Diagnosis and management of immune effector cell-associated enterocolitis after ciltacabtagene autoleucel.

Introduction

Ciltacabtagene autoleucel (cilta-cel; Carvykti) is a B-cell maturation antigen (BCMA)–targeting chimeric antigen receptor T-cell (CAR-T) therapy currently approved by the US Food and Drug Administration for the treatment of relapsed or refractory multiple myeloma. Although highly effective, uncommon but potentially devastating late-onset toxicities have been reported, notably immune effector cell (IEC) delayed neurotoxicities, including nerve palsies and parkinsonism (IEC-PKS). 1 , 2 , 3 Emerging toxicities such as IEC-associated enterocolitis (IEC-EC) have been reported in ∼2% of cilta-cel–treated patients. 4 IEC-EC is currently not well characterized but appears to present with acute-onset diarrhea (usually nonbloody) occurring ∼3 months after CAR-T infusion. Diarrheal symptoms are usually severe, persistent, and associated with malnutrition and weight loss, often requiring a period of parenteral nutrition. A clear clinical and pathological distinction has yet to be drawn between IEC-EC and an enteropathic CAR-T–associated T-cell lymphoproliferative disorder (T-LPD), although the latter would require at least demonstration of clonality through T-cell receptor gene rearrangements by polymerase chain reaction analysis on involved gastrointestinal tissue. 4 , 5 , 6 Currently, there is also a poor understanding of the pathophysiology and predisposing risk factors for IEC-EC. In addition, management strategies, which have included the use of systemic steroids, calcineurin inhibitors, lymphocyte-toxic chemotherapy, and biologic therapy (infliximab and vedolizumab), have not been described well in the literature. 4 Herein, we report 9 cases of IEC-EC diagnosed across the 3 Mayo Clinic sites, including diagnostic findings, clinical course, and associated risk factors.

Methods

Patient population

After Mayo Clinic Institutional Review Board approval, medical records of patients with relapsed or refractory multiple myeloma who received cilta-cel as standard of care between 1 February 2022 and 30 November 2024 at the Mayo Clinic in Rochester, Florida, and Arizona, were reviewed. Laboratory data at the time of evaluation, lymphodepleting therapy, and up to 3 months after cilta-cel infusion were collected retrospectively. Cytokine release syndrome (CRS) and IEC-associated neurotoxicity syndrome were graded using American Society for Transplantation and Cellular Therapy consensus criteria. 7 Other toxicities were graded using National Cancer Institute Common Toxicity Criteria for Adverse Events version 5.0. 8 Research was conducted in accordance with the Declaration of Helsinki.

Case definition, identification, and clinical course description

Cases of IEC-EC among patients treated with cilta-cel between 1 February 2022 and 30 November 2024 were identified through a prospectively maintained IEC program compliance database. The diagnosis of IEC-EC was made based on a diagnosis of exclusion using a combination of patient history, presenting symptoms, physical examination, infectious disease workup, imaging, and endoscopic and biopsy findings. Patient esophagogastroduodenoscopy (EGD) and colonoscopy reports were retrospectively reviewed by our gastroenterologist (N.C.). Patient biopsy reports and samples were retrospectively reviewed and described centrally by our pathologists (H.E.L. and Z.E.C.). Final description of disease course was centrally reviewed by N.C.

Statistical analysis of risk factors

Differences in patient characteristics were compared between IEC-EC and patients who did not develop IEC-EC. This was tested using the Fisher exact test and the Wilcoxon rank-sum test for categorical and continuous variables, respectively. Patients who died within 60 days of cilta-cel or who had <60 days of follow-up were excluded from risk factor analysis. Multivariate Firth penalized logistic regression was used to identify independent risk factors associated with increased odds of IEC-EC, given the limited number of patients with IEC-EC events. Survival outcomes were analyzed using Kaplan-Meier methods, including estimation of time point–based rates. All statistical tests were 2-sided with a significance level of 0.05. Statistical analyses were performed using JMP (version 18; SAS Institute Inc, Cary, NC; 1989-2023).

This study has received Mayo Clinic institutional review board approval.

Results

Incidence of IEC-EC

Between 1 February 2022 and 30 November 2024, 229 patients were treated with cilta-cel across the 3 Mayo Clinic sites, and 9 (3.9%) subsequently developed IEC-EC. The cutoff date for this study was 30 June 2025. Full details of baseline disease, toxicities, IEC-EC, and treatment characteristics for each case are shown in supplemental Table 1 .

IEC-EC: diagnosis and evaluation

All 9 patients with IEC-EC presented with nonresolving diarrhea (>2 weeks). Median time to symptom onset from CAR-T infusion was 85 days (range, 35-166). Diarrheal characteristics were nonbloody and severe (Common Terminology Criteria for Adverse Events [CTCAE] grade ≥3; 9/9 cases). Other common presenting symptoms include nausea and vomiting (4/9 cases) and abdominal pain/discomfort (3/9 cases). The median time from diarrheal onset to first hospitalization for diarrhea was 31 days (range, 14-154). Of the 9 (67%) patients, 6 had significant weight loss (>10% body weight) by the time they were first hospitalized.

