Hypersensitivity to romidepsin
Authors: Rohit Kakar, Jenneé Rommel, Lynn McKinley-Grant, Aarthi G. Shenoy, Jennifer A. DeSimone
Journal: Journal of the American Academy of Dermatology (2013)

To the Editor: Romidepsin is a histone deacetylase inhibitor that is FDA-approved for the treatment of refractory cutaneous T-cell lymphoma (CTCL). It is generally considered to be well tolerated, excluding previously demonstrated hematologic toxicities.1Kim M. Thompson L.A. Wenger S.D. O’Bryant C.L. Romidepsin: a histone deacetylase inhibitor for refractory cutaneous T-cell lymphoma.Ann Pharmacother. 2012; 46: 1340-1348Crossref PubMed Scopus (21) Google Scholar We report a case of a hypersensitivity reaction to romidepsin. A 34-year-old black woman with stage IIIA CTCL diagnosed in 2010 was started on romidepsin in April 2013 for refractory disease. Previous treatments included psoralen with ultraviolet light A, extracorporeal photophoresis, interferon, bexarotene, and doxorubicin with limited to no improvement. She tolerated the first 2 cycles of romidepsin well with the initial dose administered at 10 mg/m2 and the remaining doses at 14 mg/m2; however, she was noted to have a low-grade fever, tachycardia, burning sensation of her skin, and headache for 24 hours following each infusion. Immediately after completion of the second 14-mg/m2 dose of cycle 3, she became febrile to 39.5°C, tachycardic to 150 bpm, hypotensive, and erythrodermic, necessitating admission to the intensive care unit for emergent resuscitation. Following stabilization and transfer to the general medical floor, she showed remarkable therapeutic response to romidepsin with dramatic resolution of thick CTCL plaques. Although our inpatient team suspected drug reaction, she had been started on doxycycline 100 mg twice daily for an unrelated soft tissue infection before her hypersensitivity event, which complicated the clinical picture. Because of her clinical stability and marked response to the drug, 7 days after admission, while still an inpatient, another 14-mg/m2 infusion of romidepsin was administered with 125 mg of intravenous methylprednisone premedication. After 25% of the romidepsin had been infused, pruritus and urticarial pink plaques developed, prompting its discontinuation. Within 1 hour, the patient became febrile to 39.5°C, tachycardic to 160 bpm, hypotensive, erythrodermic, and complained of skin pain. Fluids, broad-spectrum antimicrobials for suspected sepsis, and systemic corticosteroids were used as supportive care, and systemic symptoms resolved within 24 hours. Of note, all cultures during her hospitalization were negative. The progressive decrease in time between the initiation of therapy and onset of symptoms, as well as the increased severity of symptoms with each successive infusion, is highly suggestive of hypersensitivity to romidepsin. In retrospect, the patient’s initial symptom of fever beginning early in the treatment course may represent a component of the same drug reaction that intensified with each infusion. Previous clinical trials have reported romidepsin therapy to be generally well tolerated with fatigue, nausea, vomiting, and infections as common adverse effects.2Piekarz R.L. Frye R. Prince H.M. Kirschbaum M.H. Zain J. Allen S. et al.Phase 2 trial of romidepsin in patients with peripheral T-cell lymphoma.Blood. 2011; 117: 5827-5834Crossref PubMed Scopus (381) Google Scholar, 3Sandor V. Bakke S. Robey R.W. Kang M.H. Balgosklonny M.V. Bender J. et al.Phase I trial of the histone deacetylase inhibitor, depsipeptide (FR901228, NSC 630176), in patients with refractory neoplasms.Clin Cancer Res. 2002; 8: 718-728PubMed Google Scholar, 4Marshall J.L. Rizvi N. Kauh J. Dahut W. Figuera M. Kang M.H. et al.A phase I trial of depsipeptide (FR901228) in patients with advanced cancer.J Exp Ther Oncol. 2002; 2: 325-332Crossref PubMed Scopus (199) Google Scholar, 5Piekarz R.L. Frye R. Turner M. Wright J.J. Allen S.L. Kirschbaum M.H. et al.Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma.J Clin Oncol. 2009; 27: 5410-5417Crossref PubMed Scopus (635) Google Scholar Leucopenia, granulocytopenia, lymphopenia, thrombocytopenia, and anemia comprise the reported hematologic side effect profile.2Piekarz R.L. Frye R. Prince H.M. Kirschbaum M.H. Zain J. Allen S. et al.Phase 2 trial of romidepsin in patients with peripheral T-cell lymphoma.Blood. 2011; 117: 5827-5834Crossref PubMed Scopus (381) Google Scholar The death of patients in a trial of romidepsin has also been reported, but these patients were noted to have significant risk factors for sudden death.2Piekarz R.L. Frye R. Prince H.M. Kirschbaum M.H. Zain J. Allen S. et al.Phase 2 trial of romidepsin in patients with peripheral T-cell lymphoma.Blood. 2011; 117: 5827-5834Crossref PubMed Scopus (381) Google Scholar Earlier trials, however, have not described the occurrence of hypersensitivity reactions among the patients studied. Additionally, to our knowledge, there are no previous reports of such reactions to romidepsin in the published literature. In view of the life-threatening reaction seen in our patient, it is paramount to consider a hypersensitivity reaction when a patient experiences symptoms suggestive of an immune-mediated response, such as fever, diffuse erythema, and/or hemodynamic changes.