Modern B-cell targeted immunotherapies have transformed hematologic oncology, but they can trigger severe gastrointestinal toxicities. Therefore, understanding intestinal histopathological changes following targeted therapy remains critical for timely diagnosis. Clinicians frequently encounter diagnostic dilemmas when distinguishing immune-mediated mucosal injury from opportunistic infection or graft-versus-host disease. In addition, comparative histological profiles across diverse therapeutic modalities have remained scarce until recently. Consequently, delineating drug-specific mucosal injury patterns helps oncologists optimize patient interventions.

Distinct Intestinal Histopathological Changes Across Immunotherapies

A landmark retrospective cohort study evaluated mucosal tissue from patients receiving BCMA-directed CAR T, teclistamab, CD19-directed CAR T, and rituximab. Notably, investigators uncovered distinctive yet overlapping microscopic features across these cohorts. Lamina propria plasma cell depletion emerged as the single most striking abnormality among BCMA-targeted therapies. Specifically, researchers detected plasma cell depletion in 88% of teclistamab recipients and 74% of BCMA CAR T recipients. In contrast, patients receiving CD19 CAR T cells exhibited this depletion in only 32% of biopsies. Furthermore, rituximab-treated patients demonstrated plasma cell loss in only 27% of cases. Because plasma cells populate the normal intestinal lamina propria to produce secretory immunoglobulin A, their profound loss directly impacts mucosal homeostasis. Pathologists also recognized significant apoptotic enteropathy and intraepithelial lymphocytosis in both bispecific antibody and CAR T cohorts. Consequently, clinicians must appreciate that plasma cell absence does not represent normal histology. Instead, it signals targeted on-target, off-tumor cytotoxicity against normal antibody-producing cells. These comparative microscopic observations provide clinicians with tangible histological biomarkers when evaluating persistent post-infusion diarrhea or enteritis.

Mechanisms Driving Mucosal Plasma Cell Depletion

Understanding the biological mechanisms underlying mucosal damage requires evaluating target antigen distribution. B-cell maturation antigen, commonly termed BCMA, maintains long-lived plasma cell survival within bone marrow and mucosal tissues. Therefore, therapeutic agents like teclistamab and BCMA CAR T cells eliminate both malignant myeloma clones and resident mucosal plasma cells. Furthermore, bispecific antibodies recruit CD3-positive cytotoxic T cells directly to BCMA-expressing targets in the gut lining. As a result, this localized immune activation triggers apoptotic enteropathy, crypt distortion, and acute mucosal inflammation. In contrast, CD19 expression primarily marks pre-B and mature B lymphocytes rather than fully differentiated plasma cells. Consequently, CD19-directed CAR T therapy spares the majority of secretory plasma cells within the gut lamina propria. Similarly, rituximab targets the CD20 surface protein, which mature plasma cells lose during terminal differentiation. Hence, rituximab administration causes transient peripheral B-cell depletion without eradicating intestinal plasma cell niches. Ultimately, these biological distinctions explain why BCMA-targeted modalities induce far more extensive plasma cell loss than other therapeutic platforms.

Clinical Manifestations and Endoscopic Presentations

Patients experiencing immunotherapy-related enteropathy usually present with severe secretory diarrhea, abdominal cramping, and malabsorption. Moreover, systemic symptoms such as fever and nutritional wasting frequently accompany these lower gastrointestinal complaints. Diagnostic endoscopy plays an essential role in delineating the anatomical extent of tissue injury across the tract. Clinicians frequently identify diffuse erythema, mucosal friability, and superficial ulcerations during colonoscopy. In addition, upper endoscopic evaluation often reveals blunted duodenal villi and marked mucosal edema. Importantly, macroscopic endoscopic findings do not always correlate perfectly with microscopic injury severity. A patient may display relatively mild endoscopic erythema while microscopic biopsies reveal extensive crypt apoptosis and complete plasma cell depletion. Furthermore, clinicians must promptly exclude infectious etiologies before initiating immunosuppressive therapy. Enteric pathogens, including Clostridioides difficile, cytomegalovirus, and adenovirus, can mimic immune-mediated enteropathy. Therefore, gastroenterologists must obtain serial mucosal biopsies alongside comprehensive stool pathogen panels. Early histological confirmation prevents misdiagnosis and directs therapy toward appropriate immunomodulatory management.