Patient evaluation was variable during their first hospital admission, but 4 of the 5 patients (80%) had elevated C-reactive protein, and 6 of the 6 (100%) had elevated ferritin. Of the patients who had subsequent stool testing for malabsorption, 3 of the 3 (100%) had elevated 24-hour fecal fat, and 4 of the 4 (100%) had evidence of bile acid malabsorption. Of the 9 patients, 5 (56%) had a gastrointestinal infection (norovirus, n = 2; sapovirus, n = 1; Clostridium difficile , n = 1; norovirus and C difficile , n = 1) diagnosed within 1 month after diarrhea onset, of whom 4 received antimicrobial-directed therapy (oral vancomycin for C difficile and nitazoxanide for viral diarrhea). Diarrhea persisted for all 4 patients after the treatment course, and 2 patients had a persistent positive result (sapovirus, n = 1; norovirus, n = 1) on serial stool testing. On imaging studies, 7 of the 9 patients underwent computed tomography of the abdomen and pelvis, but results of only 3 cases (43%) were abnormal: 1 with pneumatosis, 1 with features of EC, and 1 with both pneumatosis and features of EC.

The median time from diarrhea onset to first endoscopy was 49 days (range, 16-308). Of the 9 patients, 7 (78%) had abnormal duodenal findings on EGD, with duodenal nodularity the most common observation (5/9 cases; Figure 1 A-C). Four of 8 (50%) had abnormal findings seen on colonoscopy ( Figure 1 A,E-G). Of 9 patients, 6 (cases 2, 3, 4, 6, 8, and 9) had biopsy samples available for central pathology review ( Table 1 ; Figure 2 ). All biopsy samples (duodenum, terminal ileum, and colorectum) of all 6 patients showed plasma cell depletion. Duodenal biopsy from the 6 patients reviewed showed a graft-versus-host disease (GVHD)–like pattern of injury (characterized by increased crypt apoptosis and villous blunting; Figure 2 A) with equivocal intraepithelial lymphocytosis (IEL; cases 2, 6, and 8); celiac disease–like pattern of injury (characterized by IEL and villous blunting; case 9; Figure 2 B); CD4 + T-LPD (case 3; Figure 2 C); and CD8 + T-LPD (case 4; Figure 2 D). Of the 2 LPDs, case 4 also had a detectable pathogenic loss-of-function mutation of DNMT3A on a T-cell next-generation sequencing panel. Terminal ileal biopsies from 3 patients showed reactive hypermucinous changes (cases 3, 4, and 6). Colorectal biopsy specimens from 5 patients showed mild active colitis with mild IEL, mild crypt apoptosis, and mild crypt architectural changes (case 3), and normal/minimal nonspecific changes (cases 2, 4, 6, and 8). Figure 1. Endoscopy findings in IEC-EC. (A) Summary of endoscopic findings of 9 cases of IEC-EC. (B-C) Duodenal nodularity, the presence of small, raised bumps or nodules on the duodenal lining noted on endoscopic evaluation. (D) Ulceration in the duodenum. (E-G) Erythema and erosions in the colon on endoscopic evaluation. Table 1. Summary of biopsy findings of the gastrointestinal tract in IEC-EC cases Duodenum Terminal ileum Colon T-cell clonality in the duodenum Case 1 ∗ — † Normal Lymphocytic colitis like — † Case 2 GVHD-like with equivocal IEL — † Normal/minimal nonspecific changes — † Case 3 CD4 + T-LPD Reactive hypermucinous changes Mild IEL, mild crypt apoptosis, and mild crypt architectural changes Clonal CD4 + T cells, TCR gene rearrangement detected Case 4 CD8 + T-LPD Reactive hypermucinous changes Normal/minimal nonspecific changes Clonal CD8 + T cells, TCR gene rearrangement detected, DNMT3A mutation Case 5 ∗ GVHD-like with equivocal IEL Nonspecific inflammation Mild crypt apoptosis and mild crypt architectural changes Mixture of CD4 + /CD8 + T cells and TCR gene rearrangement equivocal Case 6 GVHD-like with equivocal IEL Reactive hypermucinous changes Normal/minimal nonspecific changes — † Case 7 ∗ — † — † — † — † Case 8 GVHD-like with equivocal IEL — † Normal/minimal nonspecific changes A mixture of CD4 + /CD8 + T cells and TCR gene rearrangement detected Case 9 Celiac disease like — † — † — † TCR, T-cell receptor. ∗ Obtained from pathology reports. Samples were not available for central pathology review. † No specimens were available for evaluation. Figure 2. Photomicrographs of CAR-T–associated enteropathy. (A) A duodenal biopsy showing a GVHD-like pattern of injury with increased crypt apoptosis (inset) and villous atrophy. Original magnification ×79. (B) A duodenal biopsy showing a celiac disease–like pattern of injury with mild intraepithelial lymphocytosis (highlighted by CD3 immunostaining; inset) and partial villous atrophy. Original magnification ×130. (C) A duodenal biopsy showing CD4 + T-LPD with lamina propria expansion with increased CD4 + T cells and intraepithelial involvement (inset: CD4 immunostaining). Original magnification ×160. (D) A duodenal biopsy showing CD8 + T-LPD with lamina propria expansion with increased CD8 + T cells and intraepithelial involvement (inset: CD8 immunostaining). Original magnification ×130.

