Immune Effector Cell-Associated Enterocolitis following Chimeric Antigen Receptor T-cell Therapy in Multiple Myeloma

doi:10.21203/rs.3.rs-4727434/v1

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Immune Effector Cell-Associated Enterocolitis following Chimeric Antigen Receptor T-cell Therapy in Multiple Myeloma

https://doi.org/10.21203/rs.3.rs-4727434/v1

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Background: Several immune effector cell (IEC) therapies have been approved for multiple myeloma (MM), including chimeric antigen receptor T-cell (CAR-T) therapies such as idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel). We report 14 cases of IEC-associated enterocolitis, in five cases fatal, following CAR-T therapy in MM.

Methods: We performed a retrospective analysis of cases of diarrhea, enterocolitis, or colitis following commercial ide-cel or cilta-cel (including out-of-specification products) at 10 centers within the United States Myeloma Immunotherapy Consortium. Patients were treated according to the local standard of care at each participating center.

Results: We identified 14 cases of IEC-associated enterocolitis out of 1159 CAR-T infusions, corresponding to a 1.2% incidence (0.2% for ide-cel and 2.3% for cilta-cel). This proportion excludes 3 cases of potential or confirmed T-cell lymphoproliferative disorders of the bowel. Patients developed acute-onset symptoms (typically non-bloody Grade 3+ diarrhea) with negative infectious workup beginning a median of 79 days (range: 22-210 days) after CAR-T therapy and a median of 74 days after cytokine release syndrome resolution (range: 2-202 days). Biopsies uniformly demonstrated inflammation, with specific findings including intra-epithelial lymphocytosis, crypt dropout on colon biopsies, and villous blunting on duodenal biopsies. Systemic corticosteroids were initiated in 10 patients (71%) a median of 26 days (range: 1-80 days) following symptom onset. Only 40% of steroid-treated patients had symptomatic improvement; subsequent infliximab or vedolizumab led to improvement in 50% and 33% of corticosteroid-refractory patients, respectively. With a median follow-up of 224 days, n = 4 have had diarrhea resolution, n = 5 have had improved or stable symptoms, and n = 5 (36%) have died from IEC-associated enterocolitis or treatment-emergent infections.

Conclusions: IEC-associated enterocolitis is a distinct but rare complication of CAR-T therapy characterized by non-bloody diarrhea typically beginning 1-3 months after infusion. Thorough diagnostic workup (including evaluation for potential T-cell malignancies) and appropriate management with an expert gastroenterologist are essential. Further research is critical to understand the pathogenesis of this novel toxicity. In the interim, the early use of infliximab or vedolizumab may potentially hasten symptom resolution and lower reliance on high-dose corticosteroids during the post-CAR-T period.

Multiple myeloma

CAR-T

BCMA

colitis

enteritis

enterocolitis

diarrhea

Several immune effector cell (IEC) therapies targeting B-cell maturation antigen (BCMA) have been approved by the United States (US) Food and Drug Administration (FDA) for the treatment of multiple myeloma (MM), including chimeric antigen receptor T-cell (CAR-T) therapies such as idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) [1,2]. Common IEC-associated adverse events include cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), while rarer toxicities include hemophagocytic lymphohistiocytosis-like syndrome and late-onset neurotoxicity [3,4]. In the past five years, 3 reports of colitis manifesting as watery diarrhea have been reported following CD19-directed CAR-T therapy [5-7]. In one case, CAR T-cells expressing α4β7 integrin were found to be enriched within the colon lamina propria following treatment with [7]. A similar case of diarrhea has recently been reported following cilta-cel in MM; however, in this case, the CAR-positive infiltrate was neoplastic consistent with T-cell lymphoma [8].

Treatment-emergent gastrointestinal toxicities following CAR-T therapy in MM have not been well characterized. Diarrhea was noted in 0.4% of patients in the ide-cel arm of KarMMa-3 (n = 1) and 2.4% of patients in the cilta-cel arm of CARTITUDE-4 (n = 5) [1,2]; however, the details of chronology, further workup, and treatment in these six cases are unclear. Diarrhea following CAR-T therapy can potentially be attributed to other causes such as bacterial infections, clinically significant cytomegalovirus (CMV) reactivation, or organ-specific manifestations of inflammation during active CRS. Whether IEC-associated enteritis or colitis can occur in the absence of a neoplastic etiology following BCMA-directed CAR-T therapy in MM, as noted in one case following CD19-directed CAR-T therapy in lymphoma [7], is unknown.

