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HDAC Inhibitors and Cardiac Safety

Ohio State University, Columbus, Ohio

In Response: In response to the Editorial (1) published about our article entitled "Cardiotoxicity of histone deacetylase inhibitor depsipeptide in patients with metastatic neuroendocrine tumors" (2) and in response to the Letter to Editor in this issue by Molife et al., we make the following points:

1. 1. Four of the six serious cardiac adverse events we reported 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 tachycardia for which hospitalization was prolonged. Although we used "serious cardiac adverse events" eight times in our article, this was preceded seven times by the term "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-threatening adverse events as grade 1, 2, 3, and 4, respectively. However, each adverse event needs to be assessed in the context of specific clinical settings. For example, grade 2 neutropenia (neutrophil counts between 1,000/mm³ and 1,500/mm³) may pose different risk than grade 2 ventricular arrhythmia (e.g., torsade de pointes requiring nonurgent medical intervention). Similarly, a QTc interval of 499 ms (grade 2) may be as risky as having a QTc of 501 ms (grade 3).
   
2. 2. On the aggregate, our group has broad experience and expertise in oncology drug development and has played a critical role in salvaging and optimizing the use of several drugs (e.g., flavopiridol, pentostatin, fludarabine, and rituximab) 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, in the past, we have been very committed to the clinical development of this compound. Our most recent report was intended to accurately convey our findings. In our opinion, six sudden deaths reported in 450 patients treated with depsipeptide in early-phase clinical trials is alarming regardless of the underlying patient risk factors for sudden death. Such results indicate that despite extensive preclinical and phase I clinical trial experience, we have not yet identified specific risk factors for sudden death that may be related to this agent. This is a particularly important point given that other therapeutic compounds within the same class of drugs of depsipeptide may lack this unacceptable toxicity. We never suggested "abandoning" this class of agents as stated in the Editorial, but stressed that continued evaluation of these agents be pursued to identify risks associated with cardiotoxicity.
   
3. 3. After weighing the risk to benefit ratio to our patients, 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 further studies to learn factors predisposing to uncommon but 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 available for clinical investigation, we have chosen to focus on alternative histone deacetylase inhibitors in our preclinical and clinical studies at The Ohio State University.
   

References

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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.[Abstract/Free Full Text]
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5. Sandor V, Bakke S, Robey RW, et al. Phase I trial of the histone deacetylase inhibitor, depsipeptide (FR901228, NSC 630176), in patients with refractory neoplasms. Clin Cancer Res 2002;8:718–28.[Abstract/Free Full Text]
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