Ruxolitinib for refractory immune effector cell enterocolitis following ciltacabtagene autoleucel CAR T-cell therapy for multiple myeloma

Abstract

Abstract Immune effector cell-associated (IEC)-enterocolitis, characterized by substantial and prolonged diarrhea following B-cell maturation antigen (BCMA)-targeted CAR-T cell therapy, has recently been identified as a rare adverse event. Clonal CAR-T cell expansion has been detected in a subset of these patients (Ozdemirli NEJM 2024; Hosoya Blood Supp 2024; Braun Nat Med 2025; Perica NEJM 2025). Resultant gastrointestinal (GI) tract barrier disruption, along with the significant immunosuppression, has been associated with infectious complications and high mortality rates. Defining the optimal clinical management of IEC-enterocolitis represents a critical unmet need. Between January 2023 and February 2025, 46 patients received commercially available ciltacabtagene autoleucel (cilta-cel) for relapsed/refractory multiple myeloma at our institution, of whom 5 patients (10.9%) developed symptomology consistent with IEC-enterocolitis. CAR T-cell infiltration in GI tissues was assessed by ddPCR. Integration site analysis was performed on genomic DNA extracted from duodenal biopsies through the Viral / Molecular High Density Sequencing Core at the University of Pennsylvania. Informed consent was obtained for clinical data collection (DFHCC #16-206). Potential off-tumor effects of cilta-cel were also modeled in a human BCMA knock-in (hBCMA KI) C57BL/6N syngeneic murine system. Median IEC-colitis onset occurred at 56 days (range 40 – 151) after CAR T-cell infusion, manifesting as at least CTCAE grade 3 non-bloody and watery diarrhea accompanied by abdominal cramping, nausea, and emesis. Median peak stool frequency was 11 times per day (range 6 – 17) with a median maximum stool volume of 4200mL/day (range 3400 – 6700). Subsequent body weight loss (median 17.4kg or 22.7% initial weight) necessitated total parental nutrition (TPN) in all patients (median duration 57 days). Symptoms resolved in patients 1 and 2 after 139 and 132 days from colitis onset, respectively, with supportive care and intermittent corticosteroids alone. Given limited responsiveness to corticosteroids and vedolizumab in patients 3 – 5, patients were treated with ruxolitinib at a median of 140 days (range 48 – 171 days) after IEC-enterocolitis onset. Clinical improvement was observed within two days, seven days, and one day for patients 3, 4, and 5, respectively, as evidenced by significantly reduced frequency and volume of diarrhea. Resolution of diarrhea permitted discontinuation of TPN at 5, 28, and 44 days post-ruxolitinib initiation for patients 3, 4, and 5. All patients achieved complete resolution of toxicities within 177, 28, and 53 days, respectively, following ruxolitinib initiation and a total duration of toxicities of 318, 200 and 102 days. However, patient 3 did have recrudescence of symptoms 36 days upon discontinuation of ruxolitinib; symptoms quickly resolved once ruxolitinib was restarted. Of note, patients 3 and 4 had disease progression while on ruxolitinib within 44 and 132 days, respectively, since enterocolitis resolution. All five patients showed active enteritis along with the infiltration of CD3+ T-cells and decreased or absent plasma cells in the lamina propria. ddPCR confirmed the presence of CAR T-cells in GI-tissue biopsies. Patient 5 had matched pre- and post-ruxolitinib duodenal biopsies, which revealed resolution of histologic signs of intestinal injury. Subsequent PCR-based T-cell receptor clonality analysis detected a clonal T-cell population in the duodenum of patient 5. IHC revealed an aberrant T-cell immunophenotype with loss of CD5 and CD7 expression, resulting in re-classification as an indolent T-cell lymphoma of the GI tract. Integration site analysis revealed no obvious insertional oncogenic events accounting for clonal expansion. However, targeted NGS sequencing revealed pathogenic mutations in TP53 and BRCA2. Correlative investigations revealed that cilta-cel-like murine CAR T-cells eradicated bone marrow plasma cells of hBCMA KI mice with additional analysis (including the GI tract) ongoing. IEC-enterocolitis is an emerging toxicity observed upon treatment with cilta-cel and characterized by high volume, life-threatening diarrhea, and is often refractory to standard immunosuppressive agents. Here, we provide preliminary evidence that ruxolitinib may facilitate rapid and sustained resolution of steroid-refractory IEC-enterocolitis. Larger studies will be needed to confirm these findings.