Pilot study of lithium to restore intestinal barrier function in severe graft-versus-host disease

PLOS ONE, Dec 2019

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. Trial Registration: ClinicalTrials.gov NCT00408681

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Pilot study of lithium to restore intestinal barrier function in severe graft-versus-host disease

August Pilot study of lithium to restore intestinal barrier function in severe graft-versus-host disease Gideon Steinbach 0 1 2 David M. Hockenbery 0 1 2 Gerwin Huls 0 2 Terry Furlong 0 1 2 David Myerson 0 1 2 4 Keith R. Loeb 0 1 2 4 Jesse R. Fann 0 2 3 Christina Castilla-Llorente 0 1 2 George B. McDonald 0 1 2 Paul J. Martin 0 1 2 0 Current address: Service dÂHe matologie, Institut Gustave Roussy , Villejuif , France 1 Division of Clinical Research, Fred Hutchinson Cancer Research Center , Seattle , Washington, United States of America, 2 Department of Medicine, University of Washington, Seattle, Washington, United States of America, 3 Department of Haematology, Radboud University Medical Center , Nijmegen , The Netherlands 2 Editor: Derya Unutmaz, Jackson Laboratory , UNITED STATES 3 Department of Psychiatry, University of Washington , Seattle, Washington , United States of America 4 Department of Pathology, University of Washington , Seattle, Washington , United States of America 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. Trial Registration: ClinicalTrials.gov NCT00408681 - Data Availability Statement: The authors attempted to provide all relevant data within the manuscript, tables, figures and Supporting Information, and will provide available additional data for publication or online appendix at the request of the editors. All the necessary underlying data that are not ethically restricted have been provided. Confidential, patient related source data for IRB protocol 2080 would be available from the Fred Hutchinson Cancer Research Center IRB for researchers who meet the criteria for access to confidential data. Address requests for protocol 2080.00 confidential data to: Fred Hutchinson Cancer Research Center; Institutional Review Office; PO Box 19024, J2-100; Seattle, WA 981091024; https://extranet.fredhutch.org/en/u/iro/ contact-information.html. Funding: This study was supported by grant CA18029 from the National Institutes of Health, Department of Health and Human Services (partial funding). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Introduction Acute graft-versus-host disease (GVHD), driven by alloreactive donor T cells, remains a significant complication of allogeneic hematopoietic cell transplantation (HCT). Among acute GVHD targets, intestinal involvement is the main source of morbidity and mortality [ 1 ]. The histological hallmark of intestinal GVHD is apoptosis of epithelial cells at the crypt base and secondary dropout of cells and crypts [ 2,3 ]. At the extreme severity GVHD results in progressive crypt loss and mucosal denudation of large segments of the intestine [4±6]. In our experience, mucosal recovery and survival at this stage are distinctly rare outcomes [ 1,5,7,8 ]. Steroid refractory intestinal GVHD is increasingly viewed as resembling a barrier dysfunction disorder characterized by an anatomic or physiologic barrier defect and a dysregulated immune respon (...truncated)


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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, 2017, Volume 12, Issue 8, DOI: 10.1371/journal.pone.0183284