Outcomes of Allogeneic Hematopoietic Stem Cell Transplant in Monogenic Inflammatory Bowel Disease

Abstract

BACKGROUND & AIMS:

Monogenic inflammatory bowel disease (IBD) can result in inborn errors of immunity and intestinal epithelial cell dysfunction, more commonly seen in patients with very early onset IBD (VEO-IBD). Hematopoietic stem cell transplant (HSCT) has emerged as an effective treatment for a subset of patients with monogenic IBD. We sought to evaluate the efficacy and safety of HSCT in these patients. We hypothesized that HSCT will lead to IBD medication-free remission or significant improvement of disease.

METHODS:

This was a single-center, retrospective study of children with monogenic IBD who underwent HSCT at The Children’s Hospital of Philadelphia from 2012 to 2022. The primary outcome was IBD medication-free sustained remission, measured by disease activity index. Secondary outcomes included all-cause mortality, growth, hospitalizations, infections, and HSCT-associated complications.

RESULTS:

Thirty-eight patients with monogenic IBD were identified as eligible for HSCT, with 25 undergoing HSCT as therapy for IBD during the study period. There was 100% survival at a median follow-up of 3 years. Prior to transplant, 76% of patients received immunosuppression, and 20% underwent IBD-related surgery. At most recent follow-up, 92% of patients achieved sustained medication-free remission of IBD and 60% with prior ostomy underwent re-anastomosis. There was significant improvement in growth, hospital days, and severe infections.

CONCLUSION:

HSCT resulted in IBD medication-free remission and reduction in disease-associated complications. This highlights the strength of genetic evaluation in patients with VEO-IBD or refractory IBD and consideration of HSCT, which can be curative and lifesaving in patients with monogenic defects involving immune dysfunction.

Graphical Abstract

Inflammatory bowel disease (IBD) is a complex disease of the gastrointestinal tract, involving diverse genetic backgrounds that shape the mucosal immune response to environmental exposures. IBD is most often a polygenic disease, involving over 200 risk loci,¹ however; over the past 15 years, discoveries of causative monogenic defects in a subset of patients have transformed the genetic landscape and generated insight into pathoetiologies of the disease.²

Monogenic and polygenic IBD can present similarly; however, certain features may point toward an underlying monogenic defect. Monogenic IBD most often presents before 6 years of age, known as very early onset IBD (VEO-IBD) and can have a more aggressive, and refractory disease course as compared with polygenic IBD.³ Additionally, patients may experience complications from underlying immunodeficiency and associated autoimmune disease.³ These factors, together with the greater duration of active disease, can result in more severe morbidity in this population.

With the advances in genetic and transcriptomic sequencing, over 90 causal genes have been identified in patients with IBD.⁴ Many of these genetic variants are involved in inborn errors of immunity (IEI), which affect the hematopoietic compartment, intestinal epithelial cell (IEC) defects, or defects that affect both compartments (IEI/IEC).⁴ Insights generated from these discoveries have led to novel targeted therapies with increased rates of remission and in some cases, have proven to be lifesaving. One of the most targeted treatments for monogenic IBD thus far is hematopoietic stem cell transplantation (HSCT).

HSCT was first identified as a cure for patients with primary immunodeficiencies in 1968, including severe combined immunodeficiency (SCID) and Wiskott-Aldrich syndrome (WAS).^5,6 Over time, HSCT has been used in many other IEIs, such as chronic granulomatous disease (CGD), which similar to SCID and WAS, can involve intestinal manifestations. However, single defects were not recognized as causative for IBD until 2009, with the discovery of autosomal recessive (AR) interleukin 10 receptor (IL-10R) deficiency.⁷ HSCT was curative for both the underlying immunodeficiency and associated IBD in these patients.⁸ HSCT has since become part of the therapeutic arsenal for a subset of patients with monogenic IBD, both as a potential cure for IBD and for the prevention of life-threatening sequelae of certain monogenic defects, such as serious infections, hemophagocytic lymphohistiocytosis (HLH), and malignancies.^9–12

