Pilot study of lithium to restore intestinal barrier function in severe graft-versus-host disease.
Severe intestinal graft-vs-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT) causes mucosal ulceration and induces innate and adaptive immune responses that amplify and perpetuate GVHD and the associated barrier dysfunction. Pharmacological agents to target mucosal barrie...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2017-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC5560707?pdf=render |
| _version_ | 1819108330278223872 |
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| author | Gideon Steinbach David M Hockenbery Gerwin Huls Terry Furlong David Myerson Keith R Loeb Jesse R Fann Christina Castilla-Llorente George B McDonald Paul J Martin |
| author_facet | Gideon Steinbach David M Hockenbery Gerwin Huls Terry Furlong David Myerson Keith R Loeb Jesse R Fann Christina Castilla-Llorente George B McDonald Paul J Martin |
| author_sort | Gideon Steinbach |
| collection | DOAJ |
| description | Severe intestinal graft-vs-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT) causes mucosal ulceration and induces innate and adaptive immune responses that amplify and perpetuate GVHD and the associated barrier dysfunction. Pharmacological agents to target mucosal barrier dysfunction in GVHD are needed. We hypothesized that induction of Wnt signaling by lithium, an inhibitor of glycogen synthase kinase (GSK3), would potentiate intestinal crypt proliferation and mucosal repair and that inhibition of GSK3 in inflammatory cells would attenuate the deregulated inflammatory response to mucosal injury. We conducted an observational pilot study to provide data for the potential design of a randomized study of lithium. Twenty patients with steroid refractory intestinal GVHD meeting enrollment criteria were given oral lithium carbonate. GVHD was otherwise treated per current practice, including 2 mg/kg per day of prednisone equivalent. Seventeen patients had extensive mucosal denudation (extreme endoscopic grade 3) in the duodenum or colon. We observed that 8 of 12 patients (67%) had a complete remission (CR) of GVHD and survived more than 1 year (median 5 years) when lithium administration was started promptly within 3 days of endoscopic diagnosis of denuded mucosa. When lithium was started promptly and less than 7 days from salvage therapy for refractory GVHD, 8 of 10 patients (80%) had a CR and survived more than 1 year. In perspective, a review of 1447 consecutive adult HCT patients in the preceding 6 years at our cancer center showed 0% one-year survival in 27 patients with stage 3-4 intestinal GVHD and grade 3 endoscopic appearance in the duodenum or colon. Toxicities included fatigue, somnolence, confusion or blunted affect in 50% of the patients. The favorable outcomes in patients who received prompt lithium therapy appear to support the future conduct of a randomized study of lithium for management of severe GVHD with extensive mucosal injury.ClinicalTrials.gov NCT00408681. |
| first_indexed | 2024-12-22T03:08:13Z |
| format | Article |
| id | doaj.art-0591c512ca62400c97ffdd36bc9ba669 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-22T03:08:13Z |
| publishDate | 2017-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-0591c512ca62400c97ffdd36bc9ba6692022-12-21T18:40:59ZengPublic Library of Science (PLoS)PLoS ONE1932-62032017-01-01128e018328410.1371/journal.pone.0183284Pilot study of lithium to restore intestinal barrier function in severe graft-versus-host disease.Gideon SteinbachDavid M HockenberyGerwin HulsTerry FurlongDavid MyersonKeith R LoebJesse R FannChristina Castilla-LlorenteGeorge B McDonaldPaul J MartinSevere intestinal graft-vs-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT) causes mucosal ulceration and induces innate and adaptive immune responses that amplify and perpetuate GVHD and the associated barrier dysfunction. Pharmacological agents to target mucosal barrier dysfunction in GVHD are needed. We hypothesized that induction of Wnt signaling by lithium, an inhibitor of glycogen synthase kinase (GSK3), would potentiate intestinal crypt proliferation and mucosal repair and that inhibition of GSK3 in inflammatory cells would attenuate the deregulated inflammatory response to mucosal injury. We conducted an observational pilot study to provide data for the potential design of a randomized study of lithium. Twenty patients with steroid refractory intestinal GVHD meeting enrollment criteria were given oral lithium carbonate. GVHD was otherwise treated per current practice, including 2 mg/kg per day of prednisone equivalent. Seventeen patients had extensive mucosal denudation (extreme endoscopic grade 3) in the duodenum or colon. We observed that 8 of 12 patients (67%) had a complete remission (CR) of GVHD and survived more than 1 year (median 5 years) when lithium administration was started promptly within 3 days of endoscopic diagnosis of denuded mucosa. When lithium was started promptly and less than 7 days from salvage therapy for refractory GVHD, 8 of 10 patients (80%) had a CR and survived more than 1 year. In perspective, a review of 1447 consecutive adult HCT patients in the preceding 6 years at our cancer center showed 0% one-year survival in 27 patients with stage 3-4 intestinal GVHD and grade 3 endoscopic appearance in the duodenum or colon. Toxicities included fatigue, somnolence, confusion or blunted affect in 50% of the patients. The favorable outcomes in patients who received prompt lithium therapy appear to support the future conduct of a randomized study of lithium for management of severe GVHD with extensive mucosal injury.ClinicalTrials.gov NCT00408681.http://europepmc.org/articles/PMC5560707?pdf=render |
| spellingShingle | Gideon Steinbach David M Hockenbery Gerwin Huls Terry Furlong David Myerson Keith R Loeb Jesse R Fann Christina Castilla-Llorente George B McDonald Paul J Martin Pilot study of lithium to restore intestinal barrier function in severe graft-versus-host disease. PLoS ONE |
| title | Pilot study of lithium to restore intestinal barrier function in severe graft-versus-host disease. |
| title_full | Pilot study of lithium to restore intestinal barrier function in severe graft-versus-host disease. |
| title_fullStr | Pilot study of lithium to restore intestinal barrier function in severe graft-versus-host disease. |
| title_full_unstemmed | Pilot study of lithium to restore intestinal barrier function in severe graft-versus-host disease. |
| title_short | Pilot study of lithium to restore intestinal barrier function in severe graft-versus-host disease. |
| title_sort | pilot study of lithium to restore intestinal barrier function in severe graft versus host disease |
| url | http://europepmc.org/articles/PMC5560707?pdf=render |
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