Cohort survival outcomes

At a median follow-up of 14.1 months (95% confidence interval [CI], 12.2-16.6) from the time of cilta-cel infusion, 60 patients had either progressed (n = 31) or died (n = 29). The estimated 12-month progression-free survival (PFS) was 77% (95% CI, 70-83), and the estimated 12-month overall survival was 88% (95% CI, 82-92). There were no significant differences in PFS (12-month PFS, 89% vs 77%; P = .89) between patients who developed IEC-EC and patients who did not. Among patients who did not develop IEC-EC, 35 had died: 14 from disease progression, 3 from IEC-related causes, and the rest from other causes. Three of the IEC-EC group had died: 1 from concurrent IEC-EC and therapy-related myelodysplastic syndrome, 1 from IEC-PKS, and 1 from progressive disease. Nonrelapse mortality rate was 22% (2/9; 95% CI, 3-60) in patients with IEC-EC and 8% (18/220; 95% CI, 5-13) among those in the non–IEC-EC group ( P = .18).

Risk factors for IEC-EC

The risk factor analysis cohort included 223 patients (9 cases and 214 controls) after excluding patients with early death (n = 4) and insufficient follow-up (n = 2). The distribution of variables at the time of evaluation, lymphodepletion, and after CAR-T infusion is detailed in Table 2 and supplemental Table 2 . At the time of evaluation for CAR-T therapy, patients with IEC-EC had higher rates of high-risk disease as recently defined by the International Myeloma Society and International Myeloma Working Group (IMS/IMWG-HR) 9 compared with patients without IEC-EC (78% vs 37%; P = .03) conferring an odds ratio of 6.1 (95% CI, 1.2-30; P = .03). At the time of lymphodepletion, there were higher rates of elevated CAR-HEMATOTOX scores 10 (≥3: 44% vs 15%; P = .043) among IEC-EC cases compared to the control group. The association between the use of alkylator-based bridging therapy and IEC-EC approached statistical significance (IEC-EC, 56% vs controls, 25%; P = .053). Table 2. Baseline and postinfusion characteristics of patients with and without IEC-EC No delayed toxicity (controls; n = 214) IEC-EC (n = 9) P value Characteristics at evaluation Age, median (range), y 65 (31-82) 66 (51-77) .87 Male sex, n (%) 116 (54) 3 (33) .31 ECOG PS 0-1, ∗ n (%) 176 (92) 9 (100) 1.00 Myeloma type, IgG, n (%) 116 (54) 7 (78) .19 IMS/IMWG HR definition 76 (37) 7 (78) .03 Deletion 17p, † n (%) 48 (27) 5 (56) .12 Gain or amplification 1q, † n (%) 95 (53) 5 (56) 1.00 Extramedullary disease, ‡ n (%) 37 (18) 0 (0) .36 CAR-HEMATOTOX score of ≥ 3, § n (%) 36 (19) 4 (44) .07 1-3 previous lines of therapy, n (%) 70 (30) 1 (11) .28 Previous ASCT, n (%) 182 (85) 9 (100) .36 Triple-class refractory, n (%) 152 (71) 5 (56) .46 Penta-drug refractory, n (%) 53 (25) 4 (44) .24 Previous BCMA therapy, n (%) 11 (5) 1 (11) .40 Characteristics at lymphodepletion Bridging therapy, || n (%) 171 (80) 8 (89) 1.00 Alkylator-based bridging therapy, n (%) 53 (25) 5 (56) .053 Bridging therapy type, || n (%) .32 Alkylator-based chemotherapy 29 (17) 3 (38) Alkylator-based triplet 22 (13) 2 (25) Bispecific antibody 10 (6) 0 (0) Monoclonal antibody combinations 52 (30) 0 (0) Other novel agent combinations 57 (33) 3 (38) Radiotherapy 4 (2) 0 (0) Response to bridging (PR or better) ¶ , n (%) 39 (23) 1 (13) .69 CAR-HEMATOTOX score of ≥3, n (%) 30 (15) 4 (44) .043 Out-of-specification infusion, n (%) 46 (22) 2 (22) 1.000 Serum ferritin, median (range), μg/L 143 (7-4340) 374 (77-1819) .08 BM plasma cell, # median (range), % 4 (0-95) 8 (1-31) .31 Involved FLC, ∗∗ median (range), mg/dL 6.4 (0.1-343) 12.5 (1.1-21.8) .91 M protein, †† median (range), g/dL 0.6 (0-5.7) 0.75 (0-3.0) .43 Elevated LDH, ‡‡ n (%) 60 (28) 2 (22) 1.00 Characteristics after infusion CRS all grade, n (%) 165 (77) 8 (89) .69 CRS grade ≥2, n (%) 48 (22) 2 (22) 1.00 CRS duration, median (IQR), d 1 (1-3) 3 (3-4) .03 ICANS, all grades, n (%) 22 (10) 2 (22) .25 ICANS, grade ≥3, n (%) 1 (0.5) 0 (0) 1.00 IEC-HS, n (%) 16 (7) 0 (0) 1.00 Corticosteroid use, n (%) 111 (52) 7 (78) .18 Cumulative Dex equivalent dose, median (IQR), mg 10 (10-58) 10 (10-60) .99 Tocilizumab use, n (%) 157 (73) 8 (89) .45 Tocilizumab use of >1 dose, n (%) 66 (31) 7 (78) .006 Anakinra use, n (%) 21 (10) 1 (11) 1.00 Serum ferritin at 1 mo, median (range), μg/L 279 (11-6190) 492 (151-1325) .25 Delayed neurotoxicity, n (%) 20 (9) 5 (56) .001 Parkinsonism n (%) 7 (3) 3 (33) .005 Cranial nerve palsy, n (%) 14 (6) 2 (22) .13 Toxicity was graded according to the ASTCT consensus grading of Lee et al. 7 ASCT, autologous stem cell transplantation; BM, bone marrow; Dex, dexamethasone; ECOG PS, Eastern Cooperative Oncology Group Performance Status; FLC, free light chain; ICANS, IEC-associated neurotoxicity syndrome; IEC-HS, IEC-associated hemophagocytic lymphohistiocytosis–like syndrome; IgG, immunoglobulin G; LDH, lactate dehydrogenase; PR, partial response. ∗ Twenty-one patients were missing. † Fifteen patients were missing. ‡ Three patients were missing. § One patient was missing. || Forty-two patients did not receive bridging. ¶ Three patients were missing. # Seventeen patients were missing. ∗∗ Nineteen patients were missing. †† Eight patients were missing. ‡‡ Forty-two patients were missing.

