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Journal of Clinical Oncology, Vol 26, No 2 (January 10), 2008: pp. 333-334 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.14.8437
In ReplyDepartment of Medical Oncology and Hematology, Princess Margaret Hospital, University Health Network; University of Toronto, Toronto, Ontario, Canada QT interval prolongation is a serious adverse drug reaction due to its potential to degenerate into malignant ventricular arrhythmia such as torsade de pointes (TdP) and sudden cardiac death. From 1990 to 2006, QT interval prolongation and TdP accounted for 29% of cardiac and noncardiac drug postmarketing withdrawals from major US and European Union markets.1 QT effects have been observed in oncological therapeutics, particularly with some molecularly targeted agents, generating interest and concern in this often-silent toxicity. The histone deacetylase (HDAC) inhibitors are an emergent class of anticancer drugs that induce histone and nonhistone protein deacetylation, chromatin condensation, and gene expression modulation.2 HDAC inhibitors in various phases of clinical development have demonstrated an assortment of adverse cardiac events, ranging from asymptomatic QT interval prolongation to TdP and sudden death.3-5 Olsen et al recently published a phase IIb clinical trial of the HDAC inhibitor vorinistat in refractory cutaneous T-cell lymphoma and reported a low incidence of drug-related QT events.6 Three of 74 patients (4%) experienced asymptomatic prolongation of the QT interval of less than grade 2 severity, and no grade 3 or worse QT events were observed. The authors suggested that the incidence and severity of vorinostat's QT-effects were "much lower" than that observed with other HDAC inhibitors, namely depsipeptide and panobinostat (LBH589). In turn, Zhang et al in this issue argue that this comparative statement is not valid, specifically with respect to panobinostat. This rebuttal is supported by a review of the accumulated phase I trial data of panobinostat on QT interval. Further, QT prolongation was referenced from our review article as being a class effect common to all HDAC inhibitors, a claim that we did not definitively make.7 In order to view QT-interval prolongation in context, one must first step back and address several important questions about our ability to detect and analyze serious adverse drug reactions. From the standpoint of detection, there is a reasonable probability that infrequent toxicities may remain unobserved during premarketing clinical trials. Table 1 outlines the mathematical likelihood of overlooking uncommon toxicities (eg, 1% and 5% true incidence rates) based on study sample size.8 As many early phase trial protocols use rapid dose escalation methods with limited numbers of patients, it is quite possible that rare but important toxicities are missed. In situations where the frequency of QT prolongation is dose-dependent, there must be sufficient numbers of patients receiving drug at or above a threshold dose for this event to be observed. A further caveat is that toxicities such as QT prolongation can often remain occult without clinical sequelae in the absence of repeated ECG screening.
Analytically, it is challenging to accurately contrast and compare data related to adverse drug effects across multiple phase I and II trials. Zhang et al acknowledged in their commentary the limitations of comparing panobinostat to vorinostat, given the heterogeneity inherent to early phase clinical trials, incongruence in ECG monitoring, and difference in patient populations. In the context of QT prolongation, this variability may be further exacerbated by the presence of confounding factors extrinsic to direct drug effects, such as electrolyte disturbances (which frequently occur in the setting of nausea, vomiting, and diarrhea), patients' pre-existing cardiac conditions, as well as concomitant usage of other medications, particularly some antiemetics that may affect the QT interval. Zhang et al suggested in their letter that the QT-prolonging effects observed with several HDAC inhibitors may be a class effect. HDAC inhibitors with different chemical structures variably demonstrate this toxicity (ie, the hydroxamic acids vorinostat, panobinostat, and LAQ824; the cyclic peptide derivative depsipeptide), while other agents have not demonstrated QT effects thus far (ie, the hydroxamic acid PXD101 and the benzamide CI-994). Interestingly, the term "class effect" is not clearly defined scientifically, clinically, or from a regulatory perspective, and this lack of consensus has led to varying interpretations of the term.9 The US Food and Drug Administration uses class labeling when "all products within a class are assumed to be closely related in chemical structure, pharmacology, therapeutic activity, and adverse reactions."10 This terminology is complex, as drug actions that are specific to an individual agent within a class may or may not contribute to the efficacy or safety attributed to a common class of actions.11 Without properly designed event trials comparing drugs of the same family, it is not possible to definitively establish comparability within a family of drugs that share a mechanism of action.12 Review of the published data on QT prolongation from completed phase I and II trials of HDAC inhibitors indicates that both the detection and analysis of this adverse drug reaction are challenging. When QT prolongation has been demonstrated, its low frequency and the presence of confounding factors have made it difficult to draw conclusions on causal relationships. When QT prolongation has not been demonstrated, one questions whether the effect has been missed, either due to small sample size or inadequate ECG screening measures. Given the fact that most HDAC inhibitors are still in relatively early stages of clinical development, clinicians and scientists alike must be cautioned that assessments of this toxicity are preliminary at best, and require further evaluation in larger studies with more directed examination of QT effects. Based on our current knowledge, it is premature to draw definitive conclusions or make sweeping in-class comparisons regarding the QT toxicity of HDAC inhibitors. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
REFERENCES 1. Shah RR: Can pharmacogenetics help rescue drugs withdrawn from the market? Pharmacogenomics 7:889-908, 2006[CrossRef][Medline] 2. Richon VM, O’Brien JP: Histone deacetylase inhibitors: A new class of potential therapeutic agents for cancer treatment. Clin Cancer Res 8:662-664, 2002 3. Fischer T, Patnaik A, Bhalla K, et al: Results of cardiac monitoring during phase I trials of a novel histone deacetylase (HDAC) inhibitor LBH589 in patients with advanced solid tumors and hematologic malignancies. J Clin Oncol 23:3106, 2005 4. Rowinsky E, de Bono J, Deangelo D, et al: Cardiac monitoring in phase I trials of a novel histone deacetylase (HDAC) inhibitor LAQ824 in patients with advanced solid tumors and hematologic malignancies. J Clin Oncol 23:16s, 2005 (suppl; abstr 3131) 5. Shah MH, Binkley P, Chan K, et al: Cardiotoxicity of histone deacetylase inhibitor depsipeptide in patients with metastatic neuroendocrine tumors. Clin Cancer Res 12:3997-4003, 2006 6. Olsen EA, Kim YH, Kuzel TM, et al: Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J Clin Oncol 25:3109-3115, 2007 7. Strevel EL, Ing DJ, Siu LL: Molecularly targeted oncology therapeutics and prolongation of the QT interval. J Clin Oncol 25:3362-3371, 2007 8. Edler L: Overview of phase I trials, in Crowley J (ed): Handbook of statistics in clinical oncology. New York, NY, Mercel Dekker Inc, pp 20, 2001 9. Furberg CD, Herrington DM, Psaty BM: Are drugs within a class interchangeable? Lancet 354:1202-1204, 1999[CrossRef][Medline] 10. Food and Drug Administration DoHaHS: Single Entity Barbiturates; Class Labeling Guidance, in Register F (ed). Rockville, MD, US FDA, 1980, pp 76356-76367 11. Furberg CD, Psaty BM: Should evidence-based proof of drug efficacy be extrapolated to a "class of agents?" Circulation 108:2608-2610, 2003 12. Antman EM, Ferguson JJ: Should evidence-based proof of efficacy as defined for a specific therapeutic agent be extrapolated to encompass a therapeutic class of agents? Circulation 108:2604-2607, 2003
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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