-proBNP
у пациентов с более высокой СД АА и у больных, получавших ВД-Ц и РЛТ, свидетельствует о том, что такое лечение является
более кардиотоксичным и не рекомендовано для применения в случае наличия факторов риска проявления кардиотоксичности.
Ключевые слова: кардиотоксичность, биохимические маркеры, трансплантация, острый лейкоз.
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