Despite this success, significant challenges remain in selecting patients for HSCT whose intestinal disease will improve without increased risk of adverse events compared with other IEI cohorts undergoing HSCT. The concern of adverse events, particularly graft vs host disease (GVHD), has led to deferment of HSCT in patients with IBD with IEI monogenic defects that have been shown to benefit from transplant. Additionally, HSCT is often not pursued in patients with combined IEI/IEC defects due to concern that the epithelial disease will persist.^13,14 We aimed to characterize our experience using allogeneic HSCT as therapy for children with monogenic IBD caused by defects involving IEIs and IEI/IECs. We hypothesized that allogeneic HSCT in patients with monogenic IBD would result in sustained medication-free remission or significant improvement of the disease. We also aimed to identify potential predictors of success with HSCT for monogenic IBD and identify adverse events.

Methods

This was a single-center retrospective study of children with monogenic IBD who underwent allogeneic HSCT at The Children’s Hospital of Philadelphia (CHOP) between 2012 and 2022, with follow up data collection through July 2023. This study was approved by the internal review board (IRB 14–010826). Patient eligibility for HSCT was determined by a multidisciplinary team, including the HSCT team, gastroenterology, and immunology. Inclusion criteria were diagnosis of IBD, confirmed causative monogenic defect that impacts the hematopoietic compartment, and both HSCT and gastroenterology care at CHOP within the study period. Exclusion criteria included incomplete data, indications for transplant that did not include IBD, and less than 6 months of follow-up data. The electronic medical record was queried to obtain demographics, pre-transplant and post-transplant disease characteristics, HSCT conditioning and prophylaxis protocols, laboratory data, medications, surgical history, growth parameters, hospitalizations, and related complications.

Outcome Measures

The primary outcome was sustained IBD medication-free remission of intestinal disease post-transplant, which was defined as Pediatric Ulcerative Colitis Activity Index (PUCAI)¹⁵ or short Pediatric Crohn’s Disease Activity Index (short PCDAI)¹⁶ <10 in the absence of IBD medications in patients without ostomies. In patients with ostomies, the definition included successful re-anastomosis or for those who were not candidates for re-anastomosis, sustained medication-free quiescence as measured by physician global assessment (PGA) post-transplant. Secondary outcomes included engraftment, endoscopic mucosal healing, improvement in growth, nutritional support requirement, hospitalizations, infection related to immunodeficiency, and adverse events, including all-cause mortality, infection, GVHD, veno-occlusive disease (VOD), development of HLH, and gastrointestinal bleeding.

Infections and Hospitalizations

Per institutional protocol, fever requires admission within the first 365 days post-transplant. Thus, to exclude admissions during this immune reconstitution period, hospitalization days were assessed for the year following this period (post-transplant d+365 to d+730) and compared with the 1 year prior to HSCT. Infections within the first-year post-transplant were reported separately.

Growth Assessment

Height Z-scores (CDC) were abstracted at the time of transplant and last available follow up. For patients who continued to gain linear height following age 20, the last height was translated onto the age 20 Z-score.

Statistical Analysis

Normally distributed continuous variables were assessed using paired t-tests, whereas non-normally distributed variables were assessed using Wilcoxon Signed Rank testing. Binary variables were assessed using McNemar’s χ² tests.

Results

Cohort Description

Thirty-eight patients followed by CHOP gastroenterology with defects that impacted the hemopoietic compartment were identified as eligible for HSCT during the study period. Patients with identified monogenic defects whose impact was limited to epithelial cells were not included. Of the 38 patients identified as eligible, 26 underwent HSCT. One patient with TTC7A was subsequently excluded as transplant was performed for the indication of SCID alone, rather than treatment of intestinal disease. Two patients passed away prior to transplant. Six patients underwent transplant after the study window. Four families declined transplant (Figure 1A). Of the 25 included patients, 72% were male. Causative variants were identified in 11 genes (Table 1; Supplementary Table 1). HSCT had not been previously reported in genetic defects in ITCH¹⁷ and STXBP3¹³ at the time of transplant. Twenty-two patients had IEI defects, and 3 patients had IEI/IEC defects.

