Monitoring of the very early changes of left ventricular diastolic function in patients with acute leukemia treated with anthracyclines

To analyze the very early changes of diastolic LV function during and after chemotherapy (CT) in patients with newly diagnosed acute leukemia. Methods: 26 patients with acute leukemia have been studied. The cardiac echo evaluation was performed at the baseline (before CT), after the first CT (mean cumulative anthracyclines dose 136.3 ± 28.3 mg m–2), after the last CT (mean cumulative anthracyclines dose 464.3 ± 117.5 mg m–2) and circa 6 months after the completion of CT. Results: We found a significant decrease in LVEF (65.3 ± 4.5% vs 60.2 ± 5.7%, p < 0.01), the fractional shortening of the LV (34.8 ± 3.7%, vs 29.5 ± 5.0%, p < 0.01), but the mitral flow rapid filling velocity (E-wave) was not changed (0.74 ± 0.18 ms–1, vs 0.67 ± 0.17 ms–1, p ns), and atrial filling velocity (A-wave) increased (0.66 ± 0.15 ms–1 vs 0.78 ± 0.18 ms–1, p < 0.01). E/A ratio significantly decreased (1.18 ± 0.35 vs 0.89 ± 0.27, p < 0.01). IVRT increased (71.5 ± 11.6 ms vs 84.0 ± 11.6 ms, p < 0.01). DT E-wave velocity increased (162.3 ± 25.8 ms vs 206.7 ± 25.5 ms, p < 0.01). After the first CT, the signs of LV diastolic dysfunction were detected in 5 (19.2%) patients. 6 months after the last CT, two of these patients (7.7%) developed LV systolic dysfunction with the clinical symptoms of heart failure. Six months after the last CT, 12 (46.2%) patients developed the signs of LV diastolic dysfunction. Conclusion: Chemotherapy can induce early changes of diastolic left ventricular function. We consider using Doppler echocardiography as the election tool not only for baseline cardiologic screening but also for the monitoring of the earliest subclinical signs of cardiotoxicity.Цель: проанализировать ранние изменения диастолической функции левого желудочка (ЛЖ) во время проведения химиотерапии (ХТ) и после ХТ у больных с первичнодиагностированной острой лейкемией. Методы: обследованы 26 больных с острой лейкемией. Эхокардиограммы снимали до ХТ, после первого курса ХТ (среднее значение суммарной дозы антрациклинов 136,3 ± 28,3 мг м-2), после окончания ХТ (среднее значение суммарной дозы антрациклинов 464,3 ± 117,5 мг м-2) и через 6 мес после завершения ХТ. Результаты: выявлено значительное уменьшение фракции выброса ЛВ (65,3 ± 4,5% против 60,2 ± 5,7%, p < 0,01), фракции укорочения диастолы ЛЖ (34,8 ± 3,7% против 29,5 ± 5,0%, p < 0,01). Скорость наполнения митрального потока (E-волна) не изменялась (0,74 ± 0,18 мс–1против 0,67 ± 0,17 м с–1), и предсердная скорость наполнения (A-волна) повышалась (0,66 ± 0,15 мс–1 против 0,78 ± 0,18 мс–1, p < 0,01). Отношение E/A существенно уменьшалось (1,18 ± 0,35 против 0,89 ± 0,27, p < 0,01). Время изоволюметрического расслабления увеличивалось (71,5 ± 11,6 мс против 84,0 ± 11,6 мс, p < 0,01). Время замедления кровотока E-волны увеличивалось (162,3 ± 25,8 мс против 206,7 ± 25,5 мс, p < 0,01). После первого курса ХТ признаки диастолической дисфункции ЛЖ выявлены у 5 (19,2%) больных. Через 6 мес после окончания ХТ у 2 больных (7,7%) развилась систолическая дисфункция ЛЖ с клиническими симптомами паралича сердца, а у 12 (46,2%) больных выявлены признаки диастолической дисфункции ЛЖ. Выводы: ХТ может вызывать ранние изменения диастолической функции ЛЖ. Предлагается использовать эхокардиографию Допплера не только для предварительного скрининга, но и для мониторнига ранних субклинических признаков кардиотоксичности

