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Table of Contents
CASE REPORT
Year : 2020  |  Volume : 24  |  Issue : 2  |  Page : 137-139

Atypical Stevens–Johnson syndrome caused by pembrolizumab in the treatment of metastatic melanoma – Are corticosteroids a safe treatment option?


1 Department of Dermatology, University Hospital Waterford, Waterford, Ireland
2 Department of Oncology, University Hospital Waterford, Waterford, Ireland

Date of Submission27-Jun-2020
Date of Acceptance16-Sep-2020
Date of Web Publication10-Nov-2020

Correspondence Address:
Dr. Cathal OConnor
Department of Dermatology, University Hospital Waterford, Waterford
Ireland
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jdds.jdds_73_20

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  Abstract 


Pembrolizumab is a humanized monoclonal antibody that targets programmed cell death receptor-1. Stevens–Johnson syndrome (SJS) secondary to pembrolizumab has rarely been described in the treatment of malignant melanoma (MM). A 62-year-old woman developed a widespread bullous eruption following administration of her third dose of pembrolizumab for the treatment of MM. A skin biopsy showed sub-epidermal bulla formation with lymphocytic infiltrate and a necrotic roof, consistent with a SJS/toxic epidermal necrolysis (TEN) disorder. Intravenous methylprednisolone was administered. Upon cessation of oral prednisolone, there was a recrudescence of the eruption. A repeat skin biopsy confirmed recurrent SJS. Following a prolonged taper with oral prednisolone, there was no further relapse of SJS. Severe cutaneous adverse reactions such as SJS/TEN have been reported with pembrolizumab and can be associated with significant morbidity and even mortality. High-dose systemic corticosteroids are frequently used in its treatment. Concerns about the potential negative effect of high-dose steroids have re-surfaced, given the observed reduced overall survival in patients with MM. Due to difficulties in performing studies in this population, the benefits and risk of steroids should be considered on a case-by-case basis.

Keywords: Corticosteroids, melanoma, pembrolizumab, Stevens–Johnson syndrome


How to cite this article:
OConnor C, Jordan E, O'Connell M. Atypical Stevens–Johnson syndrome caused by pembrolizumab in the treatment of metastatic melanoma – Are corticosteroids a safe treatment option?. J Dermatol Dermatol Surg 2020;24:137-9

How to cite this URL:
OConnor C, Jordan E, O'Connell M. Atypical Stevens–Johnson syndrome caused by pembrolizumab in the treatment of metastatic melanoma – Are corticosteroids a safe treatment option?. J Dermatol Dermatol Surg [serial online] 2020 [cited 2021 Apr 23];24:137-9. Available from: https://www.jddsjournal.org/text.asp?2020/24/2/137/300396




  Introduction Top


Pembrolizumab is a monoclonal antibody that targets programmed cell death receptor-1 (PD-1).[1] Stevens–Johnson syndrome (SJS) secondary to pembrolizumab has rarely been described.[2] Immunosuppression is complicated by the underlying malignancy.[3]


  Case Report Top


A 62-year-old woman was referred with a cutaneous eruption following administration of pembrolizumab. A 1.2-mm Breslow thickness, nonulcerated, malignant melanoma (MM) had been excised from her lower back in September 2014. Wide local excision and sentinel lymph node biopsy were negative for MM. In May 2018, neurological symptoms developed. Cerebral imaging showed a left frontal lesion. Following craniotomy, the cerebral lesion was confirmed to be MM, with a BRAFV600 mutation present. Postoperative whole-brain irradiation was performed.

Immunotherapy with pembrolizumab was initiated in August 2018. Following her second pembrolizumab dose, three small plaques developed on her thigh, but these resolved spontaneously. Following her third dose in late September, admission was required for drug-induced thyroiditis. On the 12th day after her third dose of pembrolizumab, a widespread maculopapular exanthem developed [Figure 1]. Oral prednisolone was administered at a dose of 1 mg/kg, with potent topical corticosteroids (TCS). The eruption deteriorated over days and a bullous dermatitis developed over 10% of the body surface area, with intense pruritus [Figure 2]. Intravenous methylprednisolone (IVMP) was administered at a dose of 2 mg/kg.
Figure 1: Initial maculopapular exanthema

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Figure 2: Progression to bullous dermatitis

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A skin biopsy showed subepidermal bulla formation with lymphocytic infiltrate and a necrotic roof, consistent with a SJS/toxic epidermal necrolysis (TEN) disorder. Direct immunofluorescence showed granular C3 at the dermoepidermal junction. The eruption began to improve after 7 days of IVMP, and therapy was converted to oral prednisolone. Ophthalmology review was normal, and there was no oral or genital involvement. A tapering dose of oral prednisolone and potent TCS were prescribed.