Figure 1.

(A) Cohort data. Created in BioRender. (B) Age of onset of gastrointestinal symptoms.

Table 1.

Medication Exposures by Patient Prior to HSCT, at the Time of Transplant, and at Most Recent Follow-up

Gene Category	Sex	Previous medications (IBD)	Previous immune medications (non-IBD)	IBD medications at time of transplant	IBD medications at last follow-up (post-transplant)	IgRT pre-HSCT	Infection ppx pre-HSCT
CTLA4 IEI	M	5-ASA	Ritux	Pred, 6-MP	None	Y	Pen-VK
CYBB IEI	M	N/A		Pred, 5-ASA	None	N	TMP-SMX, ITZ
CYBB IEI	M	N/A		Pred	None	N	TMP-SMX, ITZ
CYBB IEI	M	N/A		Cipro	None	N	Cipro, ITZ
CYBB IEI	M	Cipro		Flagyl	None	N	TMP-SMX, ITZ
CYBB IEI	M	N/A		5-ASA, Cipro, Flagyl	None	N	TMP-SMX, ITZ
CYBB IEI	M	N/A		Pred	None	N	TMP-SMX, ITZ
CYBB IEI	M	Flagyl		Flagyl	None	N	TMP-SMX, ITZ
CYBB IEI	M	5-ASA		Pred, 6-MP, Cipro, Flagyl	None	N	TMP-SMX, ITZ
CYBB IEI	M	N/A		5-ASA, 6-MP	None	N	TMP-SMX, ITZ
IL10RA IEI	F	Pred, 5-ASA, MTX		ANR, Flagyl	None	N	N
IL10RA IEI	F	MTX, 6-MP, IFX, ADA, Cipro, Flagyl, Vanc, TNZ		Pred, Rifax	None	N	N
IL10RB IEI	F	Pred, 5-ASA, IFX, Ruxo		ADA	None	N	N
IL10RB IEI	F	Pred		CAM	None	N	N
ITCH IEI	M	MTX, Tacro, MMF, IFX, ADA, GOM, ETC		Pred, 5-ASA, UST, ABC	None	N	Fluc, TMP-SMX
LRBA IEI	F	Pred	Ritux	Siro, ABC	None	Y	TMP-SMX, VGCV
LRBA IEI	F	Bud, 5-ASA, MTX		ABC	None	Y	N
NCF1 IEI	F	MTX, IFX, CAM, Cipro, Flagyl		Pred	None	N	TMP-SMX, ITZ
STXBP2 IEI/IEC	M	N/A	EMA, etop, dex	None	None	N	TMP-SMX, Caspofungin, ACV
STXBP3 IEI/IEC	M	Pred, Tacro		IFX	None	N	N
STXBP3 IEI/IEC	M	N/A		Tac	Siro, vedo, CAM	Y	N
WAS IEI	M	5-ASA	Ritux	Vedo	None	Y	N
WAS IEI	M	N/A		None	None	N	PTD
XIAP IEI	M	N/A		CAM, Flagyl	None	N	N
XIAP IEI	M	IFX, ADA, Flagyl		Pred, Vedo, IVIG, Ritux	None	Y	N

Note: N/A indicates this patient was not on additional IBD-targeted medications prior to the regimen they were on at time of transplant.

5-ASA, 5-aminosalacylic acid; 6-MP, 6 merceptopurine; ABC, abatacept; ACV, acyclovir; ADA, adalimumab; ANR, anakinra; Bud, budesonide; CAM, canakinumab; Cipro, ciprofloxacin; Dex, dexamethasone; ETC, etanercept; Etop, etoposide; EMA, emapalumab-Izsg; F, female; Fluc, fluconazole; GOM, golimumab; IBD, inflammatory bowel disease; IEC, intestinal epithelial cell; IEI, inborn errors of immunity; IFX, infliximab; IgRT, Immunoglobulin replacement therapy; ITZ, itraconazole; IVIG, intravenous immunoglobulin; M, male; MTX, methotrexate; Pred, prednisone; PTD, pentamidine; Siro, sirolimus; Rifax, rifaximin; Ritux, rituximab; Ruxo, ruxolitinib; Tac, tacrolimus; TMX-SMP, trimethoprim sulfamethoxazole; TNZ, tinidazole; Vedo, vedoluzimab; VGCV, valganciclovir.

