Following transplantation of blood stem cells from a donor (called allogeneic hematopoietic stem cell transplantation), many patients experience graft-versus-host-disease (GVHD). GVHD happens when the donor T cells recognize and attack the recipient cells. If cells of the gastrointestinal tract are targeted it can lead to severe mucosal injury or denudation causing significant, often fatal, complications. Intestinal GVHD is characterized by apoptosis of intestinal epithelial cells, and mucosal inflammation. Treatment of immunosuppressed patients with severely disrupted mucosal barrier exposed to the luminal microbiota is extremely challenging.
A pilot study published in the journal Plos One led by Dr. Gideon Steinbach in collaboration with other members from the Clinical Research Division at Fred Hutch, reports promising results of a new approach to treat intestinal GVHD using lithium. Dr. Steinbach said, “GVHD could be viewed as a barrier dysfunction disorder requiring a new approach to treatment focused on restoration of mucosal barrier function in addition to immunosuppression.” To do so, Dr. Steinbach and his colleagues treated patients with lithium, more commonly used to treat bipolar disorder. Lithium is an inhibitor of Glycogen Synthase Kinase (GSK3) that activates the Wnt signaling pathway and restores intestinal crypt proliferation. Indeed, many studies using Wnt overexpression or inhibition have demonstrated the importance of Wnt pathway in epithelial stem cell replication and mucosal repair, both in vitro and in vivo. Dr. Steinbach further explained “there is concern that unchecked Wnt activation might drive tumor growth. In this regard, it is reassuring that chronic lithium treatment (as prescribed for more than 60 years) has not yet been associated with increased neoplasia or pathologic hyperplasia in key organs (except that lithium can exacerbate or uncommonly induce psoriasis and acne)”. Through inhibition of GSK3, lithium also has some anti-inflammatory effects that could benefit the treatment.
Among the 20 treated patients who developed severe intestinal GVHD, 17 had extreme injury with denuded mucosa while 3 still had intact mucosa. These patients were evaluated for lithium efficiency in addition to standard immunosuppressive GVHD treatment. Extended-release lithium carbonate tablets were administered several times daily with dose adjusted to maintain predetermined serum concentrations.
Ten (50%) of the treated individuals achieved a complete response of GVHD, among whom 8 survived for more than one year. The other 10 died from severe GVHD within 3 months. Interestingly, among the 12 individuals that initiated lithium therapy promptly within 3 days following endoscopy diagnosis, 8 (67%) were the ones who achieved a complete GVHD response and survived over one year. Of the patients treated later after endoscopy, only 2 achieved a complete GVHD response but none survived a year. Seven patients were treated for more severe GVHD with a salvage therapy one week or earlier prior to starting lithium treatment, but none survived one year. These patients might have already failed therapy and might have been treated too late in the course of the mucosal injury to recover. Overall, these observations suggest the importance of starting lithium treatment early, ideally within 3 days following diagnosis by endoscopy and before failure of salvage therapy. Duration of lithium administration appeared to be of importance too, as 7 out of the 8 patients who survived for more than one year took lithium for 30 days or more.
Mucosal recovery was also observed in treated patients. Partial response could be observed as early as two weeks after lithium administration, and complete response was observed at 6 weeks. Among the 6 patients with partial response, 5 survived for more than 9 months and all the patients with complete response survived for more than one year. Overall, these data are very encouraging and support the initial postulate that lithium administration improves mucosal repair and leads to improved survival outcomes in these patients. Even though toxicities are difficult to assess in such sick patients, lithium appeared well tolerated. The main ill effects reported were fatigue, dulled sensorium and flattened affect (decrease in emotional expression).
The results observed in this study indicate better survival rates than previous data of transplanted patients with severe mucosal injury who did not receive Lithium. Could this treatment benefit other patients? Dr. Steinbach explained, “The lithium study observations and a growing body of scientific literature provide the rationale for the study of lithium treatment in inflammatory bowel disease. Since initiation of our lithium study in 2006, hundreds of studies have explored the role of GSK3 and lithium in inflammatory conditions, as well as in tissue homeostasis, regeneration, and neoplasia. Results are not yet conclusive but suggest that GSK3 may be a clinically useful therapeutic target. In the future, we hope that the study would promote awareness of the barrier dysfunction component of intestinal GVHD and promote the development of targeted treatments. We look forward to conducting further studies of lithium treatment in severe intestinal GVHD, and early phase studies of lithium in treatment of ulcerative colitis.”
Funding for this study was provided by the National Institutes of Health.
Steinbach G,Hockenbery DM,Huls G,Furlong T,Myerson D,Loeb KR,Fann JR,Castilla-Llorente C,McDonald GB,Martin PJ. 2017. Pilot study of lithium to restore intestinal barrier function in severe graft-versus-host disease. PLoS One. 12(8), e0183284.