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Fig 1. Clinical appearance before initiation of romidepsin.There is no image immediately before initiation of therapywith romidepsin.
Fig 2. Resolution of cutaneous disease after 3 cycles ofromidepsin in combination with 3 times weekly interferongamma.
Romidepsin and interferon gamma: A novelcombination for refractory cutaneous T-celllymphoma
To the Editor: A 62-year-old man presented to ourclinic with a history of red pruritic nodules and wasdiagnosed with mycosis fungoides/cutaneous T-celllymphoma (CTCL), stage IIB (T3 N2 M0 B1).Combination therapy was initiated with oral bexar-otene, interferon alfa-2b, and extracorporeal photo-pheresis. Four months later, total skin electron beamtherapy and interferon gamma were added andresulted in a complete response in the skin, butwithin 2 months, he developed widespread recur-rent skin nodules (Fig 1).
He was referred to oncology and treated withdenileukin diftitox/interferon gamma but after twocycles developed severe fatigue and edema, thenswitched to gemcitabine/interferon gamma, but be-came erythrodermic. He was subsequently treatedwith the novel histone deacetylase inhibitor (HDACi)romidepsin (14mg/m2weekly on days 1, 8, and 15 ofa 28-day cycle) and interferon gamma (2 mIU sub-cutaneously 3 times weekly). After 3 cycles, hispruritus and skin lesions dramatically improved,and by 6 cycles he had achieved a near completeresponse (Fig 2). He is currently on maintenancetreatment (romidepsin 14 mg/m2 every 2 weeks,interferon gamma 2 mIU 3 times weekly) for 3months. He has tolerated treatment well with onlygrade 1/2 fatigue, nausea, leukopenia, anemia, andthrombocytopenia and has not required dose reduc-tion. Of note, he has not experienced the typicalbacterial or viral reactivation infections typically seenin other patients with advanced refractory CTCL.
Multimodality immunomodulatory combinationtherapy is an effective approach for patients withmycosis fungoides/CTCL who have higher clinicalresponse rates and longer survivals than historicalcontrol subjects. In all, 84% experience either apartial or complete response with an increase inmedian survival in patients with stage III or IVdisease.1
We present here a case of refractory CTCL thatresponded to romidepsin and interferon gamma, anovel combination not previously reported to ourknowledge. We previously described 3 patients withaggressive refractory CTCL treated with combinationinterferon gamma and a different HDACi, oralvorinostat.2 Interferon gamma is an immunomodu-latory cytokine that is a standard systemic agent used
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in CTCL as summarized in the current NationalComprehensive Cancer Network clinical practiceguidelines for mycosis fungoides/CTCL. It acts todecrease interleukin (IL)-4 production, restoresT helper cell type 1 (Th1) cytokine profiles, andenhances cell-mediated immunity.
Romidepsin, a novel member of HDACi, wasFood and Drug Administration approved for refrac-tory CTCL in 2009. Clinical studies demonstrated anoverall response rate of 34% in all patients and 38% inthose with advanced stage disease ([IIB).3 HDACisregulate gene expression/transcription and non-histone proteins by epigenetic modifications. Theyinhibit tumor progression by multiple mechanisms:apoptosis, cell cycle arrest, growth inhibition,induction of differentiation, antiangiogenic effects,
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Fig 1. Epidermal inclusion cyst at low power.
Fig 2. High power of the cyst wall reveals pale stainingmelanocytes in cyst wall and surrounding dermis. Inset:Cells strongly positive for Melan-A with immunoperox-idase staining.
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anti-invasion, and immunomodulatory effects.4
Combination with other anticancer agents is be-lieved to be critical to enhance the myriad effectsof HDACi for synergistic antitumor activity.
It is also speculated that HDACis suppress secre-tion of proinflammatory cytokines such as interferongamma and increase FoxP3 expressing regulatory Tcells resulting in decreased IL-2 production, whichcould also result in immunosuppression.4,5 The ad-dition of interferon gamma therapy in combinationwith romidepsin may stabilize Th1 cytokine profilesand counteract the possible immunosuppressiveeffects of HDACi therapy by enhancing cytotoxicT-cell activity and promoting a more robust antitu-mor response.
Sara Samimi, MD, Kelly Morrissey, MD, SashaAnshelevich, BA, Katherine Evans, MD, JenniferGardner, MD, Amy Musiek, MD, Carmela Vit-torio, MD, Alain Rook, MD, and Ellen Kim, MD
Department of Dermatology, University of Pennsyl-vania, Philadelphia
Funding sources: None.
Conflicts of interest: None declared.
Correspondence to: Sara Samimi, MD, Departmentof Dermatology, University of Pennsylvania,3600 Spruce St, Philadelphia, PA 19104.
E-mail: [email protected]
REFERENCES
1. Suchin KR, Cucchiara AJ, Gottleib SL, Wolfe JT, DeNardo BJ,
Macey WH, et al. Treatment of cutaneous T-cell lymphoma with
combined immunomodulatory therapy: a 14-year experience at
a single institution. Arch Dermatol 2002;138:1054-60.
2. Gardner JM, Introcaso CE, Nasta SD, Kim EJ, Vittorio CC, Rook
AH. A novel regimen of vorinostat with interferon gamma
for refractory S�ezary syndrome. J Am Acad Dermatol
2009;61:112-6.
3. Whittaker SJ, Demierre MF, Kim EJ, Rook AH, Lerner A, Duvic M,
et al. Final results from a multicenter, international, pivotal
study of romidepsin in refractory cutaneous T-cell lymphoma.
J Clin Oncol 2010;28:4485-91.
4. Bolden JE, Peart MJ, Johnstone RW. Anticancer activities of
histone deacetylase inhibitors. Nat Rev Drug Discov
2006;5:769-84.
5. Reddy P, Zou W. Blocking HDACs boosts regulatory T cells. Nat
Med 2007;13:1282-4.
http://dx.doi.org/10.1016/j.jaad.2011.06.043
Melanoma arising from an epidermalinclusion cyst
To the Editor: We present a case of malignantmelanoma arising within a clinically benign appear-ing epidermal inclusion cyst.
A 55-year-old man presented with a 1-monthhistory of a lesion on the mid-anterior region of hisneck. He had a history of basal cell carcinomalocated on the right nasal sidewall which began 5years earlier. The physical examination revealed a1.3-3 1.5-cm cystic nodule in the suprahyoid regionof the anterior neck. The nodule was soft, mobile,nontender, and flesh colored. The remainder of thephysical exam was unremarkable. The nodule wasexcised and intraoperatively determined to be con-sistent with an epidermal inclusion cyst (EIC). Nopigmentation was noted on gross inspection or afterexcision in the lab.
Histopathologic examination of the excised cysticmass revealed a cytologically bland cyst lined bysquamous epithelium colonized by atypical cellswith small, hyperchromatic nuclei and scant cyto-plasm (Fig 1). More than 50% of the cyst wallcontained these atypical cells. In some foci of the