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 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

The use of cardiac biomarkers in detection of cardiotoxicity associated with conventional and high-dose chemotherapy for acute leukemia

Aim: Monitoring of cardiotoxicity of conventional and high-dose chemotherapy (HD-CT) with multiple biomarkers of cardiac injury — glycogen phosphorylase BB (GPBB), heart-type fatty acid binding protein (H-FABP), cardiac troponins (cTnT, cTnI), creatine kinase MB (CK-MB mass), myoglobin. Methods: A total of 47 adult acute leukemia patients were studied — 24 patients treated with conventional CT containing anthracyclines (ANT) and 23 patients treated with HD-CT (myeloablative preparative regimen) followed by hematopoietic cell transplantation (HCT). Cardiac biomarkers were assessed prior to treatment (before CT/HD-CT), after first CT with ANT, after last CT with ANT in the first group, after HD-CT and after HCT in the second group. Values above the reference range were considered elevated. Results: Before CT/HD-CT, all biomarkers of cardiac injury were below the cut-offs in all patients. GPBB increased above the cut-off (7.30 μg/L) in 4 (16.7%) patients after first CT and in 5 (20.8%) patients after last CT with ANT. GPBB increased above the cut-off in 5 (21.7%) patients after HD-CT and remained elevated in 5 (21.7%) patients after HCT. CTnI became elevated (above 0.40 μg/L) in 2 (8.3%) patients after first and last CT with ANT. Both patients with cTnI positivity had elevated GPBB. Other tested biomarkers remained below the cut-offs during the study. Conclusion: Our results suggest that GPBB could become a sensitive biomarker for detection of acute cardiotoxicity associated with conventional CT containing ANT and HD-CT followed by HCT. The predictive value for development of cardiomyopathy in the future is not known and should be evaluated during a prospective follow-up. Based on our data, a larger prospective and multicenter study would be most desirable to define the potential role of new circulating biomarkers in the assessment of cardiotoxicity in oncology

Use of multiple biomarkers for evaluation of anthracycline-induced cardiotoxicity in patients with acute myeloid leukemia

