Aggressive Skin Cancers Occurring in Patients Treated With the Janus Kinase Inhibitor Ruxolitinib

May 2017 | Volume 16 | Issue 5 | Case Report | 508 | Copyright © 2017

Adam B. Blechman MD,a Christine E. Cabell MD,b Christine H. Weinberger MD,c Anna Duckworth MD,d Justin J. Leitenberger MD,e Fiona O. Zwald MD,f and Mark A. Russell MDg

aDepartment of Dermatology, University of Virginia Health System, Charlottesville, VA bGeisinger Medical Center, Wilkes-Barre, PA cDivision of Dermatology, University of Vermont Medical Center, Burlington, VT dSavannah River Dermatology, Augusta, GA eDepartment of Dermatology, Oregon Health and Science University, Portland, OR fDermatology Consultants PC, Piedmont Transplant Institute, Piedmont Hospital, Atlanta, GA gDepartment of Dermatology, University of Virginia Health System, Charlottesville, VA

Abstract

The Food and Drug Administration approved Ruxolitinib in 2011 for the treatment of primary myelofibrosis. Five-year safety data showed a higher incidence of skin cancer in patients treated with Ruxolitinib compared to best available therapy for myelofibrosis. This report presents a series of five patients with history of myelofibrosis treated with Ruxolitinib who subsequently developed numerous skin cancers with aggressive biological behavior. Each patient in this report was treated by a Mohs surgeon affiliated with an academic institution. All patients had a history of myelofibrosis and were exposed to Ruxolitinib. Some patients were exposed to other immunomodulatory medications such as Hydroxyurea and Rituximab. The total number of skin cancers and skin cancers with particularly aggressive behavior were noted. All five patients in this series developed numerous skin cancers with aggressive biological behavior during or after therapy with Ruxolitinib. Also, one patient developed lentigo maligna melanoma and another developed metastatic undifferentiated pleomorphic sarcoma. The repeat observation of skin cancers with aggressive features during JAK inhibitor treatment suggests that these medications may promote cutaneous malignant transformation in at risk patients. Further surveillance and testing of JAK kinases regarding the risk of skin cancers is indicated.

J Drugs Dermatol. 2017;16(5):508-511.

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INTRODUCTION

Ruxolitinib selectively inhibits JAK1 and JAK2, two molecules of the Janus kinase (JAK) family.1 JAKs are tyrosine kinases connected in pairs to intracellular domains of transmembrane receptors. Many patients with myeloproliferative disorders have gain of function V617F mutations in JAK2. These patients have longer disease duration and increased chance of fibrosis.2 The Food and Drug Administration approved Ruxolitinib in 2011 for the treatment of primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis.1Five-year efficacy data on Ruxolitinib showed it improves quality of life and overall survival in patients with myelofibrosis compared with best available therapy. Among the side effects, 17.1% of patients on Ruxolitinib developed basal cell carcinomas (BCCs) or squamous cell carcinomas (SCCs) compared with only 2.7% of patients on best available therapy.1 We report a series of five patients with history of myelofibrosis treated with Ruxolitinib who developed multiple skin cancers with particularly aggressive features.

REPORT OF CASES

Case 1

A 60-year-old male was diagnosed with polycythemia vera (PCV) with Jak-2+ myelofibrosis. The patient was treated with Hydroxyurea 500 mg three times a week up to 2 grams daily and phlebotomy for ten years until he developed fatigue. Approximately two years later the patient was started on PO Ruxolitinib 10 mg BID, which after a few months was increased to 20 mg BID. He continued this dose for four years without any other immunomodulatory medications.The patient had a Fitzpatrick skin type II and endorsed an active outdoor lifestyle with extensive sun exposure. The patient had no known history of skin cancer prior to the diagnosis of PCV with myelofibrosis. He developed his first skin cancers, two squamous cell carcinoma in situ (SCCISs), approximately ten years after PCV diagnosis and commencing Hydroxyurea. Over the following seven years, he developed three new SCCIS, one BCC, three SCCs and one undifferentiated pleomorphic sarcoma of the scalp, the majority of which were diagnosed during the last four years of patient’s life, while he was being treated with Ruxolitinib and off Hydroxyurea.

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