After CAR-T infusion, no differences were observed in the rates of any or high-grade CRS, IEC-associated neurotoxicity syndrome, or IEC-associated hemophagocytic lymphohistiocytosis–like syndrome. However, patients with IEC-EC had longer duration of CRS (median, 3 vs 1 days; P = .03) and higher rates of repeated tocilizumab dosing (>1 dose; 78% vs 31%; P = .006).

Impact of peak lymphocyte expansion

Differences in absolute lymphocyte count (ALC) in the first month after cilta-cel infusion between IEC-EC cases and patients who did not develop IEC-EC (controls) are detailed in Figure 3 . ALC expansion began after day 8 and peaked at a median of 12 days (interquartile range [IQR], 11-13) after infusion ( Figure 3 A). The median time to peak ALC (ALC peak ) from CAR-T infusion was not different between patients with IEC-EC (11 days; IQR, 10.5-13.5) and the control group (12 days; IQR, 11-13). The median ALC peak was higher in patients with IEC-EC than those in the control group (8.13 × 10 9 /L vs 2.3 × 10 9 /L; P = .017) and so too was the ALC expansion over 28 days after infusion (area under the curve; Figure 3 B). However, these were mostly driven by patients who had developed delayed-onset neurotoxicity as patients with IEC-EC without antecedent delayed neurotoxicity had ALC peak and ALC area under the curve comparable to those in the control group ( Figure 3 C). Figure 3. Analysis of ALC in patients without IEC-EC (control) and patients with IEC-EC. (A) ALC (median; IQR) after cilta-cel infusion for the control and IEC-EC groups are plotted. (B) Total ALC expansion, calculated as AUC for 28 days, is shown (right panel) and the comparisons of ALC at LD and at the time of ALC peak . (C) Comparisons of ALC at LD, ALC peak , and total ALC expansion AUC between the control group, patients with IEC-EC with and without DNT. Controls are patients with no delayed toxicity. AUC, area under the curve; DNT, delayed neurotoxicity; LD, lymphodepletion.