Median time from genetic diagnosis to HSCT in the cohort was 6.5 months (range, 2 months to 16.6 years). Median time from gastrointestinal symptom onset to HSCT was 4.3 years (range, 0.3–18 years). One patient underwent HSCT in 2012 due to severe and refractory disease that included polyautoimmunity and immunodeficiency, prior to the discovery of CTLA4 deficiency as a cause of IEI.¹⁸ Following this discovery, due to phenotypic similarity, targeted genetic testing that occurred post-transplant revealed a causal mutation in CTLA4.

Disease Characteristics

Seventy-two percent of patients had Crohn’s Disease, and 28% were classified as IBD-unspecified. Ninety-two percent of patients had VEO-IBD, 56% presenting under age 1 (Figure 1B).

Intestinal symptoms were the initial and primary presentation in 17 patients (68%), whereas 2 patients (8%) presented concurrently with intestinal disease and other features of autoimmunity. Six patients (24%), including 4 with CGD, presented with evidence of immunodeficiency/immune dysregulation (sentinel infections or cytopenias), with the subsequent onset of intestinal manifestations ranging between age 1 and 9 years. Twenty-four patients had disease activity scores available at onset of intestinal manifestations, of whom 50% had severe disease, 12.5% had moderate disease, and 37.5% had mild disease (Figure 2).

Figure 2.

Disease activity scores at the time of IBD presentation, immediately prior to transplant, 1-year post-transplant, and at most recent follow up if ≥2 years since transplant.

Endoscopic Characteristics and Disease Location

Diagnosis of IBD was made by endoscopy and histology, except for one patient with prenatally diagnosed X-linked CGD with perianal disease and hematochezia. Endoscopy was deferred, and he was treated empirically with antibiotics until HSCT at age 6 months. All evaluated patients had colonic disease; 23 of 24 had both macroscopic and microscopic colonic disease. Eight patients also had macroscopic ileal disease. Twelve patients had macroscopic upper tract involvement. Perianal disease was present in 44% of patients (Figure 3).

Figure 3.

Location of macroscopic gastrointestinal disease (dark gray) and isolated microscopic inflammation (light gray) based on endoscopy and/or imaging in individual patients prior to HSCT. Paris classification behavior was included for those with Crohn’s disease. White, non-affected region; Black, not evaluated prior to transplant.

Pre-Transplant IBD Course

Five patients required IBD-related luminal surgery prior to transplant and had ileostomies at the time of transplant, 2 with permanent ileostomies. Most patients (19/25; 76%) required immunosuppressive therapy for the indication of IBD prior to HSCT, 56% had steroid exposure, and 64% had exposure to at least one biologic, small molecule, or immunomodulator (Table 1). Six patients did not receive IBD-targeted immunosuppressive therapy prior to transplant. Three underwent HSCT before 1 year of age (STXBP2 deficiency, WAS, and CGD). The remaining 3 patients had CGD; therefore, anti-TNFα therapy was avoided, and they were managed with antibiotic therapy.¹⁹ At the time of transplant, 7 patients had moderate or severe disease activity despite immunosuppressive therapies. Seven patients, 6 with CGD in whom HSCT is standard of care to prevent life-threatening infection, achieved remission of intestinal disease on therapy prior to transplant, including 1 patient who was steroid-dependent. One patient with LRBA deficiency achieved remission of IBD on abatacept but had severe active arthritis at time of transplant (Figure 2; Table 1). No patients were in sustained IBD medication-free remission prior to transplant.