We performed a retrospective analysis of cases of diarrhea, enterocolitis, or colitis following commercial ide-cel or cilta-cel (including out-of-specification products) at 10 centers within the United States Myeloma Immunotherapy Consortium. Institutional Review Board approval was obtained for participation within the Consortium at each participating center. Patients were treated according to the local standard of care at each center. Collected data points included baseline patient characteristics, CAR-T-related information, post-infusion toxicities, summaries of biopsy reports (if available), and patient outcomes. CRS and ICANS were graded using American Society for Transplantation and Cellular Therapy (ASTCT) consensus criteria, while other symptoms (diarrhea, colitis, and enterocolitis) were graded using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Baseline data were analyzed utilizing descriptive methods including medians, percentages, and student t-tests to compare clinical parameters in patients with resolved IEC-associated enterocolitis versus patients who died secondary to enterocolitis or associated complications. All analyses were performed using GraphPad Prism 10.2.3 (La Jolla, California, USA).

We identified 14 cases of IEC-associated enteritis and/or colitis diagnosed at one of 10 US centers, in one case following ide-cel and in 13 cases following cilta-cel (including 1 out-of-specification infusion). This corresponds to an IEC-associated enterocolitis incidence of 1.2% overall out of 1159 commercial or out-of-specification CAR-T infusions (594 ide-cel and 565 cilta-cel) across all study centers, with product-specific incidences of 0.2% for ide-cel and 2.3% for cilta-cel. Importantly, this figure excluded 3 cases of potential or confirmed T-cell lymphoproliferative disorders, including a previously characterized patient who was managed at multiple institutions [8]; features of these 3 patients are summarized separately in Supplemental Table 1.

As detailed in Table 1, patients with IEC-associated enterocolitis developed acute-onset diarrhea (non-bloody in all but one case) beginning a median of 79 days (range: 22-210 days) after CAR-T therapy and a median of 74 days after CRS resolution (range: 2-202 days). Diarrhea was grade 3 or higher by CTCAE criteria in all but one case of Grade 2 diarrhea, and 71% of patients (n = 10) reported concurrent abdominal pain. Computed tomography imaging (n= 13) showed radiographic evidence of small bowel or large bowel inflammation in 54% of cases (n= 7), including two cases of diffuse colonic pneumatosis (Figure 1A). Peripheral blood CMV assessment by quantitative polymerase chain reaction testing was performed in 10 cases: results were negative in 7 cases, below the lower level of detection in 1 case, and frankly positive in two cases (peak values 186 and 12,800 international units per milliliter, respectively). Both patients with CMV viremia received intravenous ganciclovir with CMV clearance in one case and ongoing low-level positivity in the other. With regard to antecedent CRS and ICANS, 5 patients had maximum Grade 2 CRS, 8 Grade 1 CRS, and 1 no CRS; one patient had developed Grade 2 ICANS. Management strategies for antecedent CRS or ICANS included tocilizumab (n = 11), corticosteroids (n = 9), and anakinra (n = 1). Three patients had developed delayed cranial nerve palsies following cilta-cel, with neurotoxicity resolution before enterocolitis onset in two of these cases. By the time of diarrhea onset, serum ferritin and C-reactive protein levels at symptom onset were below their peak values in all patients.

Biopsies were obtained in 79% of cases (n = 11) and uniformly demonstrated evidence of inflammation in at least one area (Supplemental Table 2). Colonic biopsies (n= 3, representative images in Figure 1B and Figure 1C) typically showed endoscopic evidence of ulceration with histological evidence of crypt dropout and increased apoptotic activity. Duodenal biopsies (n= 7; representative images in Figure 1D, Figure 1E, and Figure 1F) typically showed villous blunting and increased intraepithelial lymphocytes. In several cases (n = 5), marked intra-epithelial lymphocytosis was noted. Immunohistochemical stains for bacterial and viral infections (including CMV) were negative in all cases including patients with CMV viremia, and chronic changes such as crypt architecture distortion were only rarely seen. Biopsy findings were often noted by interpreting pathologists to resemble those seen in graft-versus-host disease (GVHD); however, all patients had received autologous CAR-T therapies and no patients had previously undergone allogeneic hematopoietic stem cell transplantation.

