Allogeneic bone marrow transplantation for patients with treatment-refractory Crohn's Disease

George B McDonald; Ole J B Landsverk; Dermot P B McGovern; Anders Aasebø; Vemund Paulsen; Talin Haritunians; Henrik M Reims; Bernadette M McLaughlin; Timothy Zisman; Dalin Li; Elisabeth T M M Elholm; Frode L Jahnsen; George E Georges; Tobias Gedde-Dahl

doi:10.1016/j.heliyon.2024.e24026

Allogeneic bone marrow transplantation for patients with treatment-refractory Crohn's Disease

Heliyon. 2024 Jan 3;10(1):e24026. doi: 10.1016/j.heliyon.2024.e24026. eCollection 2024 Jan 15.

Authors

George B McDonald^{1

2}, Ole J B Landsverk³, Dermot P B McGovern⁴, Anders Aasebø³, Vemund Paulsen⁵, Talin Haritunians⁴, Henrik M Reims³, Bernadette M McLaughlin¹, Timothy Zisman², Dalin Li⁴, Elisabeth T M M Elholm^{1

6}, Frode L Jahnsen⁷, George E Georges^{1

2}, Tobias Gedde-Dahl⁶

Affiliations

¹ Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
² Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA.
³ Department of Pathology, Oslo University Hospital, Oslo, Norway.
⁴ F. Widjaja Foundation Inflammatory Bowel & Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁵ Department of Transplantation Medicine, Section of Gastroenterology, Oslo University Hospital Rikshospitalet, Norway.
⁶ Department of Hematology, Oslo University Hospital, Norway and Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁷ Department of Pathology, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Norway.

Abstract

Background & aims: Durable remissions of Crohn's Disease (CD) have followed myeloablative conditioning therapy and allogeneic marrow transplantation. For patients with treatment-refractory disease, we used reduced-intensity conditioning to minimize toxicity, marrow from donors with low Polygenic Risk Scores for CD as cell sources, and protracted immune suppression to lower the risk of graft-versus-host disease (GVHD). Our aim was to achieve durable CD remissions while minimizing transplant-related complications.

Methods: DNA from patients and their HLA-matched unrelated donors was genotyped and Polygenic Risk Scores calculated. Donor marrow was infused following non-myeloablative conditioning. Patient symptoms and endoscopic findings were documented at intervals after transplant.

Results: We screened 807 patients, 143 of whom met eligibility criteria; 2 patients received allografts. Patient 1 had multiple complications and died at day 332 from respiratory failure. Patient 2 had resolution of CD symptoms until day 178 when CD recurred, associated with persistent host chimerism in both peripheral blood and intestinal mucosa. Withdrawal of immune suppression was followed by dominant donor immune chimerism in peripheral blood and resolution of CD findings. Over time, mucosal T-cells became donor-dominant. At 5 years after allografting, Patient 2 remained off all medications but had mild symptoms related to a jejunal stricture that required stricturoplasty at 6 years. At 8 years, she remains stable off medications.

Conclusions: The kinetics of immunologic chimerism after allogeneic marrow transplantation for CD patients depends on the intensity of the conditioning regimen and the magnitude of immune suppression. One patient achieved durable improvement of her previously refractory CD only after establishing donor immunologic chimerism in intestinal mucosa. Her course provides proof-of-principal for allografting as a potential treatment for refractory CD, but an immunoablative conditioning regimen should be considered for future studies.(ClinicalTrials.gov, NCT01570348).

Keywords: Crohn's disease; Mucosal immune chimerism; Outcomes; Polygenic risk score; Reduced-intensity conditioning.

Associated data

ClinicalTrials.gov/NCT01570348

Grants and funding

U01 DK062413/DK/NIDDK NIH HHS/United States