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Cannabidiol - An Innovative Strategy For Graft Versus Host Disease Prevention

Moshe Yeshurun, Ofer Shpilberg, Corina Herscovici, Juliet Dreyer, Anat Peck, Maly Levy Assaraf, Tsipora Gruenewald, Raphael Mechoulam and Ron Ram

Abstract

Introduction Acute graft-versus-host disease (aGVHD) is a major life-threatening complication following allogeneic stem cell transplantation (alloSCT), affecting 35%-70% of recipients despite standard prophylaxis regimens. Thus, developing innovative strategies to prevent and treat GVHD is a major unmet need. Cannabidiol (CBD), a safe and non-psychotropic ingredient of marijuana, has been shown to exhibit potent immune-modulatory and anti-inflammatory properties in animal models of various inflammatory diseases. We hypothesized that administration of CBD during alloSCT may significantly decrease GVHD incidence.

Methods We conducted a phase I/II trial. All patients were given standard GVHD prophylaxis consisting of cyclosporine and a short course of methotrexate (15 mg/m2 on day +1 and 10 mg/m2 on days +3 and +6). The investigational agent, CBD (STI Pharmaceuticals, Essex, UK), was orally administered at a dosage of 150 mg twice daily from starting of conditioning up to day +30. Primary end points were safety and cumulative incidence of grade 2-4 and grade 3-4 aGVHD by day +100. The secondary end points were cumulative incidence of chronic and chronic extensive GVHD, non-relapse mortality (NRM), relapse incidence, and overall survival (OS).

Results Between 9/2012 and 6/2013, 30 consecutive unselected adult patients undergoing alloSCT were enrolled (median age=52, range, 22-71 years). Median follow-up was 4.8 months (range, 1-10.3). Base line diseases were acute leukemia (n=21, 70%), myelodysplastic syndrome (n=2, 7%), lymphoma (n=5, 17%), aplastic anemia (n=1, 3%), and multiple myeloma (n=1, 3%). 73% were in CR/PR at transplantation. The majority of patients were given a myeloablative preparative regimen (n=22, 73%). The donor was either an HLA identical sibling (n=16) or 10/10 matched unrelated donor (n=12) or 1 antigen mismatched unrelated donor (n=2). All patients were given G-CSF mobilized peripheral blood stem cell grafts. There were no documented grade 3-4 toxicities attributed to CBD. There were no cases of graft rejection. In all, 2 patients developed aGVHD by day 100 (grade 2, n=1 and grade 3, n=1) and one patient developed late onset aGVHD (grade 4, n=1). The cumulative incidences of grade 2-4 aGVHD and grade 3-4 aGVHD by day +100 were 8.4% and 4.5%, respectively. Five patients developed chronic GVHD, 4 had limited disease and one extensive disease. There were 4 deaths because of sepsis (n=1), cardiac arrhythmia (n=1), grade 4 aGVHD (n=1) and relapse (n=1). Cumulative incidences of NRM at 3 and 6 months were both 6.9% and incidences of relapse were both 10.7%. OS at 3 and 6 months were both 90%.

Conclusion These data suggest that the combination of CBD with standard GVHD prophylaxis is a safe and promising strategy to reduce the incidence of GVHD. Nevertheless, a well designed prospective controlled study comparing this novel approach with standard GVHD prophylaxis is warranted. Follow-up data on safety, efficacy, and on additional subjects will be presented.

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Disclosures: No relevant conflicts of interest to declare.

  • * Asterisk with author names denotes non-ASH members.