Melanoma Patient on Immunotherapy Develops Severe Dermatitis

A 58-year-old Caucasian man with melanoma was started on treatment with the anti-PD-1 immune checkpoint inhibitor (ICI) pembrolizumab (Keytruda, 200 mg every 21 days) after the cancer metastasized. He had a history of pityriasis versicolor infection. After 22 weeks of treatment, he developed itchy maculopapular lesions.

In some areas, the maculopapular lesions joined together to form large patches and plaques, located primarily on his abdomen, back, arms, and legs. Many of these appeared scaly, much like the patient's previous pityriasis versicolor infection. Clinicians started him on topical betamethasone dipropionate 0.05% and miconazole nitrate 2% cream, which did improve the skin lesions.

After 25 weeks of treatment with pembrolizumab 200 mg every 21 days, the patient's melanoma advanced and clinicians changed his immunotherapy regimen to the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor ipilimumab (Yervoy) at 3 mg/kg every 21 days. After 5 weeks of this treatment, the dermatitis worsened and the patient's itch became severe. Approximately 40% of his body surface area was affected by dermatitis, primarily his torso, both hands and legs.

The patient was given a second course of topical betamethasone dipropionate 0.05% cream, daily cetirizine 10 mg tablet, and miconazole nitrate 2% cream. However, his dermatitis did not improve. As a result, clinicians prescribed oral prednisone at 0.5 mg/kg daily, and his rash improved.

Clinicians made several attempts thereafter to gradually withdraw the oral prednisone therapy, however his skin condition quickly worsened with each attempt to wean him from prednisone. Concurrently, his melanoma continued to worsen.

Clinicians decided to discontinue the ipilimumab therapy. However, his dermatitis persisted, with only moderate response to prednisone and topical antifungal cream treatment. Clinicians noted clinical similarities between his persistent dermatitis and the pityriasis versicolor eruptions that had affected the patient in the past. This led to the decision to administer a stronger oral antifungal therapy to address his fungal infection, along with ongoing prednisone treatment to manage the immune-related dermatologic toxicity associated with the ICI treatment.

They began to taper the prednisone dose by 15 mg daily, at the same time initiating treatment with fluconazole (Diflucan) 200 mg daily on day 1, followed by 100 mg daily for 6 additional days. On day 1 of fluconazole treatment, the team performed a skin biopsy of the flank torso. This revealed superficial middle dermal perivascular dermatitis with associated spongiosis. Pathology findings suggested that the patient had hypersensitivity from either medication or other potential allergens. After a few days of taking fluconazole, his rashes cleared with no reported treatment intolerance. The patient discontinued prednisone shortly thereafter, without requiring any further dose escalation.

The patient continued to have optimal performance status, and 5 weeks later, clinicians switched his treatment to temozolomide (Temodal) 5 weeks later. Unfortunately, his cancer continued to progress. About 1 year later, he was rechallenged with nivolumab (Opdivo) with no evidence of significant dermatological toxicity.

Discussion

Clinicians presenting this case of a melanoma patient who developed refractory dermatitis due to an immune-related adverse event (irAE) with underlying pityriasis versicolor stressed the importance of "look[ing] beyond the irAE when managing dermatitis in patients receiving ICI therapy."

The survival benefits associated with ICIs in patients with various types of cancer, including melanoma, has led to a rapid increase in ICI indications and their use, with a resulting "surge in a number of dermatologic toxicities due to immune-related adverse events (irAEs)," authors noted, observing that skin adverse events (AEs) are reported in 30% to 40% of patients receiving PD-1 blockers, such as nivolumab or pembrolizumab.

Additionally, authors point out that the frequent use of immunosuppressive agents in cancer patients can also increase their risk of developing opportunistic skin infections. More severe adverse events have been seen with use of CTLA-4 inhibitors, such as ipilimumab, and are significantly more severe with combined use of PD-1/CTLA-4 inhibitors.

A systemic review of ICI therapy in almost 7,000 patients reported that, among patients taking anti-PD-1 immune checkpoint inhibitors, those with melanoma were significantly more likely than those with renal cell carcinoma to develop arthralgia or hypothyroidism (OR 4.1 and 3.6 respectively), while those with renal cell carcinoma were more likely to develop pneumonitis (OR 2.9) or dyspnea (OR 2.1).

Those researchers also reported that CTLA-4 monoclonal antibodies were more likely to cause all grades colitis (OR 8.7, 95% CI 5.8-12.9), hypophysitis (OR 6.5, 95% CI 3.0-14.3), and rash (OR 2.0, 95% CI 1.8-2.3), while PD-1 monoclonal antibodies were more likely to cause pneumonitis (OR 6.4, 95% CI 3.2-12.7), hypothyroidism (OR 4.3, 95% CI 2.9-6.3), arthralgia (OR 3.5, 95% CI 2.6-4.8), and vitiligo (OR 3.5, 95% CI 2.3-5.3).

A complete diagnostic workup is recommended to identify any other possible causes of dermatologic symptoms, such as infections, or other medications or diseases, case authors noted. Patients with severe dermatologic irAEs (i.e., grade 3 or higher on the Common Terminology Criteria for Adverse Events Version 5 system) should be assessed by a dermatologist with experience in addressing ICI-related skin toxicity before treatment is continued, they wrote, citing recent guidelines.

The group observed that their patient's underlying pityriasis versicolor -- a fungal infection seen most often in tropical climates, and more likely to affect immunosuppressed individuals -- may take a variety of forms, presenting as mildly erythematous, hypopigmented, or in some cases hyperpigmented lesions. As the infection advances, small lesions may become confluent.

Although generally the only symptom is cosmetic skin changes, the infection severity can increase in individuals who are immunocompromised or taking oral corticosteroids, the case study authors wrote. Diagnosis is typically made through physical examination, and confirmed using light microscopy observation of a potassium hydroxide preparation. About 1 to 4 weeks of treatment with topical antifungal agents is generally effective, the group noted, although florid infection and disease recurrences may require more aggressive treatment with oral antifungals such ketoconazole, itraconazole, or fluconazole.

This patient developed dermatitis due to an immune-related side effect of pembrolizumab and ipilimumab treatment, which also exacerbated his pre-existing pityriasis versicolor infection, the symptoms of which authors noted were presumed to reflect the same adverse effect of ICI therapy.

Biopsy of the affected skin failed to reveal any yeast or hyphae, thus clinicians diagnosed his fungal infection based on clinical features. This presumptive diagnosis was indirectly confirmed by the rash's rapid response to a short 7-day course of antifungal treatment, authors noted, adding their suspicion that "the chronic topical antifungal and steroid cream might have contributed to a false negative biopsy result."

No further tests for fungal infection were performed when the rash cleared, and they note that the patient had no recurrence of skin toxicity after resuming treatment with nivolumab. "In this case, it is possible that fluconazole, a CYP3A4 inhibitor, could potentially have increased the serum concentration of prednisone due to drug-drug interactions," authors pointed out, although the patient was taking a low dose of prednisone when he started taking the fluconazole at a low dose.

Noting the complete response of the patient's skin condition to this dual treatment, and its durability after completion of the anti-fungal treatment, authors suggested that "his overall response to treatment was consistent with the dermatologic toxicity due to an irAE with an associated underlying fungal infection." The group concluded that despite the high risk of dermatologic irAEs, alternative differential diagnoses must be considered when presented with possible ICI-related dermatologic complications.

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