Potential Delayed Immune-Related Adverse Events in Patients Treated with Frontline Pembrolizumab + AVD for Classic Hodgkin Lymphoma

Introduction Concurrent PD1 inhibitor and chemotherapy has demonstrated high efficacy in patients with untreated classic Hodgkin lymphoma (CHL). Toxicities associated with PD-1 inhibitors are common and the majority of immune-related adverse events (irAE) occur within 3 months of initiation of therapy. However, with a half-life of 26 days, pembrolizumab may still be present after immune reconstitution following completion of therapy with doxorubicin, vinblastine, and dacarbazine (AVD), and some irAEs can occur long after exposure to PD1 inhibitor. Little is known about the delayed effects of frontline checkpoint inhibitors in patients with CHL. Here we report overall rates of potential delayed irAEs, as defined below, in our cohort of 50 patients treated with pembrolizumab and AVD (APVD). Methods We performed chart reviews for all 50 patients enrolled on a single center investigator-initiated clinical trial of APVD for untreated classic Hodgkin lymphoma. Potential delayed irAEs were defined as any adverse event likely related to pembrolizumab occurring at least 30 days after last pembrolizumab dose. We obtained all pertinent clinical data from the electronic medical record and from the clinical trial's electronic database. Results In this study, 9 (18%) patients experienced a potential delayed irAE with a total of 12 distinct irAEs. Among patients experiencing a delayed irAE, mean time to onset after completion of APVD therapy was 163 days (range 26 - 858 days), and mean time to onset after last pembrolizumab exposure was 169 days (range 33 - 858 days). Of the recorded irAEs, 4 were grade 1, 6 were grade 2, and 2 were grade 4. The average age of patients with a delayed irAE was 38.1 years, and the average age of patients without a delayed irAE was 39.4 years. The majority of the irAEs were endocrinopathies, with four cases of hypothyroidism, two cases of hyperthyroidism, and one case of adrenal insufficiency. The patient who developed adrenal insufficiency presented with grade 4 adrenal insufficiency 395 days after completion of APVD therapy. One patient had a delayed cutaneous irAE, manifesting as a lichenoid dermatitis. Another patient developed a case of grade 2 anterior scleritis/uveitis that presented 858 days after last pembrolizumab dose and was treated with steroid eye drops. There was one case of grade 2 immune-mediated arthritis requiring steroids, one case of grade 2 colitis, and one case of grade 3 pneumonitis also requiring steroids. The patient who developed grade 4 pneumonitis presented 90 days after last dose of pembrolizumab with acute shortness of breath and required bilevel positive airway pressure and intravenous corticosteroids in the intensive care unit. Three patients required oral steroids to treat their irAEs. One of these patients required it indefinitely due to adrenal insufficiency, while the other two patients required them for approximately 38 and 159 days. Conclusions Combination checkpoint inhibition and chemotherapy is an effective treatment option for patients with CHL in the frontline setting. However, treating oncologists should be aware of the potential for delayed irAEs associated with this regimen.