Ladislav Jebavy

The role of cytokines in acute myeloid leukemia: a systematic review.

BACKGROUND Acute myeloid leukemia (AML) shows a high degree of heterogeneity owing to a variety of mutations and the mechanisms of leukemogenesis. This heterogeneity is often not reflected in standard treatment approaches which while providing predictable outcomes in the majority of patients fail in particular cases even with high-dose multiagent chemotherapy regimens. Further, the unselective effect of chemotherapy leads to high treatment-related toxicity and the enormous risk of infection during prolonged pancytopenia, preventing further dose escalation. OBJECTIVES Cytokines play a role in leukemogenesis, AML cell persistence and treatment outcome. In this review we highlight cytokine dependent mechanisms essential for AML cell survival and the role of single cytokines in leukemogenesis and allogeneic transplantation-related phenomena. Cytokine-related mechanisms of leukemogenesis, AML cell persistence and resistance to chemotherapy are complex. Modulation of the cytokine network can disrupt signalling pathway activation and overcome the high resistance to treatment. It may also increase the selectivity of AML treatment, reduce the overall treatment-related toxicity and improve outcomes of AML treatment in all age groups of patients. CONCLUSIONS This review provides a deeper insight into these processes with focus on the most vulnerable step. Special attention is paid to the possibility of selective influence on defined cell populations for therapeutic target. We believe that modulating cytokine-dependent processes in AML is an approach that could be included in standard chemotherapeutic regimens for improving overall treatment outcome.

Cardiac troponin I seems to be superior to cardiac troponin T in the early detection of cardiac injury associated with anthracycline treatment.

Accessible online at: www.karger.com/onk Fax +49 761 4 52 07 14 Information@Karger.de www.karger.com liver and renal function during the study. Cardiac evaluation was performed at baseline (before CT), the day after the first CT with anthracyclines (mean cumulative dose 135.8 ± 28.5 mg/m2, median 150), the day after the last CT with anthracyclines (mean cumulative dose 472.1 ± 115.0 mg/m2, median 423), and approximately 6 months after completion of CT. Concentrations of cardiac troponins diagnostic for cardiotoxicity of oncology treatment have not yet been established. In our study, values above the reference range recommended by the manufacturer were considered elevated. The cut-off value for cTnT was 0.01 μg/l (Roche Diagnostics), and for cTnI 0.40 μg/l (Randox Laboratories Ltd.). Echocardiographic evaluation was performed on a Hewlett Packard Image Point machine by an experienced echocardiographer who was blinded to the cardiac troponin data. Parameters of systolic and diastolic left ventricular (LV) function were assessed. Systolic LV dysfunction was defined as LV ejection fraction (LVEF) ≤ 55%. Diastolic LV dysfunction was defined as E/A inversion and a E wave deceleration time above 220 ms on the transmitral Doppler curve (impaired relaxation). Statistical analysis was performed with Statistica for Windows, version 5.0 (StatSoft, Tulsa, OK, USA). Analysis of variance test was used. Correlations were evaluated with normal and Spearman correlation tests. The values are expressed as mean ± standard deviation (SD). Probability values (p) of < 0.01 were considered statistically significant. The results are summarized in table 1. Of the cardiac troponins, only cTnI became positive on the days after the first and last CT with anthracyclines, which was observed in a total of 4 (17.4%) patients. Positivity of cTnI correlated with systolic and diastolic LV dysfunction on echocardiography: r = 0.712; p < 0.00001 and r = 0.591; p < 0.0001, Cardiac toxicity is among the undesirable side effects of oncology treatment. Of the cytostatics, anthracyclines represent the greatest risk for development of cardiotoxicity [1]. Various methods have been recommended for monitoring cardiotoxicity in oncology [2, 3]. Echocardiography and electrocardiography are routinely used, and recently, the applicability of cardiac troponins in the detection of cancer therapy-induced cardiotoxicity has been investigated [4]. In some studies, administration of anthracyclines did not cause any elevation of cardiac troponins [5–7]. In other studies, cardiac troponins became positive after anthracycline treatment, correlated with disease severity, and were suggested as predictors of subsequent major cardiac events during follow-up [8–10]. The results of clinical studies are inconsistent, and cardiac troponins have not been established in clinical practice for monitoring cardiotoxicity in oncology. The aim of our study was to evaluate acute and chronic cardiotoxicity of anthracyclines with cardiac troponins. We used current immunoassays for cardiac troponin T (cTnT; Roche Diagnostics, Mannheim, Germany) and cardiac troponin I (cTnI; Randox Laboratories Ltd., Crumlin, Co. Antrim, UK), and correlated the results with echocardiography findings. A total of 23 patients (mean age 47.0 ± 11.1 years; 14 males, 9 females) with acute leukemia were studied. The patients were treated with 3–6 cycles of conventional chemotherapy (CT) containing anthracyclines at a total cumulative dose of 472.1 ± 115.0 mg/m2; to calculate the total cumulative anthracycline dose, we applied conversion factors derived from the maximum recommended cumulative doses for the individual agents used (idarubicin, daunorubicin, mitoxantrone). Six patients were treated for arterial hypertension; other patients had no history of cardiovascular disease. All patients had normal Cardiac Troponin I Seems to Be Superior to Cardiac Troponin T in the Early Detection of Cardiac Injury Associated with Anthracycline Treatment

