HDACInhibitorsandCardiacSafety InResponse: In response to the Editorial (1) published aboutourarticleentitled‘‘Cardiotoxicityofhistonedeacetylase inhibitor depsipeptide in patients with metastatic neuroendo- crinetumors’’(2)andinresponsetotheLettertoEditorinthis issuebyMolifeetal.,wemakethefollowingpoints: 1.Fourofthesixseriouscardiacadverseeventswereported met the definition of serious adverse event by the common terminology criteria for adverse events as follows: one patient had sudden death; one patient with grade 2 prolonged QTc (QTc of 499 ms) was hospitalized for close monitoring of cardiac arrhythmia; and two patients developed ventricular tachycardiaforwhichhospitalizationwasprolonged.Although we used ‘‘serious cardiac adverse events’’ eight times in our article,thiswasprecededseventimesbytheterm‘‘potential’’to underscore that prolonged QTc or ventricular tachycardia potentially could result in serious outcome. In general, the common terminology criteria for adverse events grading classifies mild, moderate, severe, and life- threateningadverseeventsasgrade1,2,3,and4,respectively. However,eachadverseeventneedstobeassessedinthecontext of specific clinical settings. For example, grade 2 neutropenia (neutrophil counts between 1,000/mm 3 and 1,500/mm 3 )may pose different risk than grade 2 ventricular arrhythmia (e.g., torsade de pointes requiring nonurgent medical intervention). Similarly,aQTcintervalof499ms(grade2)maybeasriskyas havingaQTcof501ms(grade3). 2. On the aggregate, our group has broad experience and expertise in oncology drug development and has played a criticalroleinsalvagingandoptimizingtheuseofseveraldrugs (e.g.,flavopiridol,pentostatin,fludarabine,andrituximab)that are now in the advanced stages of clinical trials or routinely used as standard of care. Additionally, we have been active in reporting many toxicities associated with common oncology drugs. Similarly, our group has a decade-long experience working with depsipeptide both preclinically and clinically (3–7);thus,inthepast,wehavebeenverycommittedtothe clinicaldevelopmentofthiscompound.Ourmostrecentreport wasintendedtoaccuratelyconveyourfindings.Inouropinion, six sudden deaths reported in f450 patients treated with depsipeptideinearly-phaseclinicaltrialsisalarmingregardless of the underlying patient risk factors for sudden death. Such results indicate that despite extensive preclinical and phase I clinicaltrialexperience,wehavenotyetidentifiedspecificrisk factorsforsuddendeaththatmayberelatedtothisagent.This is a particularly important point given that other therapeutic compoundswithinthesameclassofdrugsofdepsipeptidemay lack this unacceptable toxicity. We never suggested ‘‘abandon- ing’’ this class of agents as stated in the Editorial, but stressed thatcontinuedevaluationoftheseagentsbepursuedtoidentify risks associated with cardiotoxicity. 3.Afterweighingtherisktobenefitratiotoourpatients,we collectively decided to terminate the phase II depsipeptide study in patients with metastatic neuroendocrine cancers and not to initiate additional studies with this agent in leukemia and lymphoma. Given the enormous potential histone deacetylase inhibitors have in oncology, we do believe that furtherstudiestolearnfactorspredisposingtouncommonbut fatal events are of great importance. It is the process of identifying, reporting, and learning the management of toxicities of several chemotherapeutic agents that has allowed us to use most of the oncology drugs effectively in the clinic today. However, given that promising alternative agents targeting histone deacetylase may lack the risk of sudden cardiac death as an unpredicted rare toxicity are currently availableforclinicalinvestigation,wehavechosentofocuson alternativehistonedeacetylaseinhibitorsinourpreclinicaland clinical studies at The Ohio State University. Manisha H. Shah Miguel A. Villalona-Calero Guido Marcucci John C. Byrd Michael R. Grever Ohio State University, Columbus, Ohio References 1. Bates SE, Rosing DR, FojoT, Piekarz RL. Challenges of evaluating the cardiac effects ofanticanceragents.Clin Cancer Res 2006;12:3871^4. 2. Shah MH, Binkley P, Chan K, et al. Cardiotoxicity of histone deacetylase inhibitor depsipeptide in patients with metastatic neuroendocrine tumors. Clin Cancer Res 2006;12:3997^4003. 3. ChanKK,BakhtiarR,JiangC.Depsipeptide(FR901228,NSC-630176)pharma- cokinetics in the rat by LC/MS/MS. Invest New Drugs1997;15:195^206. 4. Byrd JC, Shinn C, Ravi R, et al. Depsipeptide (FR901228): a novel therapeutic agent with selective, in vitro activity against human B-cell chronic lymphocytic leukemiacells.Blood1999;94:1401^8. 5. Sandor V, Bakke S, Robey RW, et al. Phase I trial of the histone deacetylase in- hibitor, depsipeptide (FR901228, NSC 630176), in patients with refractory neo- plasms.Clin Cancer Res 2002;8:718^28. 6. Klisovic MI, Maghraby EA, Parthun MR, et al. Depsipeptide (FR 901228) pro- motes histone acetylation, gene transcription, apoptosis andits activity is en- hanced by DNA methyltransferase inhibitors in AML1/ETO-positive leukemic cells.Leukemia2003;17:350^8. 7. ByrdJC,MarcucciG,ParthunMR,etal.AphaseIandpharmacodynamicstudyof depsipeptide (FK228) in chronic lymphocytic leukemia and acute myeloid leuke- mia.Blood2005;105:959^67.Epub2004Oct5. F 2007AmericanAssociationforCancerResearch. doi:10.1158/1078-0432.CCR-06-2380 Letters to the Editor www.aacrjournals.org ClinCancerRes2007;13(3)February1,2007 1068 Research. on May 27, 2017. © 2007 American Association for Cancer clincancerres.aacrjournals.org Downloaded from