Brincidofovir (CMX001) Toxicity Associated With Epithelial Apoptosis and Crypt Drop Out in a Hematopoietic Cell Transplant Patient: Challenges in Distinguishing Drug Toxicity From GVHD

Abstract

Brincidofovir (CMX001) is an oral agent with activity against double-strand DNA viruses undergoing clinical trials in immunocompromised patients. We report a patient clinically diagnosed with brincidofovir-related gastrointestinal (GI) toxicity and his histologic findings. A 2-year-old boy with medulloblastoma undergoing autologous hematopoietic cell transplantation developed adenovirus viremia 9 days posttransplant. After initial treatment with intravenous cidofovir he was started on oral brincidofovir as part of a clinical trial. He developed hematochezia, anorexia, and emesis 11 weeks later. Sigmoid colon biopsy showed marked crypt drop out, moderate epithelial apoptosis, and lamina propria edema. The pathologic diagnosis was drug-related injury versus infection. Brincidofovir toxicity was diagnosed clinically and the drug was discontinued. His GI symptoms improved in 2 weeks with supportive care and octreotide. Brincidofovir causes GI toxicity and histologically demonstrates epithelial apoptosis and crypt injury, similar to graft versus host disease and mycophenolate mofetil toxicity.

Serinol-Based Benzoic Acid Esters as New Scaffolds for the Development of Adenovirus Infection Inhibitors: Design, Synthesis, and In Vitro Biological Evaluation

“…27,28 Phases II and III of clinical trials (NCT01231344, NCT02087306) confirmed the anti-HAdV activity of BCV with reductions in HAdV-related symptoms; nevertheless, it induced some gastrointestinal disorders, limiting its use in therapy. 29,30 These features support the need for the development of new antiviral agents with activity against HAdV and a good therapeutic index. Different new nucleoside derivatives or nitrogen base-based analogues have been described.…”

Respiratory Virus Infections in Hematopoietic Cell Transplant Recipients

“…In phase I and phase II trials as well as in retrospective studies, brincidofovir has been shown to be highly efficacious in controlling and clearing adenoviraemia (Grimley et al, 2017; Hiwarkar et al, 2017; Ramsay et al, 2017; Averbuch et al, 2018). Gastrointestinal toxicity is the major side effect observed and might be associated with epithelial apoptosis and crypt injury, as might be observed with GvHD (Detweiler et al, 2018).…”

Recent Advances in Novel Antiviral Therapies against Human Adenovirus

“…For example, ganciclovir, a common antiviral against CMV and herpes simplex virus type 1 (HSV-1), is less effective in HAdV infections, as the drug must first undergo phosphorylation to an active form and unlike CMV and HSV-1, HAdV does not encode a viral kinase to facilitate this modification in infected cells [ 118 ]. Brincidofovir, a phospholipid conjugate of cidofovir, is currently in clinical trials and has received FDA Fast Track status for treatment of HAdV-induced diseases [ 119 , 120 ]. This drug has several advantages over cidofovir, including oral delivery and increased cellular uptake.…”