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

David Myerson,Gideon Steinbach,David M Hockenbery,Christina Castilla-Llorente,George B Mcdonald,Gerwin Huls,Jesse R Fann,Terry Furlong,Paul J Martin,Keith R Loeb

doi:10.1371/journal.pone.0183284

Abstract

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

Highlights

Acute graft-versus-host disease (GVHD), driven by alloreactive donor T cells, remains a significant complication of allogeneic hematopoietic cell transplantation (HCT)
Patients and methods Study design. This was an open-label, single arm, observational pilot study conducted among allogeneic HCT recipients ! 18 years of age and aimed to provide preliminary observations to potentially guide the design of a structured, randomized clinical trial of lithium
We conducted an observational study of lithium in patients with severe steroid refractory intestinal GVHD with a focus on those with extensively denuded mucosa

Summary

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]. At the extreme severity GVHD results in progressive crypt loss and mucosal denudation of large segments of the intestine [4,5,6]. 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 response, resulting in a self-perpetuating cycle of chronic inflammation and barrier disruption [9,10,11,12]. The mucosal inflammation amplifies and perpetuates systemic GVHD and sustains the targeting of intestinal epithelium by effector immune cells and cytokines [22,9]. Therapeutic agents to induce mucosal regeneration and target the mucosal inflammatory cycle are lacking

Methods

Results

Conclusion