Diagnostic Pathology and Differential Challenges

Surgical pathologists face substantial challenges when evaluating mucosal biopsies from heavily pretreated hemato-oncology patients. For example, acute graft-versus-host disease exhibits profound crypt apoptosis and epithelial sloughing, closely mimicking cellular CAR T-cell injury. Additionally, immune checkpoint inhibitor colitis presents with prominent mucosal lymphocytosis and neutrophilic cryptitis. Pathologists must therefore integrate patient treatment history, drug timelines, and immunohistochemical staining profiles to achieve diagnostic precision. Specifically, CD138 and MUM1 immunostains allow pathologists to quantify lamina propria plasma cell densities reliably. Furthermore, pathologists should routinely employ cytomegalovirus immunohistochemistry to rule out opportunistic viral reactivation in immunosuppressed hosts. In teclistamab recipients, the near-complete absence of CD138-positive cells provides a vital diagnostic clue. However, clinicians must remember that common variable immunodeficiency also causes mucosal plasma cell absence. Consequently, pathologists and treating oncologists must engage in active multidisciplinary discussions. Correlating histological features with the exact immunotherapeutic regimen ensures rapid therapeutic decisions and avoids unnecessary antimicrobial interventions.

Therapeutic Strategies and Clinical Perspectives

Managing gastrointestinal toxicity from cellular therapies and bispecific antibodies demands a proactive, stepwise approach. First, clinicians should rule out active enteric infections through comprehensive microbiological testing. If symptoms persist and histology reveals immune-mediated enteritis, systemic corticosteroid therapy represents the primary therapeutic intervention. For instance, oral budesonide provides targeted topically active steroid delivery for mild ileal or right-sided colonic involvement. In contrast, severe or refractory mucosal inflammation requires high-dose intravenous methylprednisolone to suppress cytotoxic T-cell activity. Furthermore, biologic agents targeting inflammatory cytokines, such as infliximab or vedolizumab, offer viable rescue therapy in steroid-refractory colitis. In India and developing healthcare settings, clinicians must exercise extreme vigilance regarding latent tuberculosis reactivation before escalating biologic immunosuppression. In addition, prolonged mucosal plasma cell depletion predisposes patients to chronic mucosal infections and persistent hypogammaglobulinemia. Therefore, physicians should monitor serum immunoglobulin levels regularly and administer intravenous immunoglobulin replacement therapy when indicated. Ultimately, coordinated multidisciplinary care between oncologists, gastroenterologists, and pathologists optimizes mucosal healing while preserving anti-myeloma efficacy.

Why do BCMA-targeted therapies cause profound intestinal plasma cell depletion?

B-cell maturation antigen promotes survival signals in mature, long-lived plasma cells residing within bone marrow and gut mucosal tissues. Consequently, therapies like teclistamab and BCMA-directed CAR T cells eliminate these antibody-producing cells alongside malignant myeloma clones. In contrast, CD19-targeted and CD20-targeted agents preserve mature plasma cells because these cells downregulate CD19 and CD20 surface markers. Therefore, BCMA-directed modalities produce profound, selective intestinal plasma cell loss.

How can pathologists differentiate immunotherapy enteropathy from graft-versus-host disease?

Pathologists distinguish these conditions by evaluating clinical history, cellular composition, and immunohistochemical markers. Both disorders demonstrate prominent crypt apoptosis, but graft-versus-host disease rarely displays profound plasma cell depletion unless complicated by profound conditioning toxicities. Furthermore, teclistamab toxicity shows selective loss of CD138-positive cells while preserving certain mucosal architecture. Pathologists must also perform cytomegalovirus immunohistochemistry to exclude viral colitis before confirming an immune-mediated toxicity.

What is the recommended initial management for immunotherapy-induced intestinal injury?

Clinicians first rule out infectious enteritis by performing stool microbiological analyses and endoscopic mucosal biopsies. Once infection is excluded, systemic corticosteroid therapy serves as the primary treatment for symptomatic immune enteropathy. Mild cases respond well to gut-directed oral budesonide, whereas severe presentations require intravenous methylprednisolone. Furthermore, clinicians should measure serum immunoglobulin levels and provide intravenous immunoglobulin replacement if hypogammaglobulinemia persists.

Disclaimer: This content is for informational and educational purposes only... Refer to the latest local and national guidelines for clinical practice.

References

Leung OJ et al. Comparison of intestinal histopathological changes following teclistamab, BCMA-directed CAR T, CD19-directed CAR T and rituximab therapies. Histopathology. 2026 Sep 13. doi: 10.1111/his.70277. PMID: 42732998.

Malo SJ, et al. Gastrointestinal toxicities associated with chimeric antigen receptor T-cell therapy: Clinical presentation and endoscopic features. Journal of Clinical Oncology. 2023;41(16_suppl):e14589.

Moreau P, et al. Teclistamab in relapsed or refractory multiple myeloma. New England Journal of Medicine. 2022;387(6):495-505.