Cytotoxic Cutaneous Adverse Drug Reactions during Anti-PD-1 Therapy

Abstract

Purpose: Immunotherapy has experienced impressive progress in cancer treatment. Antibodies against PD-1 improved survival in different types of cancer including melanoma. They are generally well tolerated. However, skin toxicities including pruritus, rashes, and vitiligo are reported. Although frequent, they have not been characterized further yet. In this analysis, we aimed to systematically assess and characterize the adverse cutaneous reactions observed in patients with melanoma treated with anti-PD-1 antibodies. Experimental Design: Patients with melanoma were treated with anti-PD-1 antibodies within clinical trials and an early-access program. Adverse cutaneous eruptions that emerged in our melanoma patient cohort were systematically investigated and classified using histology and gene expression profiling in comparison with maculopapular drug rash, cutaneous GVHD, and the severe drug eruption toxic epidermal necrolysis (TEN). Results: Between February 2013 and September 2015, 68 patients with stage IV melanoma were treated at the University Hospital Zurich (Zurich, Switzerland); 15 patients (22%) developed cutaneous reactions and 10 (15%) vitiligo. The cutaneous reactions ranged from small erythematous papules with mild pruritus to disseminated erythematous maculopapular rashes (MPR) without signs of epidermal involvement to severe MPRs, including epidermal detachment and mucosal involvement. Although skin involvement varied from mild rash to bullous drug eruptions, gene expression profiling pathogenically classified all investigated cases as TEN-like reactions. Conclusions: As predicted by the PD-1 knockout mouse, anti-PD-1 antibodies frequently cause adverse cutaneous reactions. Gene expression profiling reminds in all cases of a TEN-like pattern, suggesting that PD-1/PD-L1 interaction is required to preserve epidermal integrity during inflammatory skin reactions. Clin Cancer Res; 22(16); 4023–9. ©2016 AACR.

Characterization of nivolumab-associated skin reactions in patients with metastatic non-small cell lung cancer

“…Several authors reported higher numbers of skin irAEs in melanoma patients during nivolumab treatment. 4,5,7,8 An association between appearance of skin irAEs and OS in melanoma has been reported. [13][14][15]17 Similarly, our data suggest an association between skin irAEs and tumor response.…”

“…Rash and pruritus are frequent immune-related dermatologic adverse reactions (skin irAEs) during immunotherapy, which have been reported to occur in up to 25% of melanoma patients. 4,5,7,8 In NSCLC patients treated with nivolumab skin irAEs are reported in approximately 10% or more. 2,3,[9][10][11] Grading of toxicity is commonly classified according to Common Terminology Criteria for Adverse Events (CTCAE version 4.0).…”

Nivolumab-associated vitiligo-like depigmentation in a patient with acute myeloid leukemia: A novel finding

“…Systemic irAEs include enterocolitis, pneumonitis, hepatitis, nephritis, hypophysitis, and autoimmune thyroid disease. In addition, dermatologic toxicity is the most common irAE of checkpoint inhibitors and ranges from pruritus and mild dermatoses to severe reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis 2 . Vitiligo-like depigmentation is well described in melanoma patients receiving immunotherapy with PD-1 inhibitors and may be associated with favorable outcomes 3 …”

Atezolizumab-Induced Stevens-Johnson Syndrome in a Patient with Non-Small Cell Lung Carcinoma

“…Thus, it is speculated that PD-1 antagonism results in the loss of T-cell homeostasis within the skin, thereby causing self-directed cytotoxic and inflammatory reactions [8]. This hypothesis was supported by Vivar et al [5] and Goldinger et al [9]. The former showed a significant increase in the expression of PD-L1 in lymphocytes and keratinocytes after the 3rd cycle of nivolumab (anti-PD-1 immune checkpoint antibodies) treatment as skin eruptions progressed from morbilliform eruptions to TEN.…”

“…The former showed a significant increase in the expression of PD-L1 in lymphocytes and keratinocytes after the 3rd cycle of nivolumab (anti-PD-1 immune checkpoint antibodies) treatment as skin eruptions progressed from morbilliform eruptions to TEN. The latter demonstrated that immune checkpoint inhibitors can activate T cells and target keratinocytes leading to apoptosis which manifests clinically as TEN [9]. The mainstay of SJS/TEN treatment is supportive care, which includes identification and discontinuation of potential offending medications, appropriate wound care, maintenance of fluids and electrolytes homeostasis, temperature control, and consultation of appropriate specialties (ophthalmology and urology) for evaluation and support [10].…”