Cardiotoxicity of Novel Targeted Hematological Therapies

Abstract

Chemotherapy-related cardiac dysfunction, also known as cardiotoxicity, is a group of drug-related adverse events negatively affecting myocardial structure and functions in patients who received chemotherapy for cancer treatment. Clinical manifestations can vary from life-threatening arrythmias to chronic conditions, such as heart failure or hypertension, which dramatically reduce quality of life of cancer survivors. Standard chemotherapy exerts its toxic effect mainly by inducing oxidative stress and genomic instability, while new targeted therapies work by interfering with signaling pathways important not only in cancer cells but also in myocytes. For example, Bruton’s tyrosine kinase (BTK) inhibitors interfere with class I phosphoinositide 3-kinase isoforms involved in cardiac hypertrophy, contractility, and regulation of various channel forming proteins; thus, off-target effects of BTK inhibitors are associated with increased frequency of arrhythmias, such as atrial fibrillation, compared to standard chemotherapy. In this review, we summarize current knowledge of cardiotoxic effects of targeted therapies used in hematology.

Bortezomib-Induced Perimyocarditis in a Multiple Myeloma Patient: A Case Report

“…The ubiquitin-proteosome system, under normal conditions, “tags” altered or misfolded intracellular proteins for degradation [ 2 ]. Its substrates include signaling molecules, cell cycle regulators, transcription factors, and antiapoptotic proteins [ 8 ].…”

“…Bortezomib (BTZ) is a proteasome inhibitor that is currently used for the treatment of several hematologic malignancies including multiple myeloma (MM), mantle cell lymphoma, systemic light chain amyloidosis, T-cell lymphoma, Waldenstrom's macroglobulinemia/lymphoplasmacytic lymphoma, and others [ 1 ]. Although rare, several cardiovascular complications including heart failure, ischemic heart disease, and arrythmias have been reported in association with its use [ 2 ]. Here, we report the case of a patient who developed perimyocarditis and myocardial scaring after a brief exposure to subcutaneous BTZ in the context of treatment for newly diagnosed international staging system stage I standard risk multiple myeloma.…”

Novel Multiple Sclerosis Agents-Induced Cardiotoxicity

“…Even rarer (<1%), pericarditis, heart failure and myocardial infarction cases were reported to be associated with ofatumumab use [18]. Fingolimod, the first SPR modulator introduced into the market, is well known its cardiovascular side effects, mainly bradycardia and AV block.…”

“…One case of atrial fibrillation has been linked to Ofatumumab in a trial comparing ofatumumab versus Ibrutinib[17]. Even rarer (<1%), pericarditis, heart failure and myocardial infarction cases were reported to be associated with ofatumumab use[18].…”

Table_2.xlsx

“…Even with the improved selectivity of acalabrutinib, regulatory agencies have confirmed this adverse event persists. While drug off target causation of arrhythmias, such as atrial fibrillation, is complex, one possible factor mediating this activity is with interference of class I phophoinositide 3-kinase isoforms involved in cardiac hypertrophy, contractility, and regulation of various channel forming proteins (128). In a retrospective cohort study with Chronic lymphocytic leukemia (CLL) atrial fibrillation was the most common cause of ibrutinib discontinuation (129).…”