Cannabidiol – an Innovative Strategy for Graft Versus Host Disease Prevention – an Update of a Phase I/II Study

Introduction: 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 have recently presented data suggesting that the combination of CBD with standard GVHD prophylaxis is a safe and promising strategy to reduce the incidence of GVHD.   We herein update the data in a larger cohort, analyzing both short and long term transplantation outcomes.

 

Methods: We conducted a phase I/II trial. All patients were given standard GVHD prophylaxis consisting of cyclosporine and short course methotrexate. CBD was orally administered at a dose of 150 mg twice daily from starting of conditioning up to day +30. We sequentially monitored a panel of 4 serum cytokines (soluble TNF receptor 1 (sTNFRI), soluble IL-2 receptor alpha (sIL2R-alpha), hepatocyte growth factor (HGF), and IL8)). Blood samples were taken at days -7(A), 0(B), +14(C), and +28(D). We assessed the difference in blood levels between the various time points (B-A, C-B and D-C).

Results: Between 9/2012 and 10/2013, 34 consecutive patients with hematological malignancies undergoing allogeneic transplantation were enrolled (median age=52, range, 22-71 years). Most patients had acute leukemia/MDS (n=28). Most (73%) were in CR/PR at transplantation. Majority (n=26) of patients were given a myeloablative conditioning.  The donor was either a HLA identical sibling (n=17), a 10/10 matched unrelated donor (n=14) or 1 antigen mismatched unrelated donor (n=3). All patients were given G-CSF mobilized peripheral blood stem cell grafts. Median follow-up was 8 months (range, 3-13). There were no grade 3-4 toxicities attributed to CBD.  There were no cases of graft rejection. Cumulative incidences of grade 2-4 and 3-4 acute GVHD by day +100 were 15% and 7%, respectively. Cumulative incidences of overall and extensive chronic GVHD at 12 months were 41% and 12%, respectively. Cumulative incidences of relapse, NRM and OS at 12 months were 27%, 16.5% and 71%, respectively. Patients with increased D-C serum levels of IL8 and sIL2R-alpha had a relative risk of 3.8 (95% CI .8-17.1, p=.1) and 2.8 (95% CI 1.1-7.5, p=.05), respectively, for developing chronic GVHD.

Conclusion:  combination of CBD with standard GVHD prophylaxis is a safe and promising strategy to reduce the incidence of GVHD. Further studies comparing this novel approach with standard GVHD prophylaxis are warranted.