Multiple Myeloma and Mimicry: Gastrointestinal Tract Histologic Findings in Patients Following Chimeric Antigen Receptor T-cell Therapy and Anti-CD38 Monoclonal Antibodies.

Abstract

Chimeric antigen receptor T-cell (CAR-T) therapy is a type of immunotherapy that uses genetically engineered T-cells with synthetic receptors targeting malignant cells that express specific antigens. CAR-T therapy primarily targets B-cell maturation antigen expressed by multiple myeloma and CD19 expressed in several lymphoid malignancies. Data regarding patterns of gastrointestinal injury associated with CAR-T therapy are limited, and thus, we conducted this study to characterize the changes observed in biopsy samples from patients who have received this treatment. We retrospectively reviewed 14 cases from 8 patients who received CAR-T therapy, including 43 sets of mucosal biopsies and 3 surgical resection specimens. Information regarding symptoms, endoscopic findings, medications, and infections was recorded. The study patients were adults (mean age, 63 years; median, 62.5 years) and included 5 men and 3 women. Seven had refractory/relapsed multiple myeloma, and 1 had diffuse large B-cell lymphoma. Gastrointestinal symptoms included diarrhea (88%) or nausea and/or vomiting (22%), which developed a mean of 294 days (range, 41-700 days) after CAR-T therapy. Endoscopic findings were variable; a minority of patients had normal examinations or only mild erythema, whereas others had mucosal granularity and ulcers in the upper and lower gastrointestinal tract. Five patients underwent evaluation for gastrointestinal infection; enteropathogenic Escherichia coli was detected in 1 patient. None of the patients received any medications known to cause gastrointestinal injury for at least 3 months before the endoscopic procedure. Tissue samples contained regenerative-appearing glands and/or crypts lined by cells with attenuated cytoplasm; apoptotic epithelial cells and intraepithelial lymphocytosis were uniformly present, being most pronounced in the deep mucosa. Inflammation was minimal; the lamina propria was mostly hypocellular to normocellular with decreased or absent plasma cells. Immunohistochemical stains were negative for cytomegalovirus and adenovirus. Our findings suggest that CAR-T therapy causes gastrointestinal injury characterized by epithelial cell apoptosis and intraepithelial lymphocytosis and predominantly affects crypts and glands in the deep mucosa. Recognizing this pattern may help pathologists suggest the presence of CAR-T therapy-induced injury in the appropriate clinical context.