Systemic Disease and Comorbidities

At baseline, 10 patients had extraintestinal manifestations of IBD, including arthritis (2/25), fevers (5/25), oral ulcers (6/25), and uveitis (2/25). Four patients had concurrent autoimmune disease including autoimmune cytopenias, type 1 diabetes mellitus, and juvenile idiopathic arthritis. One patient with IL-10R deficiency developed diffuse large B cell lymphoma, a known malignant potential of this defect, was successfully treated, and was in remission at the time of HSCT. One patient with STXBP2 deficiency developed HLH prior to transplant, an established potential complication of this familial HLH gene, with complete recovery prior to HSCT.

Outcomes

The median age at transplant was 6.2 years (range, 4 months to 18.9 years). The median length of follow up was 3 years (range, 1–10 years) post-transplant. There were no mortalities in this cohort.

Sustained IBD medication-free remission.

Overall, 23 of 25 patients (92%) achieved medication-free remission of IBD (and immunodeficiency) at the most recent follow-up (range, 1–10 years post-transplant).

Of the 20 patients without ostomies, 80% had achieved sustained IBD medication-free remission at 1-year post-transplant, as compared with 0% at the time of transplant (P < .001) (Table 1; Figure 2). Two additional patients achieved sustained IBD medication-free remission by last follow-up, including 1 patient with CTLA4 deficiency and 1 with XIAP deficiency with a prior rectal stricture that ultimately resolved, and he maintained medication-free remission.

Patients with prior luminal surgeries.

All 5 patients with ileostomies in place at the time of transplant achieved sustained IBD medication-free remission by PGA through last follow up. Two patients (STXBP3 deficiency and IL-10R deficiency) successfully underwent re-anastomosis. A patient with CGD underwent colectomy (fibrotic stricture that developed pre-transplant) with ileorectal anastomosis post-transplant. Two patients with permanent ostomies created pre-transplant achieved sustained IBD-medication-free remission.

Patients with active IBD post-transplant.

Two patients had mild disease activity scores (PUCAI = 10) at last follow up. One with STXBP2 deficiency remains IBD medication-free at 1 year post-transplant. One patient with STXBP3 deficiency developed complications of immune dysregulation with intestinal manifestations post-transplant requiring vedolizumab and canakinumab and ultimately a diverting ileostomy. He was scheduled to undergo re-anastomosis by the end of the study window.

Secondary Outcomes

Endoscopic evaluation.

Eight patients underwent restaging endoscopic evaluations post-transplant. Six of these patients demonstrated endoscopic mucosal healing, including both patients with mild disease activity (STXBP2 and STXBP3), as well as patients with STXBP3 deficiency, CYBB mutations, and CTLA4 deficiency, who achieved IBD-medication-free remission. The 2 patients who did not demonstrate mucosal healing had ileostomies in place (IL-10R deficiency and AR-CGD) and had diversion colitis. Both these patients subsequently underwent re-anastomosis and remained in medication-free remission.

Infections and hospitalizations.

Twenty-two patients experienced serious infections prior to transplant. The remaining 3 patients underwent transplant prior to age 1 year (Figure 4A). Within the first 365 days post-transplant, 76% of patients developed infections requiring treatment, including viremia (52%) and bacteremia (28%). Following the initial 365-day post-transplant period, 15 of 20 patients with >18 months follow up remained infection-free (P = .0003). Of the 5 patients who experienced infections post-transplant, 4 were bacterial, treated with oral antibiotics. One patient with a post-transplant viral illness required hospitalization for dehydration (Figure 4B).

Figure 4.

Secondary outcomes. Percentage of patients with infection pre-transplant (A) and post-transplant (B). (C) Number of hospitalization days in the years prior to HSCT compared with the number of days spent in the hospital from years 1 to 2 post-transplant. N = 18 patients with ≥2 years of follow up data. *P < .05 (D) Change in height Z-score from time of transplant to most recent follow-up.

Similar to infections, average hospitalization days were significantly reduced post-transplant from 23 days in the year prior to HSCT to 1 day in second year post-transplant (P = .0002) (Figure 4C).

Growth and nutrition.

