S4582 Biopsy Beyond the Surface: A Challenging Case of Refractory Diarrhea Secondary to CAR-T Therapy

Introduction: Chronic diarrhea in immunocompromised patients presents a broad range of differentials. In recipients of chimeric antigen receptor T-cell (CAR-T) therapy, delayed-onset diarrhea is often attributed to immune effector cell (IEC)–associated enterocolitis and typically responds to steroid treatment. However, persistent, steroid-refractory diarrhea may represent a rare but emerging complication: CAR-T–associated gastrointestinal (GI) lymphoproliferative (LP) disorders. Case Description/Methods: A 70-year-old woman with multiple myeloma presented with chronic, non-bloody, mucoid diarrhea (>5 episodes/day) 7 months after Cilta-cel CAR-T therapy. Her workup was negative for inflammatory, autoimmune, and common infectious causes. Cytomegalovirus DNA polymerase chain reaction was mildly elevated (555 copies/mL) and was refractory to ganciclovir and empiric antibiotics. She was later treated with steroids for suspected graft versus host disease, but diarrhea persisted. She had normal mucosa on upper and lower endoscopies, but random biopsies revealed diffuse granzyme B-positive CD8+ T-cell infiltration in the colon, duodenum, and esophagus. Sequencing verified CAR-T construct integration and clonal proliferation consistent with indolent CD8+ CAR-T cell lymphoma. She was started on intravenous cyclosporine 2.5 mg/kg for 14 days with symptom resolution. Although she recovered from a GI perspective, she developed influenza pneumonia and expired. Discussion: This case highlights an extremely rare but increasingly recognized GI complication following CAR-T therapy that warrants timely diagnosis and intervention. IEC-associated enterocolitis occurs in ∼1.2% of CAR-T recipients, but CAR-T–induced T-cell lymphoma following Cilta-cel has only been reported twice. The gut may act as a reservoir for clonal CAR-T expansion, with potential for systemic dissemination. Persistent diarrhea unresponsive to corticosteroids should prompt bidirectional endoscopy with biopsy. Cyclosporine is thought to treat this condition by uniquely targeting persistent engineered CAR-T cells by inhibiting IL-2-mediated mucosal proliferation and is administered at 3–5 mg/kg/day with goal troughs between 150–250 ng/mL. Given the similarity between CAR-T cell lymphoma and inflammatory bowel disease, further research is needed on the potential role of biologics in treating this rare disease entity.