With regard to treatment, systemic corticosteroids were initiated in 71% of cases (n = 10). This included six patients who received oral prednisone with a median starting dose of 0.87 milligrams (mg) per kilogram (kg) per day (range: 0.19-2 mg/kg/day) for a median duration of 22 days (range: 1-145 days) as well as four patients who received intravenous methylprednisolone with a median starting dose of 1.40 mg/kg/day (range: 1-2 mg/kg/day) for a median duration of 51 days (range: 20-68 days). Corticosteroids were initiated a median of 26 days (range: 1-80 days) following symptom onset, and 40% of steroid-treated patients had symptomatic improvement thereafter. Six patients with corticosteroid-refractory symptoms (43% of all cases) were subsequently started on infliximab based on American Society of Clinical Oncology (ASCO) guidelines for managing immune-related adverse events (irAEs) following checkpoint inhibitors [9]. Median time to infliximab initiation was 61 days (range: 34-100 days) after diarrhea onset, and half of infliximab-treated patients had symptomatic improvement after 1-3 doses of infliximab. Given that α4β7 integrin may be overexpressed on CAR T-cells within the colon [7], the α4β7 integrin antagonist vedolizumab was prescribed in three patients (21% of all patients). Vedolizumab was initiated a median of 59 days (range: 40-120) after diarrhea onset, with one of three patients having symptomatic improvement but subsequently developing Clostridioides difficile infection requiring fecal microbiota transplantation.

With a median follow-up of 224 days since diarrhea onset (range: 56-664 days), 4 patients have had diarrhea resolution (median time to resolution 95 days), including one patient who required a 145-day prednisone course with a taper and two patients who required 1-5 doses of infliximab concomitantly with corticosteroids. Five patients have ongoing diarrhea, including two patients with improved but ongoing symptoms. Five patients (36% of all cases) have died, either directly from IEC-associated enterocolitis (n = 3) or from treatment-emergent infections (n = 2). Characteristics of patients with symptom resolution (n = 4) versus deceased patients (n = 5) are shown in Supplemental Table 3. Albeit with small n, no significant differences were noted in terms of age, pertinent biomarkers, time to symptom onset, or time to corticosteroid initiation.

This represents the largest case series of IEC-associated enterocolitis following any type of CAR-T therapy. Clinical and histological presentations were strikingly similar in most cases, suggesting that IEC-associated enterocolitis is a rare but distinct toxicity of CAR-T therapy characterized by non-bloody diarrhea with negative infectious workup beginning 1-3 months following CAR-T therapy. Inflammation is typically seen on enteric biopsies with a specific resemblance to the pattern seen in GVHD following allogeneic transplantation. The addition of biologic immunosuppressive agents (e.g., infliximab or vedolizumab dosed at weeks 0, 2, and 6) may benefit patients with corticosteroid-refractory symptoms. Indeed, in the setting of colitis as an irAE following checkpoint inhibition, ASCO guidelines recommend initiating infliximab as soon as 3 days after corticosteroids if symptoms do not begin to improve [9]. Vedolizumab may also be helpful given that α4β7 integrin (the target of vedolizumab) has been shown to be overexpressed on gut-trafficking CAR T-cells [7]. However, further research is needed to validate the utility of biologic immunosuppressive agents in this specific scenario.