Following cessation of oral prednisolone and TCS, there was a recrudescence of the eruption (3 months following the last dose of pembrolizumab). A repeat skin biopsy confirmed a recurrent blistering dermatitis consistent with SJS. Oral prednisolone and potent TCS were re-started with good therapeutic effect. After a prolonged taper with oral prednisolone, there was no further relapse of SJS.


  Discussion Top


Pembrolizumab is a humanized monoclonal IgG4 antibody approved for the therapy of several malignancies, including MM.[1] Disruption of the PD-1 receptor and PD-1 ligands permits engagement of T-cells in cytotoxic anticancer effects.[4] Therefore, it acts as an immune checkpoint inhibitor and has shown significant survival benefits in patients with advanced MM.[5]

The development of cutaneous adverse reactions to pembrolizumab is associated with improved outcome.[6] However, severe cutaneous adverse reactions have been reported with their use and can be associated with significant morbidity and even mortality.[7] SJS/TEN develops secondary to an immune response to an antigenic drug–host tissue complex. High-dose systemic corticosteroids are frequently used in its treatment. SJS/TEN secondary to immune checkpoint inhibition may not respond as well to steroids.[8] Previously, it was thought that high-dose steroid use did not attenuate the beneficial effects of anti-tumor immune stimulation. However, concerns about the potential negative effect of high-dose steroids have re-surfaced, given the observed reduced overall survival.[9],[10]

Clinicians should be aware that the half-life of pembrolizumab is 26 days,[1] suggesting that it may be pharmacologically active for several months following the final dose. The slow rate of elimination explains the recurrent SJS seen in this case on cessation of oral steroids. This is the first report of recurrent SJS secondary to pembrolizumab following cessation of corticosteroid therapy, despite withdrawal of pembrolizumab.

Minimal data are available about the implications of high-dose steroid use in patients who develop SJS/TEN secondary to immunotherapy for melanoma. Due to difficulties performing studies in this population, the benefits and risk of steroids should be considered on a case-by-case basis.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that her name and initial will not be published, and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Robert C, Soria JC, Eggermont AM. Drug of the year: Programmed death-1 receptor/programmed death-1 ligand-1 receptor monoclonal antibodies. Eur J Cancer 2013;49:2968-71.  Back to cited text no. 1
    
2.
Maloney N. J, Ravi V, Cheng K, Bach DQ, Worswick S. Stevens-Johnson syndrome and toxic epidermal necrolysis-like reactions to checkpoint inhibitors: a systematic review. International Journal of Dermatology (2020). doi:10.1111/ijd.14811.  Back to cited text no. 2
    
3.
Teufel A, Zhan T, Härtel N, Bornschein J, Ebert MP, Schulte N. Management of immune related adverse events induced by immune checkpoint inhibition. Cancer Lett. 2019;456:80-87. doi:10.1016/j.canlet.2019.04.018.  Back to cited text no. 3
    
4.
Sahni S, Valecha G, Sahni A. Role of anti-PD-1 antibodies in advanced melanoma: The era of immunotherapy. Cureus 2018;10:e3700.  Back to cited text no. 4
    
5.
Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, et al. Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. Ann Oncol 2019;30:582-8.  Back to cited text no. 5
    
6.
Sanlorenzo M, VujicI, Daud A, Algazi A, Gubens M, Luna SA,et al. Pembrolizumab cutaneous adverse events and their association with disease progression. JAMA Dermatol 2015;151:1206-12.  Back to cited text no. 6
    
7.
Demirtas S, El Aridi L, Acquitter M, Fleuret C, Plantin, P. Stevens Johnson syndrome from anti-PD1 therapy with fatal outcome. Annales de Dermatologie et de Vénéréologie, 2017:144;65–66. doi:10.1016/j.annder.2016.11.012.  Back to cited text no. 7
    
8.
Pollack MH, Betof A, Dearden H, Rapazzo K, Valentine I, Brohl AS. Safety of resuming anti-PD-1 in patients with immune-related adverse events (irAEs) during combined anti-CTLA-4 and anti-PD1 in metastatic melanoma. Ann Oncol 2018;29:250-5.  Back to cited text no. 8
    
9.
Pan EY, Merl MY, Lin K. The impact of corticosteroid use during anti-PD1 treatment. J Oncol Pharm Pract 2020;26:814-22.  Back to cited text no. 9
    
10.
Faje AT, Lawrence D, Flaherty K, Freedman C, Fadden R, Rubin K, et al. High-dose glucocorticoids for the treatment of ipilimumab-induced hypophysitis is associated with reduced survival in patients with melanoma. Cancer, 2018:124; 3706-14. doi:10.1002/cncr.31629.  Back to cited text no. 10
    


    Figures

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