There was significant improvement in height Z-scores at the most recent follow up as compared to pre-transplant (average 3.7 years post-transplant; P = .03) (Figure 4D).

Prior to transplant, 10 patients required enteral tube feeds as compared with 4 patients at most recent follow up (P = .08). All three patients with combined IEI/IEC defects required total parenteral nutrition (TPN) pre-transplant, however none required TPN at most recent follow-up.

Engraftment.

In 23 of 25 patients, donor chimerism was >97% at last follow-up. The 2 patients with mixed chimerism had 60% and 85% chimerism at >3 years from HSCT and remained asymptomatic.

Two other patients required repeat HSCT for donor chimerism loss. Both patients remain durably engrafted with 99% chimerism >1 year.

HSCT complications within the first 365 days post-transplant.

In addition to infections, some patients experienced complications in the post-transplant period. Three patients developed acute cutaneous GVHD, with a maximum of grade I in a patient with a mutation in CYBB and grade III in 2 patients (XIAP deficiency and STXBP3 deficiency). The patient with STXBP3 deficiency also developed chronic cutaneous GVHD that resolved with methylprednisolone, ruxolitinib, and tacrolimus. One patient with a mutation in CYBB developed cutaneous, intestinal, and liver GVHD, successfully treated with tacrolimus and systemic steroids without sequalae. Four patients developed VOD, all with complete recovery. One patient with STXBP2 deficiency developed a GI bleed from a g-tube site ulceration 2 weeks following repeat transplant, treated endoscopically.

Discussion

A subset of patients with IBD, particularly VEO-IBD, have severe and refractory disease. The recent discoveries of monogenic defects dramatically changed the management and outcomes of disease with new insights into the pathophysiology and potential therapeutic options.

Allogeneic HSCT, as shown here and in the literature, has led to sustained IBD-medication free remission in a proportion of patients with monogenic IBD, in addition to curing the underlying immunodeficiency.^9,10 The evolving conditioning regimens with decreased toxicity, together with approaches used to prevent GVHD, have dramatically improved HSCT outcomes in IEI. Survivorship typically is cited around 85%, varied by genetic defect.²⁰ Despite this, positioning of HSCT within the therapeutic spectrum has remained an area of debate for patients with monogenic IBD with defects in IEI and in IEI/IEC. Here we show excellent outcomes, with 92% of patients in sustained medication-free remission of IBD following allogeneic HSCT. Importantly, there was no mortality in this cohort.

The reticence to proceed with HSCT for patients with monogenic IBD largely centers on the concern that IBD itself may increase the risk of GVHD and survival, although our data and other recent studies show otherwise.²¹ Delay of HSCT with the goal of obtaining remission of IBD prior to transplant may prove to be determinantal, as outcomes of HSCT are in general improved for younger patients,²⁰ and medical remission is often unattainable for more severe forms of monogenic IBD. Within our cohort, 32% of patients had moderate or severe disease at the time of transplant despite medical optimization. None of these patients developed intestinal GVHD, which was a rare event in our total cohort. Therefore, although efforts should be made to stabilize the intestinal disease prior to HSCT, our data does not support deferring HSCT in patients with active disease to minimize the likelihood of GVHD.

Within our cohort, patients with previous debilitating, refractory IBD and immunodeficiency requiring frequent hospitalizations achieved cure of immunodeficiency and IBD medication-free remission post-transplant, with significantly reduced hospitalization days and restoration of growth. Thus, early pursuit of transplant, particularly at a transplant center with expertise in primary immunodeficiencies, is preferable to prevent the development of life-threatening infections, debilitating refractory IBD, or other sequalae of these defects such as HLH and malignancies.