Limitations of our study include the lack of correlative data to better elucidate the pathophysiology of IEC-associated enterocolitis, including definitive identification of CAR-positive T cells within gut (for which confirmatory work is ongoing at several centers). Biopsy findings were not reviewed centrally, making it difficult to uniformly estimate histological patterns or proportions of immune cell subsets within biopsy specimens. While our consortium has tentatively identified up to 3 separate cases of lymphoproliferative disorders presenting with diarrhea (Supplemental Table 1), T-cell lymphomas were not suspected in these 14 cases based on morphologic and immunophenotypic features. As boundaries between reactive lymphoid infiltrates and neoplastic lymphoid infiltrates are not always distinct, any suspicious infiltrate should undergo thorough evaluation by an expert lymphoma pathologist. If a lymphoma is diagnosed, it should be reported to the FDA given the rare occurrence of T-cell lymphomas following BCMA CAR-T therapy [8,10,11]. Testing for the presence of CAR-positive T cells is reasonable to pursue in all cases of gut biopsies demonstrating lymphocytic infiltrates following CAR-T therapy. Despite the absence of this testing to date, our experience highlights the urgent need for our field to immediately recognize this entity as a unique IEC-associated toxicity. This need is underscored by the fact that diarrhea persisted for almost a month before median corticosteroid initiation, in most cases well after patients had been discharged from their CAR-T treatment centers.

IEC-associated enterocolitis remains a rare phenomenon, with an incidence of 1.2% out of over 1100 commercial or out-of-specification BCMA CAR-T infusions across all study centers. Comparing our observed product-specific incidences of 0.2% for ide-cel and 2.3% for cilta-cel is difficult given the novelty and rarity of this toxicity. The voluntary FDA Adverse Events Reporting System (FAERS) database, which has been used previously to characterize rare toxicities of CAR-T therapy [12], includes 15 reactions that may potentially be linked to IEC-associated enterocolitis (Supplemental Table 4). However, FAERS data do not have a denominator and it is unclear whether any of these reported reactions represent infectious sequelae, pre-existing conditions, or duplicate entries (either with each other or with cases described here). The recently characterized case of CAR-positive T-cell lymphoma following cilta-cel is not isolated [8], but such cases are even rarer in our experience. Failure of enterocolitis symptoms to improve with corticosteroids and biological immunosuppressive agents should prompt consideration of a lymphoproliferative process for which, after diagnostic confirmation of neoplastic T cells, drugs such as cyclosporine may be more appropriate [13].

In conclusion, IEC-associated enterocolitis is a distinct but rare complication of CAR-T therapy characterized by non-bloody diarrhea beginning 1-3 months after infusion. Notably, this toxicity thus generally occurs after patients have been discharged from their CAR-T treatment facilities. Thorough diagnostic workup (including evaluation for potential T-cell malignancies) and appropriate management with an expert gastroenterologist are essential. Further research into the pathogenesis of this toxicity is critical to understand this novel complication, an urgent need underscored by the fact that over a third of patients in our cohort died due to IEC-associated enterocolitis or the immune compromise associated with its treatment. In the interim, the early use of infliximab or vedolizumab may potentially hasten symptom resolution and lower reliance on high-dose corticosteroids during the post-CAR-T period.

ASCO American Society of Clinical Oncology
ASTCT American Society for Transplantation and Cellular Therapy
BCMA B-cell maturation antigen
CAR-T Chimeric antigen receptor T-cell therapy
Cilta-cel Cilcabtagene autoleucel
CRS Cytokine release syndrome
CTCAE Common Terminology Criteria for Adverse Events
FAERS Food and Drug Administration Adverse Events Reporting System
FDA Food and Drug Administration
GVHD Graft versus host disease
ICANS Immune effector cell-associated
Ide-cel Idecabtagene vicleucel
IEC Immune effector cell
irAE Immune-related adverse event
MM Multiple myeloma
US United States

Ethics approval: We performed a retrospective analysis of data from centers within the United States Myeloma Immunotherapy Consortium. Institutional Review Board approval was obtained for participation within Consortium activities at each center.

Consent for publication: Consent for use of data for research obtained from patients at the time of CAR-T infusion. No patient-identifying information is included in this manuscript.

Availability of data and materials: Deidentified data available upon reasonable request from the corresponding author.