Association with delayed neurotoxicity

Of the 9 patients with IEC-EC, 5 (56%; 95% CI, 21-86) had preceding delayed neurotoxicity (3 with IEC-PKS and 2 with IEC nerve palsies). This was a significantly higher rate than 20 of the 214 patients (9%; 95% CI, 6-14) without IEC-EC ( P = .001). This conferred a 10.6-times (95% CI, 2.0-69.3; P = .006) greater odds of developing IEC-EC when there was an antecedent delayed neurotoxicity.

Independent factors associated with IEC-EC

Based on our aforementioned findings, we next performed multivariable analysis using Firth penalized logistic regression given the rarity of IEC-EC cases. We included IMS/IMWG-HR status, high prelymphodepletion CAR-HEMATOTOX score (≥3), prolonged CRS (≥3 days), and antecedent delayed neurotoxicity into the multivariable model. IMS/IMWG-HR disease ( P = .009), prolonged CRS ( P = .009), and antecedent delayed neurotoxicity ( P = .006) emerged as independent risk factors for IEC-EC ( supplemental Table 3 ).

IEC-EC: management strategies and outcomes

First-line management of IEC-EC included varying combinations of IV immunoglobulin (100%), budesonide (89%), or systemic corticosteroids (56%). Three (33%) patients (cases 6, 8, and 9) had a transient (<1 month) reduction in stool count per day but subsequently had symptom recurrence and required additional lines of therapy. The other 6 patients (67%) were refractory to first-line intervention. Figure 4 A summarizes the treatment course in 9 patients with IEC-EC, and Figure 4 B summarizes treatment response rates to individual interventions. Of the 9 patients, 5 received a second-line biologic therapy with a median time from symptom onset to start of biologic therapy of 3 months (range, 0.2-11). Two patients (cases 4 and 6), including 1 (case 4) with CD8 + T-LPD and DNMT3A mutation seen on duodenal biopsy, received vedolizumab. Both achieved a durable response (defined as improvement to grade ≤1 diarrhea and not requiring total parenteral nutrition [TPN] for >1 month) within 5 and 6 months, respectively. One patient (patient 4) continued vedolizumab therapy as maintenance after symptom resolution. Figure 4. IEC-EC cases and their clinical course and response to therapy. (A) Swimmer plot displaying the timing of toxicity and management strategies of 9 patients with IEC-EC. Timing and duration of toxicities. CRS (pink bars), ICANS (blue bars), IEC-NTX, including IEC–nerve palsies and IEC-PKS (light green bars), IEC-EC (orange bars), toxicity-free period (white bars), viral gastroenteritis (green X symbol), C difficile infection (black X symbol), and death (black cross). Yellow and red symbols represent the start of the intervention, and black lines represent the duration of the intervention. (B) Table displaying individual therapeutic strategies used and the durable response rate. C. Diff., Clostridium difficile ; ICANS, IEC-associated neurotoxicity syndrome; IEC-NTX, IEC-associated delayed neurotoxicity.

Three patients (cases 1, 2, and 3) received infliximab, of whom 1 (case 2) achieved a durable response after 16 months. Of the 2 patients with infliximab-refractory disease, 1 (patient 1), after receiving infliximab therapy for 2.5 months, received third-line cyclophosphamide (1.5 g/m 2 single dose IV) and has yet to respond after 1 month. The second patient with infliximab-refractory disease (case 3) was found to have CD4 + T-LPD on duodenal biopsy and failed to respond after 2.7 months of infliximab therapy. She then received cyclosporin, ruxolitinib, and upadacitinib sequentially with no durable response and currently remains on TPN.

Of the 4 patients who did not receive biologic therapy as second line, 1 (case 8) was treated with high-dose cyclophosphamide (1.5 g/m 2 single dose), with no response after 1 month. Three patients did not receive second-line therapy (cases 5, 7, and 9); all 3 died without symptom resolution or improvement after 4 to 24 months from diarrhea onset. Notably, of the 3 patients who had durable responses to biologic-based therapy, none had any demonstrable concurrent gastrointestinal tract infections at the time of diarrhea onset and throughout their disease course.

