Jin, Jie

7533 Background: Ciltacabtagene autoleucel (cilta-cel) shows benefit for patients (pts) with relapsed/refractory multiple myeloma (RRMM). A recently recognized uncommon adverse reaction, IEC-EC is characterized by severe/persistent diarrhea typically 1–3 months post CAR-T cell infusion. Here we summarize incidence and features of IEC-EC in clinical trials of cilta-cel for RRMM. Methods: 483 pts across RRMM studies (CARTITUDE-1, -2, -4, and CARTIFAN-1) were evaluated for evidence of IEC-EC. The clinical picture and nomenclature for IEC-EC were described in the real-world setting after infusion of most pts. As such, retrospective analysis was performed to identify cases consistent with IEC-EC, defined as prolonged (≥3 weeks) and severe (≥grade 3) diarrhea after cilta-cel infusion, without clear infectious etiology. Correlative biomarker analyses included peripheral CAR-T cell expansion/persistence, immune cell composition, and cytokines/inflammatory markers. Centralized pathomorphological review and immunohistochemical analysis of available biopsies was conducted. Results: Across RRMM studies, 6/483 (1.2%) pts demonstrated the clinical picture of IEC-EC, presenting 12–214 days after receiving cilta-cel (median onset 67 days post infusion). Best response was CR/sCR for all subjects. Pts received therapies including steroids (4/6). Four pts experienced symptom resolution within 123–227 days; 2 had persistent symptoms until death (causes: multiorgan failure and COVID19). Pts with IEC-EC had lower levels of B cells and higher levels of CAR+ T cells and inflammatory cytokines (eg, IL-6) at onset compared to a GI symptom-free control group at comparable time; while all cilta-cel–treated pts experienced B cell depletion, pts with IEC-EC had more prolonged deficiency. Histological analyses of GI biopsies from 5 pts with IEC-EC revealed plasma cells, normally present in the GI tract, were absent. CAR-T cells were detected and localized to the lamina propria and were not observed juxtaposed with epithelia, making it unlikely direct damage to epithelia was caused by CAR-T cells. Histologic damage was greater in the small intestine (predominantly duodenum) than the colon. Conclusions: Retrospective analysis of cilta-cel trials identified a low IEC-EC incidence (1.2%). Findings support a reactive mechanism involving plasma cell depletion and immune dysregulation rather than direct CAR-T cell cytotoxicity and highlight the importance of upper endoscopy to identify injury patterns in the small intestine that may be less pronounced in the colon. Although the pathophysiology is not fully defined, increased awareness and earlier diagnosis may improve understanding of management and enhance likelihood of IEC-EC reversibility.

PURPOSE Patients with the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) historically showed inferior survival with standard rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Phase II studies demonstrated that adding the immunomodulatory agent lenalidomide to R-CHOP improved outcomes in ABC-type DLBCL. The goal of the global, phase III ROBUST study was to compare lenalidomide plus R-CHOP (R2-CHOP) with placebo/R-CHOP in previously untreated, ABC-type DLBCL. METHODS Histology and cell-of-origin type were prospectively analyzed by central pathology prior to random assignment and study treatment. Patients with ABC-DLBCL received lenalidomide oral 15 mg/d, days 1-14/21 plus standard R-CHOP21 versus placebo/R-CHOP21 for six cycles. The primary end point was progression-free survival (PFS) per independent central radiology review. RESULTS A total of 570 patients with ABC-DLBCL (n = 285 per arm) were stratified by International Prognostic Index score, age, and bulky disease, and randomly assigned to R2-CHOP or placebo/R-CHOP. Baseline demographics were similar between arms. Most patients completed six cycles of treatment: 74% R2-CHOP and 84% placebo/R-CHOP. The most common grade 3/4 adverse events for R2-CHOP versus placebo/R-CHOP were neutropenia (60% v 48%), anemia (22% v 14%), thrombocytopenia (17% v 11%), and leukopenia (14% v 15%). The primary end point of PFS was not met, with a hazard ratio of 0.85 (95% CI, 0.63 to 1.14) and P = .29; median PFS has not been reached for either arm. PFS trends favoring R2-CHOP over placebo/R-CHOP were seen in patients with higher-risk disease. CONCLUSION ROBUST is the first DLBCL phase III study to integrate biomarker-driven identification of eligible ABC patients. Although the ROBUST trial did not meet the primary end point of PFS in all patients, the safety profile of R2-CHOP was consistent with individual treatments with no new safety signals.