Competing interests: R.B. reports consulting: Adaptive Biotech, BMS, Caribou Biosciences, Genentech, GSK, Janssen, Karyopharm, Legend Biotech, Pfizer, Sanofi, SparkCures; Research: Novartis, Pack Health. R.F. reports consulting: AbbVie, Adaptive, Amgen, Apple, BMS/Celgene, GSK, Janssen, Karyopharm, Pfizer, RA Capital, Regeneron, Sanofi; Scientific Advisory Board: Caris Life Sciences; Board of Directors: Antengene; Patents for certain FISH tests in MM. C. F. reports consulting: Janssen; research: Regeneron, Janssen; stock ownership: Affimed. P.M.V. reports consulting: Abbvie, Astra Zeneca, BMS, GSK, Janssen, Karyopharm, Lava Therapeutics, Regeneron, Sanofi; research: Abbvie, Janssen, Regeneron. S.D.R. reports honoraria: Janssen, BMS; steering committee involvement, Gracell Therapeutics, BMS; research support, Janssen, BMS, C4 Therapeutics, Gracell Therapeutics, Heidelberg Pharma; consulting: Genentech, Janssen, BMS. J.Y.S. reports consulting: Kite, Immpact Bio. L.L. reports consulting: Allogene, Sanofi. S.F.P. reports Consulting: Cartography Biosciences; Scientific Advisory Board: Leica Biosystems. A.J.C. reports consulting: BMS, Adaptive; Research: Adaptive Biotechnologies, Harpoon, Nektar, BMS, Janssen, Sanofi, AbbVie. D.W.S. reports consulting: GlaxoSmithKline, Janssen, Sanofi, Abbvie, Bristol Myer Squibb, Pfizer, Bioline, Arcellx, AstraZeneca, Genentech; Research: Gilead, Pfizer, Janssen, Bioline, GlaxoSmithKline, Sanofi, Amgen, Cantex, Arcellx, Roche; Steering Committee: Janssen; Data safety and monitoring: Karyopharm, and Independent Review Committee: Parexel.D.K.H. reports consulting: BMS, Janssen, legend Biotech, Pfizer, Karyopharm; Research: BMS, Karyopharm, Adaptive Biotechnologies, and Pentecost Myeloma Research Center. The remaining authors have no interests to disclose.

Funding: None.

Author contributions: G.G.F. and R.B. wrote the first draft of the manuscript. All authors contributed substantially to data collection and manuscript revision. All authors have approved the final manuscript.

Acknowledgments: The authors would like to acknowledge all the patients and their caregivers involved in this study. The authors would also like to acknowledge the research coordinators and hematopathology teams at each institution who assisted with data collection and interpretation.

Rodriguez-Otero P, Ailawadhi S, Arnulf B, Patel K, Cavo M, Nooka AK, et al. Ide-cel or Standard Regimens in Relapsed and Refractory Multiple Myeloma. N Engl J Med. 2023;388(11):1002-1014.
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Table 1: Patient, disease, and enterocolitis characteristics

Demographic characteristics at infusion	n (%)
Male gender	6 (43)
Age in years, median (range)	64 (39-79)
ECOG performance status, median (range)	1 (0-1)
History of inflammatory bowel disease	2 (14)
Disease and treatment characteristics
Extramedullary disease at infusion	2 (14)
Prior lines of therapy, median (range)	4.5 (4-7)
Prior stem cell transplantation	11 (79)
CAR-T product type
Cilta-cel	13 (93)
Ide-cel	1 (7)
Biomarkers at infusion, median (range)
Absolute lymphocyte count (x10⁹/L) (n = 13)	0.3 (0.02-0.96)
C-reactive protein (mg/L) (n = 13)	3.45 (0.51-60.9)
Ferritin (ng/mL) (n = 13)	160.5 (43-1819)
Biomarker maximum values, median (range)
C-reactive protein (mg/L) (n = 13)	35.6 (3.8-194.8)
Ferritin (ng/mL) (n = 13)	1062.5 (111-11214)
Any-grade CRS	13 (93)
CRS grade ≥ 2	5 (36)
Any-grade ICANS	1 (7)
ICANS grade ≥ 2	1 (7)
≥PR to CAR-T	11 (79)
AE characteristics at symptom onset
Days after infusion, median (range)	79 (22-210)
Days after CRS resolution, median (range)	74 (2-202)
Highest CTCAE grade, median (range)	3 (1-5)
Diagnostic presentation
Non-bloody diarrhea	13 (93)
Radiographic enteritis or colitis^†(n = 13)	7 (54)
Biomarkers at onset, median (range)
Absolute lymphocyte count (x10⁹/L) (n = 13)	0.75 (0.12-1.68)
C-reactive protein (mg/L) (n = 10)	4.15 (0.3-14.7)
Ferritin (ng/mL) (n = 7)	101 (33-3462)
AE treatment and outcomes
Systemic corticosteroid use	10 (71)
Intravenous corticosteroids	4 (40)
Oral corticosteroids	6 (60)
Duration of corticosteroids in days, median (range)	44.5 (1-270)
Infliximab use	6 (43)
Infliximab doses, median (range)*	2 (1-3)
Clinical benefit from infliximab (n = 6)	3 (50)
Vedolizumab use	3 (21)
Vedolizumab doses, median (range)*	2 (2-2)
Clinical benefit from vedolizumab (n = 3)	1 (33)
AE status (as of data cutoff)
Resolution of symptoms	4 (28)
Ongoing symptoms	5 (36)
Death due to enterocolitis	5 (36)
Days to symptom resolution, median (range)^†	76 (17-113)

