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

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

^*Corresponding author for this work

Medicine, Hematology Oncology Division

Research output: Contribution to journal › Article › peer-review

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,

Original language	English (US)
Article number	e24026
Journal	Heliyon
Volume	10
Issue number	1
DOIs	https://doi.org/10.1016/j.heliyon.2024.e24026
State	Published - Jan 15 2024

Funding

Funding for Seattle-based research for the Crohn's Allogeneic Transplant Study was provided by a generous grant from the Eli and Edythe Broad Foundation , a donation from an anonymous source, and support from the Seattle Cancer Care Alliance. Genotyping data at Cedars-Sinai Medical Center , Los Angeles CA. was supported by the Helmsley Charitable Trust and the National Institutes of Health NIDDK IBD Genetics Consortium (U01 DK062413). Follow-up evaluation of Patient 2 was carried out in Oslo, Norway, and supported by research funds from South-Eastern Norway Regional Health Authority .

Keywords

Crohn's disease
Mucosal immune chimerism
Outcomes
Polygenic risk score
Reduced-intensity conditioning

ASJC Scopus subject areas

General

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10.1016/j.heliyon.2024.e24026

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McDonald, G. B., Landsverk, O. J. B., McGovern, D. P. B., Aasebø, A., Paulsen, V., Haritunians, T., Reims, H. M., McLaughlin, B. M., Zisman, T., Li, D., Elholm, E. T. M. M., Jahnsen, F. L., Georges, G. E., & Gedde-Dahl, T. (2024). Allogeneic bone marrow transplantation for patients with treatment-refractory Crohn's Disease. Heliyon, 10(1), Article e24026. https://doi.org/10.1016/j.heliyon.2024.e24026

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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,",

keywords = "Crohn's disease, Mucosal immune chimerism, Outcomes, Polygenic risk score, Reduced-intensity conditioning",

author = "McDonald, {George B.} and Landsverk, {Ole J.B.} and McGovern, {Dermot P.B.} and Anders Aaseb{\o} and Vemund Paulsen and Talin Haritunians and Reims, {Henrik M.} and McLaughlin, {Bernadette M.} and Timothy Zisman and Dalin Li and Elholm, {Elisabeth T.M.M.} and Jahnsen, {Frode L.} and Georges, {George E.} and Tobias Gedde-Dahl",

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doi = "10.1016/j.heliyon.2024.e24026",

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T1 - Allogeneic bone marrow transplantation for patients with treatment-refractory Crohn's Disease

AU - McDonald, George B.

AU - Landsverk, Ole J.B.

AU - McGovern, Dermot P.B.

AU - Aasebø, Anders

AU - Paulsen, Vemund

AU - Haritunians, Talin

AU - Reims, Henrik M.

AU - McLaughlin, Bernadette M.

AU - Zisman, Timothy

AU - Li, Dalin

AU - Elholm, Elisabeth T.M.M.

AU - Jahnsen, Frode L.

AU - Georges, George E.

AU - Gedde-Dahl, Tobias

PY - 2024/1/15

Y1 - 2024/1/15

N2 - 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,

AB - 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,

KW - Crohn's disease

KW - Mucosal immune chimerism

KW - Outcomes

KW - Polygenic risk score

KW - Reduced-intensity conditioning

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

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