To assess cardiac toxicity of anthracycline treatment with six biomarkers of cardiac injury: myoglobin, creatine kinase MB (CK-MB mass), cardiac troponin T (cTnT), cardiac troponin I (cTnI), heart-type fatty acid binding protein (H-FABP), glycogen phosphorylase BB (GPBB). Methods: We evaluated anthracycline-induced cardiotoxicity in 12 acute myeloid leukemia patients (mean age 51.3 ± 10.7 years, 7 females). All biomarkers were measured at the baseline, after first chemotherapy (CT) with anthracyclines, after last CT with anthracyclines (total cumulative dose 479.8 ± 106.2 mg/m2) and 6 months thereafter. Values above the reference range were considered elevated. Results: GPBB increased above the cut-off (7.30 µg/L) in 2 (16.7%) patients after first CT, in 3 (25.0%) patients after last CT and remained elevated in 2 (16.7%) patients within 6 months after CT. CTnI became elevated (above 0.40 µg/L) in 1 (8.3%) patient after first and last CT and within 6 months after CT. CTnT remained negative (below 0.01 µg/L) during CT in all patients. Six months after CT, delayed cTnT positivity was found in 1 (8.3%) patient. All patients with cTnI or cTnT positivity had elevated GPBB. Other biomarkers (myoglobin, CK-MB mass, H-FABP) remained within the reference range in all patients. Conclusion: Our preliminary results suggest that GPBB could be a new promising marker for detection of anthracycline-related cardiotoxicity and probably superior to cardiac troponins. The predictive value for development of cardiomyopathy in the future is not clear and will be evaluated during a prospective follow-up.Цель: провести оценку кардиотоксичности, вызываемой антрациклином, с помощью ряда биомаркеров поражения сердца: миоглобина, креатин-киназы MB (CK-MB mass), кардиального тропонина T (cTnT), кардиального тропонина I (cTnI), белка, связывающего жирные кислоты (H-FABP), и гликогенфосфорилазы BB (GPBB). Методы: оценку кардиотоксичности проводили у 12 больных острой миелоидной лейкемией (средний возраст — 51,3 ± 10,7 года, 7 женщин). Измерены начальные показатели всех биомаркеров, а также таковые после проведения первой и последней химиотерапии (ХT) антрациклинами (общая накопленная доза — 479,8 ± 106,2 мг/м2 ) и через 6 мес после завершения терапии. Значения выше начальных рассматривали как повышенные. Результаты: уровень GPBB превысил норму (7,30 µg/L) у 2 больных (16,7%) после первой ХT, у 3 (25,0%) — после последней ХT и оставался повышенным у 2 больных (16,7%) и через 6 мес после ХT. Уровень CTnI повысился (более 0,40 µg/L) у 1 больного (8,3%) после первой и последней ХT, а также и через 6 мес после ХT. Значения CTnT оставались в пределах нормы (ниже 0,01 µg/L) во время проведения CT у всех пациентов. Через 6 мес после ХT отдаленная положительная реакция на cTnT выявлена у 1 больного (8,3%). У всех пациентов с положительными cTnI или cTnT установлен повышенный уровень GPBB. Другие биомаркеры (миоглобин, CK-MB, H-FABP) оставались в пределах нормы у всех больных. Выводы: предварительные результаты, полученные в данном исследовании, позволяют предположить, что GPBB можно рассматривать как новый перспективный маркер для выявления кардиотоксичности, вызванной антрациклинами, и, возможно, превосходит предложенные ранее тропонины. Возможная прогностическая ценность этого маркера при развитии кардиомиопатии пока не установлена

Biochip array technology and evaluation of serum levels of multiple cytokines and adhesion molecules in patients with newly diagnosed acute myeloid leukemia

Aim: Evaluation of serum levels of 17 cytokines and 5 adhesion molecules in patients with newly diagnosed acute myeloid leukemia (AML) and in healthy subjects using biochip array technology. Methods: A total of 15 AML patients and 15 healthy subjects (blood donors) were studied. Serum samples were analyzed by biochip based immunoassays on the Evidence Investigator analyzer. This approach allows multi-analytical determination from a single sample. T-tests were used for statistical analysis. Results: In newly diagnosed AML patients, we found significant increase (p < 0.01) in serum VCAM-1, ICAM-1, E-selectin, L-selectin, and significant increase (p < 0.05) in serum IL-6, IL-8. No significant differences were found in the levels of other evaluated cytokines and adhesion molecules. Conclusion: Our results indicate that serum levels of specific cytokines and adhesion molecules ­(­VCAM-1, ICAM-1, E-selectin, L-selectin, IL-6, IL-8) are significantly altered in patients with newly diagnosed AML, showing activity of the disease. Whether these alterations could serve as a prognostic marker for AML is not known. Further studies will be needed to define the potential role of these and additional markers in the risk stratification of AML. Key Words: cytokines, adhesion molecules, biochip array, acute myeloid leukemia

Cardiovascular changes associated with infusion of hematopoietic cell grafts in oncohematological patients — impact of cryopreservation with dimethylsulfoxide