* When administered, infliximab and vedolizumab were dosed with an interval of 2 weeks between the second dose and the first dose and an interval of 6 weeks between the third dose and the second dose.

^†Only in patientswith resolved symptoms
Abbreviations: AE, adverse event; CAR-T, chimeric antigen receptor T-cell therapy; CRS, cytokine release syndrome; CTCAE, Common Terminology Criteria for Adverse Events; dl, deciliter; ECOG, Eastern Cooperative Oncology Group; ICANS, immune effector cell-associated neurotoxicity syndrome; L, liter; mg, milligrams; mL, milliliter; ng, nanograms; PR, partial response.

Competing interest reported. R.B. reports consulting: Adaptive Biotech, BMS, Caribou Biosciences, Genentech, GSK, Janssen, Karyopharm, Legend Biotech, Pfizer, Sanofi, SparkCures; Research: Novartis, Pack Health. R.F. reports consulting: AbbVie, Adaptive, Amgen, Apple, BMS/Celgene, GSK, Janssen, Karyopharm, Pfizer, RA Capital, Regeneron, Sanofi; Scientific Advisory Board: Caris Life Sciences; Board of Directors: Antengene; Patents for certain FISH tests in MM. C. F. reports consulting: Janssen; research: Regeneron, Janssen; stock ownership: Affimed. P.M.V. reports consulting: Abbvie, Astra Zeneca, BMS, GSK, Janssen, Karyopharm, Lava Therapeutics, Regeneron, Sanofi; research: Abbvie, Janssen, Regeneron. S.D.R. reports honoraria: Janssen, BMS; steering committee involvement, Gracell Therapeutics, BMS; research support, Janssen, BMS, C4 Therapeutics, Gracell Therapeutics, Heidelberg Pharma; consulting: Genentech, Janssen, BMS. J.Y.S. reports consulting: Kite, Immpact Bio. L.L. reports consulting: Allogene, Sanofi. S.F.P. reports Consulting: Cartography Biosciences; Scientific Advisory Board: Leica Biosystems. A.J.C. reports consulting: BMS, Adaptive; Research: Adaptive Biotechnologies, Harpoon, Nektar, BMS, Janssen, Sanofi, AbbVie. D.W.S. reports consulting: GlaxoSmithKline, Janssen, Sanofi, Abbvie, Bristol Myer Squibb, Pfizer, Bioline, Arcellx, AstraZeneca, Genentech; Research: Gilead, Pfizer, Janssen, Bioline, GlaxoSmithKline, Sanofi, Amgen, Cantex, Arcellx, Roche; Steering Committee: Janssen; Data safety and monitoring: Karyopharm, and Independent Review Committee: Parexel. D.K.H. reports consulting: BMS, Janssen, legend Biotech, Pfizer, Karyopharm; Research: BMS, Karyopharm, Adaptive Biotechnologies, and Pentecost Myeloma Research Center. The remaining authors have no interests to disclose.

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Immune Effector Cell-Associated Enterocolitis following Chimeric Antigen Receptor T-cell Therapy in Multiple Myeloma

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