Characterization of Histologic Spectrum and T-Cell Clonality in Immune Effector Cell-Associated Enteritis

Immune effector cell (IEC) therapies using chimeric antigen receptor T cells (CAR-T) targeting B-cell maturation antigen or CD19 are FDA-approved treatments for refractory B -cell lymphoma, B-lymphoblastic leukemia, and multiple myeloma. Increasing evidence has suggested that these therapies can induce gastrointestinal injury, but the clinicopathologic spectrum and its association with clonal T-cell proliferation remain poorly defined. We retrospectively analyzed 42 GI biopsy specimens from 11 CAR-T-treated patients (8 with multiple myeloma, 2 diffuse large B-cell lymphoma, 1 acute B-lymphoblastic leukemia), comprising 4 women and 7 men (median age 68 years), with diarrhea as the predominant symptom (94%), arising at a median 4.9 months post CAR-T. Histologic evaluation, particularly of the duodenum, revealed a distinctive four-component composite histologic signature, termed a "CVID-peptic-celiac-autoimmune enteropathy-like" enteritis, characterized by plasma cell paucity (CVID-like), gastric foveolar metaplasia and Brunner gland hyperplasia (peptic duodenitis-like), intraepithelial lymphocytosis (celiac-like), and goblet cell loss with villous blunting and increased crypt epithelial apoptosis (autoimmune enteropathy-like), accompanied with atypical lamina propria lymphoid infiltrates. Those changes were most prominent in the duodenum and jejunum, less so in the ileum, and were generally mild to absent in the stomach, colon, and esophagus. Integration of histology with T-cell clonality analysis stratified the cases into two groups: the not tested/likely non-clonal group (n=6) showed limited histologic features with isolated CVID-, peptic-, and/or autoimmune enteropathy-like changes, milder, transient symptoms, and favorable outcomes. The clonal group (n=5) demonstrated more severe enteritis with a full composite CVID-peptic-celiac-autoimmune enteropathy-like enteritis, persistent symptoms, repeat biopsies, and higher mortality (40%). Our findings suggest a spectrum of histopathologic features of IEC-associated enteritis, characterized by a composite histologic signature that may progress to atypical lymphocytosis, often in association with clonal T-cell expansion. Recognition of this histologic pattern and incorporation of clonality testing may aid in diagnosis, risk stratification, and prognostication.