Monitoring and patient-management strategies

Our experience to date underscores the importance of early recognition and evaluation of IEC-EC as well as the need to identify early, effective management strategies. We have developed and implemented diagnostic and management recommendations at the Mayo Clinic sites ( Figure 5 ) and have made them available on the msmart.org website. 11 We recommend that all persistent CTCAE grade ≥2 diarrhea be thoroughly assessed, and IEC-EC remains a diagnosis of exclusion. Early endoscopic studies (including both EGD and colonoscopy) with biopsies are recommended. Duodenal biopsies appear to have the highest yield, and findings resembling GVHD should raise suspicion. Given the possibility of clonal T-LPD, the exclusion of T-cell clonality on biopsy samples through immunohistochemistry, T-cell receptor gene rearrangement studies, and next-generation sequencing should always be attempted. Initial treatment (first-line management) should still be trialed because it may elicit an initial response in milder cases. However, refractoriness to first-line management (no reduction in diarrhea frequency or ongoing TPN requirement) after 1 week should trigger early institution of second-line management with early corticosteroid taper, similar to management guidelines for acute severe ulcerative colitis and immune checkpoint inhibitor colitis. 12 , 13 Based on the current literature and our experience, we recommend the use of biologic therapies, infliximab or vedolizumab, with vedolizumab being slower acting. More than 1 dose of biologic is needed before considering the IEC-EC biologic refractory. JAK inhibitors such as ruxolitinib or upadacitinib, cyclosporin, or cyclophosphamide may be considered in cases refractory to biologic therapies, particularly those with a proven clonal T-LPD on biopsy samples. 14 However, the evidence of their efficacy is yet to be determined. Figure 5. Flow diagram for the diagnosis and management of IEC-EC. C. Diff., Clostridium difficile ; CMV, cytomegalovirus; CT, computed tomography; IBD, inflammatory bowel disease; ID, infectious disease; IVIG, IV immunoglobulin; PCR, polymerase chain reaction; TCR, T-cell receptor. The figures were created with biorender.com . Lim K (2025).

Discussion

IEC-EC is now a documented post–cilta-cel adverse event and is associated with high morbidity. Current understanding of pathogenesis is limited, which has hampered the development of effective management strategies. What likely confounds and delays diagnosis is that diarrhea is a common symptom among patients with multiple myeloma, particularly in the setting of prolonged immune suppression, previous lenalidomide exposure, polypharmacy, hospitalization, and exposure to broad-spectrum antibiotics. In addition, symptom onset usually occurs after patients have transitioned from the CAR-T treatment centers back to their local providers. Awareness of this entity and referral back to the CAR-T center is critical. In our 9 cases of IEC-EC, referrals back to the CAR-T center for workup were delayed, with the median time to first endoscopy being >1 month after symptom onset. It is important to educate patients and primary/referring hematology/oncology clinics that severe diarrhea without an infectious cause or refractory to antimicrobial therapy should trigger consideration for IEC-EC. In the CARTITUDE-4 study, although all-grade diarrhea was common and reported in ∼30% of the patients, rates of severe diarrhea (CTCAE grade ≥3) were low, affecting <5%. 15 We report an incidence of <5% of IEC-EC in our standard-of-care cohort. Among our 9 cases, all presented with persistent high-grade nonbloody diarrhea after cilta-cel infusion, which was associated with significant weight loss and requirements for TPN. In most cases, diarrheal patterns appear similar to those seen in malabsorption syndromes in which patients’ diarrhea transiently improves after elimination of any oral intake and reemerges on reintroduction of an oral diet. Similar to the US Myeloma Immunotherapy Consortium study that reported on 14 cases of IEC-EC, we found that a minority of patients presented with computed tomography findings consistent with enteritis/colitis, with 2 cases of pneumatosis intestinalis. 4 Regardless, early EGD with duodenal biopsies appears to have the highest histopathological yield, demonstrating findings akin to those seen in GVHD. It is also important to note that all biopsy samples were devoid of plasma cells in light of anti–plasma cell–directed CAR-T therapy; therefore, pathological findings can also sometimes be misinterpreted as common variable immunodeficiency EC. Fortuna et al also reported the local eradication of BCMA-positive immunoglobulin A plasma cells in the gastrointestinal tract and posited that its subsequent modulation of gut immunity and microbiome may be a potential mechanism. 4 , 16

Viral gastrointestinal coinfections after diarrheal onset were common in our IEC-EC cases. These viral pathogens, although usually self-limiting, may confer prolonged viral shedding and chronic persistent diarrhea in an immunocompromised CAR-T host with a modified gut microenvironment, possibly from the loss of local plasma cells. 17 , 18 Certainly, all 3 patients in our series who had subsequent symptom resolution did not have evidence of coinfections. In contrast, of the 5 cases with coinfections, none had durable symptom responses, regardless of evidence of pathogen clearance and institution of biologic therapy, with diarrhea exceeding 4 months in all cases, reflective of a more refractory course.

There is now increasing evidence that a subset of IEC-EC cases may resemble a T-LPD, which was also observed in our series. 5 , 6 We identified 2 cases with CD3 + T-cell expansion in the lamina propria, 1 with CD8 + predominance and 1 with CD4 + predominance, with clonality demonstrated on T-cell gene rearrangement studies. We further observed a pathogenic variant of DNMT3A in the case with CD8 + T-LPD. 19 Previous reports have also demonstrated CAR + T-cells on duodenal biopsies in a case of IEC-EC. 4 , 16 However, mechanistic studies are beyond the scope of this study, and we are unable to confirm the malignant potential of these T-cell infiltrates because clonal T-cell gene rearrangements can also occur in settings in which there is physiological restriction of the T-cell repertoire (ie, autoimmune conditions and aging). As such, further clarification on the role of autoimmune T-cell activation vs CAR-driven dysregulation may lend further insight into the pathogenesis of IEC-EC.