Biomarkers for the early detection of anthracycline-induced cardiotoxicity: current status

BACKGROUND Cardiotoxicity is a well-known and potentially serious complication of anticancer therapy. Anthracycline-based chemotherapy represents the greatest risk. Early detection of cardiotoxicity is crucial for applying preventive and supportive therapeutic strategies. METHODS AND RESULTS Various methods have been recommended for monitoring of cardiotoxicity. In our conditions, echocardiography and electrocardiography are routinely used. However, this approach shows low sensitivity for the early prediction of cardiomyopathy when the possibilities of appropriate management could still improve the patients outcome. Recently, biomarkers of cardiac injury have been investigated in the assessment of chemotherapy-induced cardiotoxicity. Cardiospecific biomarkers, such as cardiac troponins, show high diagnostic efficacy in the early subclinical phase of the disease before the clinical onset of cardiomyopathy. Increase in their concentrations correlates with disease severity. As for natriuretic peptides, some studies, including ours, have shown promising results. Definitive evidence of their diagnostic and prognostic role in this context is still lacking and natriuretic peptides have not been routinely used for monitoring of cardiotoxicity in clinical practice. Other perspective biomarkers of cardiotoxicity in oncology are under study, especially heart-type fatty acid-binding protein (H-FABP) and glycogen phosphorylase BB (GPBB). Our studies using GPBB have provided encouraging results. However, the available data are limited and their practical use in this context cannot be recommended until their clinical efficacy is clearly defined. CONCLUSIONS This review covers the current status of biomarkers for the early detection of anthracycline-induced cardiotoxicity. The authors present in brief, their own experience with multiple biomarkers in the detection of cardiotoxicity.

New biomarkers of myocardial injury and assessment of cardiac toxicity during preparative regimen and hematopoietic cell transplantation in acute leukemia

No Abstract available

Serum cytokine and adhesion molecule profile differs in newly diagnosed acute myeloid and lymphoblastic leukemia.

AIMS To compare serum levels of 17 cytokines and 5 adhesion molecules in patients with newly diagnosed acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) using biochip array technology. METHODS A total of 15 AML and 15 ALL patients were studied. Serum samples were taken prior to anticancer therapy and were analyzed by biochip based immunoassays on the Evidence Investigator analyzer. This approach allows simultaneous detection of multiple analytes from a single sample. T-tests were used for statistical analysis. RESULTS Comparing cytokine and adhesion molecules levels in newly diagnosed AML and ALL patients, we found significant increase in AML in serum IL-4 (P < 0.0001), IL-2 (P < 0.01), IL-3 (P < 0.05), and significant decrease (P < 0.05) in serum VEGF and VCAM-1. DISCUSSION Our results indicate that serum profile of cytokines and adhesion molecules differs in newly diagnosed AML and ALL patients. Further studies are needed to establish if these alterations could be used as a clinically relevant biomarker for acute leukemias.

Multi-analytical evaluation of serum levels of cytokines and adhesion molecules in patients treated for acute myeloid leukemia using biochip array technology

AIMS Evaluation of serum levels of 17 cytokines and 5 adhesion molecules in patients treated for acute myeloid leukemia (AML) using biochip array technology. This approach allows multi-analytical determination from a single sample. METHODS A total of 15 AML patients were studied. Blood samples were taken at the diagnosis (active leukemia) and at circa 6 months after completion of last chemotherapy (durable complete remission in all patients). RESULTS Comparing cytokine and adhesion molecule levels in active leukemia and in durable complete remission, we found significant increase (P<0.01) in serum interleukin-7 (IL-7), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), and significant decrease (P<0.01) in serum E-selectin. DISCUSSION Our results indicate that serum levels of specific cytokines and adhesion molecules (IL-7, EGF, VEGF, E-selectin) are significantly altered in patients treated for AML, reflecting activity of the disease. Further investigation is needed to establish if the changes observed in the levels of these molecules could be used as a prognostic indicator of AML.

