natriuretic-peptide--brain and Leukemia--Myelogenous--Chronic--BCR-ABL-Positive

Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myelogenous leukaemia (CML). However, cardiotoxicity of these agents remains a serious concern. The underlying mechanism of these adverse cardiac effects is largely unknown. Delineation of the underlying mechanisms of TKIs associated cardiac dysfunction could guide potential prevention strategies, rescue approaches, and future drug design. This study aimed to determine the cardiotoxic potential of approved CML TKIs, define the associated signalling mechanism and identify potential alternatives.. In this study, we employed a zebrafish transgenic BNP reporter line that expresses luciferase under control of the nppb promoter (nppb:F-Luciferase) to assess the cardiotoxicity of all approved CML TKIs. Our in vivo screen identified ponatinib as the most cardiotoxic agent among the approved CML TKIs. Then using a combination of zebrafish and isolated neonatal rat cardiomyocytes, we delineated the signalling mechanism of ponatinib-induced cardiotoxicity by demonstrating that ponatinib inhibits cardiac prosurvival signalling pathways AKT and extra-cellular-signal-regulated kinase (ERK), and induces cardiomyocyte apoptosis. As a proof of concept, we augmented AKT and ERK signalling by administration of Neuregulin-1β (NRG-1β), and this prevented ponatinib-induced cardiomyocyte apoptosis. We also demonstrate that ponatinib-induced cardiotoxicity is not mediated by inhibition of fibroblast growth factor signalling, a well-known target of ponatinib. Finally, our comparative profiling for the cardiotoxic potential of CML approved TKIs, identified asciminib (ABL001) as a potentially much less cardiotoxic treatment option for CML patients with the T315I mutation.. Herein, we used a combination of in vivo and in vitro methods to systematically screen CML TKIs for cardiotoxicity, identify novel molecular mechanisms for TKI cardiotoxicity, and identify less cardiotoxic alternatives.

Topics: Animals; Animals, Genetically Modified; Antineoplastic Agents; Apoptosis; Cardiotoxicity; Cells, Cultured; Extracellular Signal-Regulated MAP Kinases; Heart Diseases; Imidazoles; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Myocytes, Cardiac; Natriuretic Peptide, Brain; Niacinamide; Proof of Concept Study; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pyrazoles; Pyridazines; Rats; Signal Transduction; Zebrafish

We present the case of a 72-year-old male with chronic phase myeloid leukemia. Elevation of the pulmonary artery pressure due to nilotinib therapy was noted. This effect on pulmonary artery pressure was nilotinib dose dependent.

Topics: Aged; Antineoplastic Agents; Echocardiography, Doppler; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Natriuretic Peptide, Brain; Peptide Fragments; Pyrimidines

Cardiotoxicity has been feared as a potential side effect of imatinib therapy. Studies with short-term follow-up failed to identify an excess of cardiac events, but longer-term observations are needed to more definitely exclude this adverse effect. This study was designed to assess the cardiac effects of imatinib in patients under long-term treatment. We included 90 chronic myeloid leukaemia (CML) patients under imatinib therapy for a median treatment time of 3.3 years (mean age 48.9 ± 15.1 years). Patients underwent clinical evaluation, electrocardiography, echocardiography (two-dimensional, colour flow, tissue Doppler and strain imaging), brain natiuretic peptide (BNP) and troponin I measurements. Twenty healthy volunteers were included as a control group for strain measurements. The mean ejection fraction was 68 ± 7% and the median BNP level was 9.6 pg/ml (interquartile range [IQR] 5.7-17.0 pg/ml). Two patients had either an elevated BNP or a depressed ejection fraction (2.2%; 90%CI 0.9-6.8%). Most of troponin I measurements were lower than the detection limit, except for two patients. Longitudinal strain was similar to measurements in healthy controls. A weak relation was observed between log BNP and imatinib treatment duration and dose. There was no relation between these variables and left ventricle ejection fraction. In conclusion, matinib-related cardiotoxicity is an uncommon event in CML patients, even during long-term treatment. Therefore, its use should not be cause of great concern, and the usefulness of regular cardiac monitoring all patients while on imatinib therapy is questionable.

Topics: Adult; Aged; Antineoplastic Agents; Benzamides; Case-Control Studies; Cross-Sectional Studies; Drug Administration Schedule; Echocardiography; Female; Heart; Heart Failure; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Middle Aged; Natriuretic Peptide, Brain; Piperazines; Pyrimidines; Treatment Outcome

Topics: Adult; Aged; Aged, 80 and over; Benzamides; Cardiotoxins; Female; Heart Function Tests; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Middle Aged; Natriuretic Peptide, Brain; Piperazines; Pyrimidines

Since its introduction 6 years ago, imatinib mesylate, a selective tyrosine kinase inhibitor, has been a phenomenon in treating chronic myelogenous leukemia (CML) with remarkably superior cytogenetic and molecular response rates at all stages of CML followed by longer progression free survival. Despite its extraordinarily high efficacy, adverse effects of imatinib mesylate such as edema, liver toxicity and fluid retention syndromes have been reported. Here we, for the first time, report development of heart failure in patients on imatinib mesylate medication and the possibility of brain natriuretic peptide (BNP) as a potential diagnostic (or predicting) marker for heart failure. Since plasma BNP levels in the two patients were exceptionally high, we then explored the possibility of genetic association of BNP with the development of heart failure to find no positive association.

Topics: Adult; Aged; Alleles; Base Sequence; Benzamides; Biomarkers, Tumor; Diarrhea; DNA Mutational Analysis; Edema; Exanthema; Female; Gastrointestinal Stromal Tumors; Gene Frequency; Genotype; Heart Failure; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Middle Aged; Natriuretic Peptide, Brain; Piperazines; Polymorphism, Single Nucleotide; Protein Kinase Inhibitors; Pyrimidines; Treatment Outcome