This is, to our knowledge, the first study to identify clinical and laboratory factors associated with IEC-EC. We note that high-risk disease, defined by the IMS/IMWG criteria, was associated with increased odds of IEC-EC. In addition, a trend toward higher rates of alkylator-based bridging (3 patients with high-dose alkylators and 2 with low-dose alkylators) in IEC cases compared with patients without IEC-EC was also observed. A recent publication demonstrated that high-risk cytogenetic abnormalities may influence the composition of a patient’s bone marrow T-cell compartment. 20 Of interest, reductions in Interferon–gamma-responsive CD4 + memory T-cell populations were observed in patients with t 4 , 15 and 1q21 gain, whereas late-activated CD8 + HLA + T-effector cells were enriched in patients with high-risk genetic abnormalities. Alkylators such as cyclophosphamide are lymphodepleting at high doses, whereas at lower doses, they promote antitumor immunity by selectively depleting native regulatory T-cells and enhancing effector T-cell function. 21 Downregulation of regulatory T-cells have been shown to be associated with increased severity of gut GVHD. 22 Of note, prolonged CRS, often associated with expansion of CAR-Ts with a highly differentiated effector phenotype, was also found to be an independent associated factor for IEC-EC. 23 As such, we postulate that changes to the patient’s native T-cell landscape in the preapheresis, preinfusion, and postinfusion stages may have a role in IEC-EC pathogenesis and require further study.

Patients with IEC-EC also had higher ALC peak after cilta-cel infusion than those in the control group. However, on further interrogation, this risk was clearly driven by the IEC-EC cases with antecedent delayed neurotoxicity and may not be as impactful in predicting IEC-EC risk in patients without antecedent delayed neurotoxicity. However, more strikingly, we observed that 5 of the 9 IEC-EC cases had antecedent delayed neurotoxicity, translating to 10 times increased odds in developing IEC-EC in patients with IEC-associated delayed neurotoxicity compared with patients without. This suggests a possible unifying pathogenic process between the 2 conditions. A postulated mechanism may involve on-target off-tumor effects of the BCMA CAR-T, given that IEC-NT and IEC-EC have been reported in both idecabtagene vicleucel (ide-cel) and cilta-cel recipients. 3 , 4 In the IEC-NT setting, postmortem findings in a patient with IEC-PKS found a T-cell infiltrate in the basal ganglia with BCMA-expressing astrocytes and neurons in the caudate nucleus and adjacent frontal cortex. 24 Similarly, preclinical studies have demonstrated that BCMA is highly expressed in healthy plasma cells, including in the gastrointestinal tract (lamina propria of the esophagus, stomach, and intestine). 25 Long-term CAR-T persistence and the homing potential of the CAR-T to the gastrointestinal tract should be investigated. 26 However, for patients who developed IEC-EC without antecedent delayed neurotoxicity, further identification of risk factors is required.

Current management relies on the experience of treating other EC, especially those linked to immune checkpoint inhibitors and stem cell transplants. Based on our series of 9 cases, symptom improvement from systemic steroids appears to be poor, with no patient achieving durable responses. Durable responses appear to have been achieved in 3 of the 5 patients who received biologic therapy, with both patients receiving vedolizumab doing so, including the case with CD8 + T-LPD. Vedolizumab, a monoclonal antibody that inhibits α4β7 integrin, blocks the homing of T cells to the intestinal endothelium. 27 A previous case report of a patient who developed chronic diarrhea after treatment with an anti-CD19 CAR-T product had similar findings of CD3 + T cells in the colon lamina propria that were predominantly CAR + . 28 Flow cytometry of in the peripheral blood then showed that α4β7 expression was enriched in the CAR + cells. This may argue for the early use of vedolizumab at symptom onset to prevent further CAR-T localization to the gastrointestinal tract. Interestingly, a recent publication also suggests that immediate symptom improvement can be observed in patients treated with ruxolitinib 14 ; however, treatment required a prolonged course, and IEC-EC symptoms may recur after ruxolitinib taper. Patient access to this medication for prolonged use can also be challenging. Furthermore, 2 of the 5 patients treated with ruxolitinib had early relapse of myeloma.

Limitations of our study include those expected in any retrospective design, including the burden of missing data and the potential underreporting of cases, leading to a selection bias toward more severe cases. Although we used a more robust method for modeling rare events in our analyses, we recognize that the limited number of identified IEC-EC cases does limit our ability to fully generalize these findings. This single-institution experience also does not account for any treatment-access disparities. However, given the poorly understood nature of this entity, our single-institution study allowed for greater data granularity, control over confounders, and a centralized pathology and gastroenterology review process.