The selection of patients who would benefit from HSCT requires multidisciplinary discussion. Patients with defects that impact the hemopoietic compartment are frequently considered amenable to transplant. Although there was robust long-term response to HSCT, there were differences in intestinal symptoms post-transplant between patients with IEI and combined IEI/IEC defects in our cohort. All patients with IEI achieved sustained medication-free remission of IBD post-transplant. However, despite significant improvement in IBD disease activity, the 3 patients with combined IEI/IEC defects, all with mutations in syntaxin-binding protein genes, experienced a more protracted post-transplant course. One patient with STXBP3 had an uncomplicated course and ultimately achieved sustained medication-free remission of IBD; however, the second patient with STXBP3 deficiency experienced transient immune dysregulation immediately post-transplant, requiring immunosuppressive therapy and a diverting ileostomy. He ultimately achieved mucosal healing and therapy has been deescalated. The patient with STXBP2 deficiency remains therapy-free and demonstrated mucosal healing on subsequent colonoscopy, with histologic resolution of disease. His disease activity score remains mild for 3 to 4 loose stools daily, without associated IBD symptoms. This suggests that HSCT may lead to remission for patients with combined IEI/IEC defects, and these patients may have more prolonged post-transplant course than patients with IEI. Risks and benefits of transplant must be carefully weighed with the risks of forgoing transplant—such as the potential complications of the underlying defect, including HLH. Studies investigating the mechanisms of intestinal epithelial cell dysfunction in these defects may help predict outcomes and identify adjuvant therapeutics.

HSCT is not without risk, and complications occurred in our cohort, at rates typical of other IEI cohorts.^20,22,23 There were not specific genes or patient characteristics that appeared to pre-dispose to the development of GVHD, gastrointestinal (GI) bleeding or VOD. Infections were common in the first-year post-transplant, consistent with previously published infections rates for IEI.^22,23

To our knowledge, this study represents one of the largest reported cohorts assessing outcomes of HSCT for monogenic IBD and demonstrating the success of this approach in a cohort of patients with severe IBD. We recognize the limitations of this work, including the retrospective study design and the relatively small sample size for each individual genetic defect. Additionally, disease activity was assessed using clinical disease activity scoring as endoscopic evaluation post-transplant was not available for most patients in this study. This reflects the change in practice standards for assessment of mucosal healing over the study period and variable clinical indication for endoscopic evaluation post-transplant. Given the high rate of sustained medication-free remission, traditional biomarkers of disease activity, such as calprotectin, were infrequently obtained for these patients following transplant.

Conclusion

In conclusion, herein we show that for patients with monogenic IBD with defects amenable to transplant, HSCT can be curative for immunodeficiency, prevent life-threatening complications, and induce sustained medication-free remission of IBD.

Supplementary Material

Note: To access the supplementary material accompanying this article, visit the online version of Clinical Gastroenterology and Hepatology at www.cghjournal.org, and at https://doi.org/10.1016/j.cgh.2025.03.018.

What You Need to Know.

Background

Monogenic inflammatory bowel disease (IBD) may be refractory to treatment with conventional therapies. Novel therapeutic approaches are necessary for this group of diseases.

Findings

Allogeneic hematopoietic stem cell transplant (HSCT) resulted in sustained, IBD medication-free remission of intestinal disease in patients with monogenic IBD.

Implications for patient care

These findings support that allogeneic HSCT can successfully and safely lead to medication-free remission in patients with IBD with monogenic defects involving immune response.

Abbreviations used in this paper:

AR

autosomal recessive

CGD

chronic granulomatous disease

CHOP

Children’s Hospital of Philadelphia

GI

gastrointestinal

GVHD

graft vs host disease

HLH

hemophagocytic lymphohistiocytosis

HSCT

hematopoietic stem cell transplantation

IBD

inflammatory bowel disease

IEC

intestinal epithelial cell

IEI

inborn errors of immunity

IL-10R

interleukin 10 receptor

PCDAI

Pediatric Crohn’s Disease Activity Index

PGA

physician global assessment

PUCAI

Pediatric Ulcerative Colitis Activity Index

SCID

severe combined immunodeficiency

TPN

total parenteral nutrition

VEO IBD

very early onset IBD

VOD

veno-occlusive disease

WAS

Wiskott-Aldrich syndrome

Data Availability

Deidentified individual participant data that underlie the reported results will be made available 3 months after publication for a period of 5 years after the publication date. Proposals for access should be sent to the corresponding author.