Serum levels of soluble adhesion molecules in newly diagnosed acute myeloid leukemia and in complete remission suggest endothelial cell activation by myeloblasts

BACKGROUND AND AIMS Despite high-dose multi-agent chemotherapy and allogeneic stem cell transplantation, the relapse rate of acute myeloid leukemia (AML) is high. Further, the disease is highly resistent to drugs. We speculated that deeper understanding of AML-endothelial cell interactions might provide new targets for selective modulation of the AML microenvironment and form the basis for novel treatment approaches. In this study, we evaluated levels of endothelium derived soluble adhesion molecules in active disease and in complete remission (CR) and their relationship with inflammatory cytokines. METHODS Baseline serum levels of 25 cytokines and 5 soluble adhesion molecules were measured in 84 AML patients using biochip array technology. CR samples were evaluated in 44 patients of this cohort. The control group consisted of 15 healthy blood donors. RESULTS All analytes were independent of age or disease origin. Some correlations were restricted to active AML, some were ubiquitous and some were found in remission. In active disease, E-selectin (E-SEL) and VCAM-1 correlated with leukocyte count, E-SEL correlated with P-selectin (P-SEL). Platelet count related to IL-7, EGF and VEGF but not to P-SEL. In CR, P-SEL correlated with platelet count and EGF but not with E-SEL. There was no relationship of P-SEL and E-SEL in the control group. CONCLUSIONS Leukemic activity is associated with a different pattern of soluble adhesion molecule levels. Both E-SEL and P-SEL may be derived from endothelial cells. Their levels correlated in active disease. E-SEL correlated with leukocyte count. In CR, P-SEL physiologically correlated with platelet count. The correlation with E-SEL was insignificant and absent in the control group. Our data suggest activation of endothelial cells in the presence of myeloblasts.

Evaluation of cytokines and soluble adhesion molecules in patients with newly diagnosed acute myeloid leukemia: the role of TNF-alpha and FLT3-ITD

OBJECTIVES Acute myeloid leukemia (AML) cells are highly resistant to therapy. The presumed molecular basis of this resistance is the effect of tumor necrosis factor alpha (TNF-α) and other cytokines on endothelial adhesion molecule expression. The aim of this study was to test the hypothesis that cytokines and soluble adhesion molecules correlate in AML. METHODS Baseline serum levels of 17 cytokines and 5 soluble adhesion molecules were measured in 53 AML patients using biochip array technology. Age, leukocyte count, secondary AML, CRP, FLT3-ITD and remission were variables. Statistical analysis was performed in R version 3.1.2. RESULTS VCAM-1 correlated with ICAM-1 (P < 0.0001), E-selectin (P < 0.0001), leukocyte count (P = 0.0005) and TNF-α (P = 0.0035). E-selectin correlated with leukocyte count (P < 0.0001), P-selectin (P = 0.0032) and MCP-1 (P = 0.0119). CRP correlated with IL-6 (P < 0.0001), leukocyte count negatively correlated with IL-7 (P = 0.0318). FLT3-ITD was associated with higher E-selectin (P = 0.0010) and lower IL-7 (P = 0.0252). Secondary AML patients were older. Failure of induction therapy was associated with significantly higher CRP and lower P-selectin. Leukocyte count (P < 0.0001), FLT3-ITD (P = 0.0017) and secondary AML (P = 0.0439) influenced the principal component. CONCLUSIONS Leukemic cells can modulate the microenvironment. Cytokine, adhesion molecule levels and leukocyte count correlate in AML. Understanding these mechanisms may form the basis of novel therapeutic approaches.

The role of adhesion molecules in acute myeloid leukemia and (hemato)oncology: a systematic review.

BACKGROUND The treatment of malignancies like acute myeloid leukemia (AML) is often complicated by the heterogeneity of the disease and the mechanisms of the disease progression. This heterogeneity is often not reflected in standard treatment approaches which provide predictable outcomes in the majority of patients but fail in individual cases even with high-dose multi-agent chemotherapy regimens and allogeneic stem cell transplantation. Further, the unselective effect of chemotherapy causes high treatment-related toxicity and accelerates the risk of infection during prolonged pancytopenia, preventing further dose escalation. Despite rapid progress in therapeutic strategies, the fatality of high-grade malignancies remains enormous. OBJECTIVES Adhesive interactions trigger signal transduction pathway activation and this prevents the apoptosis of both normal and malignant cells. A correlation between expression of defined adhesion molecules and patient outcome has been found for several malignant diseases including AML. We aim to describe how disruption of these signalling pathways can overcome the high resistance to treatment and increase the selectivity of targeting malignant cells. This could effectively reduce the overall treatment-related toxicity and improve the general outcome. CONCLUSIONS Adhesion molecules facilitate growth of malignant diseases. This review provides a deeper insight into these processes. Modulation of adhesion molecules-mediated interactions is an innovative and feasible approach in treatment of AML and many other malignancies. Due to expected low toxicity it is an acceptable addition to standard chemotherapeutical regimens for all age groups of patients. This approach could improve the overall treatment outcome in the future.