In summary, IEC-EC is a severe adverse event associated with cilta-cel, and a greater understanding of its pathogenesis is still required. We have identified important associative factors, including higher rates of antecedent delayed neurotoxicity. Duodenal biopsy may be key to diagnosis, whereas the presence of coinfection and T-LPD biopsy patterns may be associated with more severe, protracted, and treatment-refractory symptoms. Biologic therapy currently remains the most successful treatment modality in achieving durable responses and should be instituted early. Improved understanding of T-cell factors and the immune-microenvironment in the gastrointestinal tract remains key in formulating effective management strategies.

Conflict-of-interest disclosure: K.J.C.L. reports research funding from Sanofi. R.P. reports advisory board roles for Sanofi Aventis and AstraZeneca; and research funding from Bristol Myers Squibb and GSK. S.C. reports honoraria from Sanofi, Ascentage Pharma, Sobi, Legend Biotech, Bristol Myers Squibb, and Pfizer; and institutional research funding from Johnson & Johnson, Takeda, C4 Therapeutics, AbbVie, Ascentage Pharma, and AstraZeneca. M.G. reports personal fees from Ionis/Akcea; honoraria from Alnylam; personal fees from Prothena, Sanofi, and Janssen; personal fees for data and safety monitoring board participation from AbbVie and Arcellex; fees from Johnson & Johnson; and honoraria from AstraZeneca, Medscape, Dava Oncology, and Alexion. P.K. reports honoraria from Pharmacyclics, Sanofi, BeiGene, MustangBio, AstraZeneca, and AbbVie; a consulting or advisory role with Sanofi; and research funding from Amgen, Takeda, Sanofi, AbbVie, GSK, Sorrento Therapeutics, Karyopharm Therapeutics, Regeneron, Ichnos Sciences, and Bristol Myers Squibb/Celgene. P.L.B. reports consulting roles with Oncopeptides, Salarius, Radmetrix, Omeros, CellCentric, AbbVie, and Pfizer. S.K. reports consulting or advisory roles with Takeda, Janssen Oncology, Genentech/Roche, AbbVie, Bristol Myers Squibb/Celgene, Pfizer, Regeneron, Sanofi, and K36 Therapeutics; funds for travel, accommodation, and expenses from AbbVie and Pfizer; and research funding from Takeda, AbbVie, Novartis, Sanofi, Janssen Oncology, MedImmune, Roche/Genentech, CARsgen Therapeutics, Allogene Therapeutics, GSK, Regeneron, and Bristol Myers Squibb/Celgene. S.A. reports consulting or advisory roles with Takeda, BeiGene, GSK, Sanofi, Pharmacyclics, Bristol Myers Squibb, Amgen, Janssen, Regeneron, and Cellectar; and research funding from Pharmacyclics, Janssen Biotech, Cellectar, Bristol Myers Squibb, Amgen, GSK, AbbVie, Ascentage Pharma, and Sanofi. R.F. reports consultancy for AbbVie, Adaptive, Amgen, Apple, Bristol Myers Squibb/Celgene, GSK, Janssen, Karyopharm, Pfizer, RA Capital, Regeneron, and Sanofi; scientific advisory board membership with Caris Life Sciences; serves on the board of directors for Antengene; and holds a patent for fluorescence in situ hybridization in multiple myeloma. Y.L. reports advisory board roles with Janssen, Sanofi, Bristol Myers Squibb, Regeneron, Genentech, Tesserae, Legend, and NExT Therapeutics; steering committee participation for Janssen and Kite/Gilead; research funding from Janssen and Bristol Myers Squibb; served on scientific advisory boards for Nonimmune and Caribou; and served on a data and safety monitoring board for Pfizer. The remaining authors declare no competing financial interests.

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Supplementary Material

Supplemental Tables

Acknowledgments

The authors thank the Immune Effector Cell Compliance Program managers and data coordinators for sharing the chimeric antigen receptor T-cell outcome data and patients and their families for participating in the study.

Authorship

Contribution: K.J.C.L., N.C., and Y.L. were responsible for conceptualization, data curation, and writing the original manuscript draft; K.J.C.L. performed the statistical analyses; H.E.L. and Z.E.C. performed a central review of the biopsy specimens; A.B., R.P., S.C., K.D., A.D.M.S.C., M.G., L.H., H.S., P.K., M.T., T.K., R.W., J.C., M.B., P.L.B., U.Y., E.W.-N., S.G., S.K., S.A., R.F., and Y.L. performed data curation and critical appraisal and edited the manuscript; and all authors made substantial contributions to the acquisition of data, critically revised the manuscript, and gave final approval of the manuscript to be submitted for publication.

N.C. and Y.L. are joint senior authors.

The data sets generated during and/or analyzed during this study are available from the corresponding author, Yi Lin ( lin.yi@mayo.edu ), on reasonable request.

The full-text version of this article contains a data supplement.