MILAN – Among the dermatologic adverse effects of immune checkpoint inhibitor therapy, bullous disorders are relatively infrequent but associated with a high likelihood of treatment interruption, according to results of a single-center study described at the World Congress of Dermatology.
, and nearly all required systemic steroids and were associated with interruptions and discontinuations of the anti-cancer treatment, reported Jonathan Leventhal, MD, director of the oncodermatology clinic at Yale University, New Haven, Conn.
“This series highlights a very important, clinically relevant, cutaneous immune-related adverse event,” Dr. Leventhal said in an oral presentation at the congress. “These disorders manifested in most patients as bullous pemphigoid, occurred several months after starting therapy, and at a frequency rate of 1%” among all patients treated with these agents, “at least in our institution.”
The retrospective review presented by Dr. Leventhal was based on medical records of patients evaluated at Yale New Haven Hospital between 2016 and 2018. This included a total of 853 patients who received anti-PD-1/PD-L1 therapy, of whom 98 (11.5%) were evaluated at the oncodermatology clinic or inpatient consultative service.
Nine patients – five men, four women – developed bullous disorders, representing about 1% of patients treated with PD-1/PD-L1 blocking therapy, according to Dr. Leventhal. The mean age of the patients was 67.4 years. Seven of the nine patients had received PD-1 inhibitors, while two received PD-L1 inhibitors, for tumors of the lung in four cases, melanoma in two, genitourinary tumors in two, and acute myeloid leukemia in one.
“The time from rash onset to first administration of the drug was over 6 months, which is quite long compared to a lot of the other (checkpoint inhibitor–associated) toxicities that we see more commonly, which often occur in several weeks to just a few months,” Dr. Leventhal said.
Of the 853 patients in this retrospective study, 463 (54.3%) were treated with nivolumab (Opdivo) and 242 (28.4%) were treated with pembrolizumab (Keytruda), both PD-1 blockers. Of the remainder, 112 (13.1%) received the PD-L1 blockers atezolizumab (Tecentriq), 29 (3.4%) received durvalumab (Imfinzi), and 7 (0.8%) received avelumab (Bavencio), Dr. Leventhal reported.
All these patients presented with both pruritus and vesiculobullous eruptions seen mainly on the trunk and extremities, while two patients had oral ulcerations. Other presentations included urticarial-predominant bullous pemphigoid, dyshidrosiform pemphigoid, and lichenoid papules and vesicles. The diagnosis was bullous pemphigoid in seven of nine cases, Dr. Leventhal said.
The best management approach for immune-related bullous disorders would be use of high-potency topical steroids to avoid systemic steroids and avoid interruptions in checkpoint inhibitor therapy, he pointed out. However, eight of the nine patients in this retrospective series required systemic steroids due to progression of the bullae, he added.
Several notable cases were described, including one patient refractory to prednisone and omalizumab who eventually achieved control with methotrexate, a second patient who was well controlled with omalizumab monotherapy and able to resume treatment with an anti PD-1 inhibitor, and another patient who responded to prednisone and dapsone maintenance therapy.
The immunotherapy treatment for cancer was interrupted in four of nine patients due to the bullous disorders, and was permanently discontinued in another four, Dr. Leventhal said.
It’s not clear why patients receiving cancer immunotherapy treatment develop bullous pemphigoid. However, the 180-kd bullous pemphigoid antigen (BP180) is expressed in melanoma and non-small cell lung cancer, which may lead to production of antibodies against tumor cell antigens that also impact the skin, according to Dr. Leventhal.
Further studies are needed to evaluate whether immune-related bullous disorders have any prognostic significance in cancer patients, he added.
Dr. Leventhal reported that he had no relevant disclosures.