Cardiac Studies in Patients Treated with Depsipeptide, FK228, in a Phase II Trial for T-Cell Lymphoma

Abstract

Purpose: The histone deacetylase inhibitor depsipeptide (FK228) has activity in patients with cutaneous or peripheral T-cell lymphoma. Electrocardiogram abnormalities, thought to be a class effect, were observed in preclinical animal studies and phase I testing and led to the incorporation of intensive cardiac monitoring in an ongoing efficacy trial. Patients and Methods: This report summarizes the cardiac monitoring of 42 patients enrolled and treated on a phase II trial with depsipeptide. Cardiac evaluations included serial electrocardiograms to evaluate T-wave, STsegment, and QT interval effects and serial serum cardiac troponin I levels and left ventricular ejection fraction (LVEF) evaluations to exclude myocardial damage. Results: Cardiac studies from 282 cycles and 736 doses of depsipeptide included 2,051 electrocardiograms and 161 LVEF evaluations. Although T-wave flattening (grade 1) or ST segment depression (grade 2) was observed in more than half of the electrocardiograms obtained posttreatment, these electrocardiogram abnormalities were not associated with elevation of cardiac troponin I or with altered left ventricular function. No significant changes in LVEF were observed, even in 16 patients treated for z6 months and regardless of prior anthracycline exposure. Posttreatment electrocardiograms had a mean heart rate^corrected QT interval prolongation of 14.4 milliseconds compared with baseline. Electrolyte replacement has been instituted to mitigate potential untoward effects. Conclusion: The data obtained in this study show that the administration of depsipeptide is not associated with myocardial damage or impaired cardiac function. The potential effect of heart rate^corrected QT interval prolongation remains under study.

A phase II multiple dose clinical trial of histone deacetylase inhibitor ITF2357 in patients with relapsed or progressive multiple myeloma

“…Quite likely, they were related to ITF2357 because they developed after a few weeks of treatment and resolved after drug discontinuation. Similar cardiac abnormalities have also been reported for other HADACIs [20,21]. Only one patient needed anti-arrhythmic therapy for atrial fibrillation, which developed 2 months after the end of ITF2357 treatment.…”

Cutaneous T‐cell lymphoma: 2011 update on diagnosis, risk‐stratification, and management

“…A toxicity profile similar to that described for vorinostat was observed. Intensive annual clinical updates in hematological malignancies: a continuing medical education series American Journal of Hematologycardiac monitoring in a subset of these patients failed to demonstrate any clinically significant cardiotoxicity [276].…”

Will broad-spectrum histone deacetylase inhibitors be superseded by more specific compounds?

“…7,55,56 In general, depsipeptide has a similar toxicity profile to SAHA, 23 however, there is concern about cardiac toxicity with this compound, which requires further evaluation. [57][58][59] Furthermore, depsipeptide has been identified to be a substrate of the P-glycoprotein pump (Pgp) and multidrug resistance associated protein 1 and to induce the expression of Pgp, [60][61][62][63][64] which could limit its clinical utility. 65,66 In the context of HDAC inhibitor-mediated toxicity, the recent correlation of the teratogenic effects of valproic acid with the inhibition of HDAC enzymes is important.…”