Mogamulizumab, a defucosylated humanized anti-CCR4 monoclonal antibody, recently gained approval from the US Food and Drug Administration for pretreated relapsed or refractory mycosis fungoides and Sézary syndrome (SS). Mogamulizumab has been associated with a variety of cutaneous adverse events, sometimes prompting treatment discontinuation in initial studies.1 In this 12-patient case series, we found that mogamulizumab-associated cutaneous granulomatous drug eruption (CGDE) may herald a superior treatment outcome despite clinically mimicking progressive disease. Furthermore, we show a helper T cell, type 1 (TH1)-preponderant response reflecting mogamulizumab’s targeted cytotoxic effects against CCR4-expressing malignant SS and benign TH2/regulatory T (Treg) cells.
With approval of the Washington University institutional review board, all patients treated with mogamulizumab at Washington University under the auspices of the phase III MAVORIC trial (NCT01728805) who developed biopsy-proven CGDE were included. All patients provided their written informed consent. Progression-free survival (PFS) and treatment response were assessed using global response criteria.2
Of the 12 patients receiving mogamulizumab, 6 with stage IVA SS developed an asymptomatic CGDE clinically mimicking cutaneous disease progression after a median of 4.6 months (range, 1.4-6.0 months) of therapy (Table).3 Lesions presented as erythematous macules (Figure, A) with a predilection for photoprotected sites and evolved into scaly, erythematous plaques (Figure, B) following successive mogamulizumab infusions. All eruptions reached grade 2 severity and improved following application of topical clobetasol ointment or interruption or discontinuation of mogamulizumab therapy.
Among the patients who developed CGDE, treatment with mogamulizumab yielded a median PFS of 19.0 months (range, 4.6-36.6 months) and an overall response rate of 67% (4 of 6) including global complete response (CR) in 50% (3 of 6). For comparison, the median PFS and overall response rate in the mogamulizumab group in the MAVORIC trial were 7.7 months and 28%, respectively.1 Following study protocol, 3 patients withdrew from the study (1 after 35.4 months of CR, 1 after 12.2 months of partial response, and 1 after 11.0 months of stable disease) because their CGDE remained grade 2 in severity after a 4-week course of topical corticosteroids.1 Two patients withdrew consent, one at 12.6 months (recurrent CGDE) and the other at 15.1 months (recurrent infections) while in CR. Both of these patients showed durable disease control with PFS of 28.3 and 25.8 months, respectively. Five of the 6 patients maintained their best global clinical response, including CR in blood, throughout the course of their CGDE.
The 6 patients underwent 12 total skin punch biopsies. All biopsies demonstrated granulomatous infiltrates consisting of loosely clustered epithelioid histiocytes with accompanying lymphocytes, eosinophils, and/or multinucleated giant cells (Figure, C and D), normalization or inversion of CD4:CD8 ratios, and preservation of CD7. Histiocytes were highlighted by CD68 immunohistochemical analysis, and granulomatous differentiation was confirmed by strong membranous staining for E-cadherin.4,5 Granulomata had not been noted on any biopsies prior to mogamulizumab therapy, and molecular studies showed polyclonal T-cell receptor gene rearrangements, excluding disease progression with mogamulizumab-associated histomorphological change into a granulomatous phenotype. While SS lesions typically exhibit strong TH2 skewing, CGDE lesional biopsies revealed a predominance of TH1 cells (CD3+/T-bet+) and T-bet–expressing histiocytes (CD68+/T-bet+) with diminished TH2 cells (CD3+/GATA-3+) and reduced Treg cells (FoxP3+/CD25+).3
While interpretation of results may be limited by sample size, all patients who achieved global clinical response to mogamulizumab in the present study also developed CGDE. These observations suggest that CGDE correlates with durable mogamulizumab response, most likely reflecting a shift toward an antitumoral TH1 inflammatory milieu. Mechanistically, anti-CCR4 effects induce TH1 polarization and reduce Treg cells, producing granulomatous eruptions while suppressing disease activity.6
Distinguishing mogamulizumab-associated CGDE from disease progression is crucial. In initial trials, CGDE may have been either a reason for study discontinuation or misinterpreted as progressive disease, potentially resulting in underrepresentation of mogamulizumab’s therapeutic benefit. In our view, a new skin eruption in a mogamulizumab-treated patient with mycosis fungoides or SS should prompt peripheral blood flow cytometry and skin biopsy with T-cell receptor sequencing. Accordingly, histologic diagnosis of CGDE may support continued mogamulizumab administration with an appropriate adjunctive therapy (eg, topical corticosteroids, modified mogamulizumab schedule, narrowband UV-B) and the ultimate goal of extending PFS.
Corresponding Author: Amy Musiek, MD, Division of Dermatology, Department of Medicine, Washington University School of Medicine in St Louis, 660 S Euclid Ave, Campus Box 8123, St Louis, MO 63110 (firstname.lastname@example.org).
Published Online: May 29, 2019. doi:10.1001/jamadermatol.2019.0369
Author Contributions: Drs Chen and Musiek had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Carson, Schaffer, Musiek.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Chen, Staser.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Chen, Mehta-Shah, Musiek.
Obtained funding: Chen, Rosman.
Administrative, technical, or material support: Carson.
Study supervision: Carson, Mehta-Shah, Schaffer, Musiek.
Conflict of Interest Disclosures: Dr Carson is employed by Flatiron Health and received consultancy fees from Roche; he also reports grants from Kyowa Hakko Kirin and personal fees from Flatiron Health and Roche outside the submitted work. Dr Mehta-Shah received research support from Celgene, Verastem, Bristol-Myers Squibb, and Genentech and consultancy fees from Spectrum; she also reports personal fees from Kyowa Hakko Kirin outside the submitted work. Dr Schaffer received personal fees and honoraria from Wolters Kluwer for his textbook Hematopathology of the Skin. Dr Musiek served as an investigator for Actelion Pharmaceuticals, Kyowa Hakko Kirin, and Soligenix and as an advisory board member for Actelion Pharmaceuticals, Kyowa Hakko Kirin, and Seattle Genetics; she also reports other associations and personal fees from Kyowa Hakko Kirin during the conduct of the study as well as other associations with Elorac, miRagen, Soligenix, and personal fees from Seattle Genetics and Actelion outside the submitted work. While Dr Musiek was an investigator for Kyowa Hakko Kirin for the MAVORIC trial, the observations reported herein were made independently of Kyowa Hakko Kirin and first noticed only during weekly clinicopathological conferences with dermatologic, oncologic, and dermatopathologic colleagues. No other disclosures were reported.
Funding/Support: This work was supported in part by research funding from the Washington University School of Medicine Department of Pathology and Immunology Research Grant Program to Drs Chen and Rosman.
Role of the Funder/Sponsor: The Washington University School of Medicine Department of Pathology and Immunology had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Information: Per the MAVORIC data sharing agreement, representatives of Kyowa Hakko Kirin have read the manuscript of this article. However, no edits or changes were made based on their reading. Kyowa Hakko Kirin did not provide any funding and had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contributions: We thank patient 2 for granting permission to publish this information. We also thank Mary Tabacchi, Dermatology Clinical Trials Unit, Division of Dermatology, Department of Medicine, Washington University School of Medicine in St Louis, St Louis, Missouri, for administrative support. She received no compensation for her contributions.
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