Aim: Dimethylsulfoxide (DMSO) is the most frequently used agent for hematopoietic cell (HC) graft cryopreservation. This study aimed to monitor blood pressure and heart rate (HR) during HC graft infusion and assess the impact of cryopreservation with DMSO. Methods: 153 HC graft infusions in 153 consecutive hematological patients (mean age 49.1 ± 12.6 years; 80 males) were evaluated. Cryopreservation with DMSO was used in 133 grafts (DMSO group). Twenty grafts were infused directly without cryopreservation (control group). Systolic blood pressure (SBP), diastolic blood pressure (DBP) and HR were measured immediately before and after HC graft infusion. Results: SBP and DBP increased significantly after graft infusions cryopreserved with DMSO (p 10 mmHg) in SBP were seen in 42 (31.6%) patients; in DBP in 31 (23.3%) patients. Changes in HR were non-significant in DMSO group. Increases in BP and HR correlated with increasing DMSO dose (p < 0.01; p < 0.05, respectively). Changes in SBP, DBP and HR were non-significant in control group. Conclusion: HC graft infusions cryopreserved with DMSO could cause statistically significant increases in SBP and DBP, without changes in HR. These changes were mostly transient and asymptomatic, not requiring therapeutic intervention. However, they might cause complications, especially in patients with preexisting cardiovascular disease, who should be monitored closely during HC transplantation

Assessment of anthracycline-induced cardiotoxicity with electrocardiography

Aim: Monitoring of anthracycline-induced cardiotoxicity with electrocardiography (ECG) and comparing ECG changes with findings on echocardiography (ECHO). Methods: A total of 26 adult acute leukemia patients (mean age 46.2 ± 12.4 years, 15 males) treated with 2–6 cycles of anthracycline-based chemotherapy (CT) were studied. Cardiac evaluation was performed at the baseline (before CT), after first CT, after last CT (cumulative anthracycline dose 464.3 ± 117.5 mg/m2 ) and circa 6 months after CT. Time ECG parameters, QRS voltage, presence of repolarization changes, arrhythmias and other abnormalities were evaluated. Results: During treatment and follow-up, we found a statistical significant QTc interval prolongation — 414.7 ± 16.0 ms (before CT), 419.6 ± 21.6 ms(after first CT), 428.0 ± 16.2 ms(after last CT) and 430.1 ± 18.4 ms(6 months after CT). Significant QTc interval prolongation (> 450 ms) occurred in 3 patients after first CT, in 4 patients after last CT and in 5 patients within 6 months after CT. Significant total QRS voltage lowering in the limb leads (> 1.0 mV versus before CT) occurred in 3 patients after first CT, in 5 patients after last CT and in 6 patients within 6 months after CT. We found a statistically significant correlation between decreased QRS voltage, QTc interval prolongation and left ventricular (LV) dysfunction on ECHO. Repolarization changes associated with oncology treatment were present in 9 patients within 6 months after CT. Conclusion: Anthracycline treatment is associated with changes in electrical activity of the myocardium. Prolonged QTc interval represents a risk for development of malignant ventricular arrhythmias. Decreased QRS voltage and prolonged QTc interval after anthracycline treatment could correlate with LV dysfunction on ECHO. Further studies will be needed to prove whether these ECG changes could serve as an accessible and non-invasive screening method indicating LV dysfunction after anthracycline treatment

Evaluation of serum levels of multiple cytokines and adhesion molecules in patients with newly diagnosed acute lymphoblastic leukemia using biochip array technology

Aim: Evaluation of serum levels of 17 cytokines and 5 adhesion molecules in patients with acute lymphoblastic leukemia (ALL) and in healthy subjects using biochip array technology. This approach allows multi-analytical determination from a single sample. Methods: A total of 15 ALL patients and 15 healthy subjects (blood donors) were studied. Serum samples were analyzed by biochip based immunoassays on the Evidence Investigator analyzer. T-tests were used for statistical analysis. Results: Comparing cytokine and adhesion molecule levels in ALL patients and in healthy subject, we found significant increase in serum VCAM-1 (p < 0.000001), ICAM-1 (p < 0.0001), L-selectin (p < 0.0001), IL-8 (p < 0.001), MCP-1 (p < 0.01), and significant decrease (p < 0.01) in serum IL-3 and IL-4. Conclusion: Our results indicate that serum levels of specific cytokines and adhesion molecules (VCAM-1, ICAM-1, L-selectin, IL-8, IL-3, IL-4, MCP-1) are significantly altered in patients with newly diagnosed ALL, reflecting acti­vity of the disease. Further investigation is needed to establish if these alterations could be used as a prognostic indicator for ALL