title: Cannabidiol for the Prevention of Graft-versus-Host-Disease after Allogeneic Hematopoietic Cell Transplantation: Results of a Phase II Study.
abstract: Graft-versus-host-disease (GVHD) is a major obstacle to successful allogeneic hematopoietic cell transplantation (alloHCT). Cannabidiol (CBD), a nonpsychotropic ingredient of Cannabis sativa, possesses potent anti-inflammatory and immunosuppressive properties. We hypothesized that CBD may decrease GVHD incidence and severity after alloHCT. We conducted a phase II study. GVHD prophylaxis consisted of cyclosporine and a short course of methotrexate. Patients transplanted from an unrelated donor were given low-dose anti-T cell globulin. CBD 300 mg/day was given orally starting 7 days before transplantation until day 30. Forty-eight consecutive adult patients undergoing alloHCT were enrolled. Thirty-eight patients (79%) had acute leukemia or myelodysplastic syndrome and 35 patients (73%) were given myeloablative conditioning. The donor was either an HLA-identical sibling (n = 28), a 10/10 matched unrelated donor (n = 16), or a 1-antigen-mismatched unrelated donor (n = 4). The median follow-up was 16 months (range, 7 to 23). No grades 3 to 4 toxicities were attributed to CBD. None of the patients developed acute GVHD while consuming CBD. In an intention-to-treat analysis, we found that the cumulative incidence rates of grades II to IV and grades III to IV acute GVHD by day 100 were 12.1% and 5%, respectively. Compared with 101 historical control subjects given standard GVHD prophylaxis, the hazard ratio of developing grades II to IV acute GVHD among subjects treated with CBD plus standard GVHD prophylaxis was .3 (P = .0002). Rates of nonrelapse mortality at 100 days and at 1 year after transplantation were 8.6% and 13.4%, respectively. Among patients surviving more than 100 days, the cumulative incidences of moderate-to-severe chronic GVHD at 12 and 18 months were 20% and 33%, respectively. The combination of CBD with standard GVHD prophylaxis is a safe and promising strategy to reduce the incidence of acute GVHD. A randomized double-blind controlled study is warranted. (clinicaltrials.gov: NCT01385124).
authors.affiliation: Bone Marrow Transplantation Unit, Institute of Hematology, Davidoff Center, Beilinson Hospital, Rabin Medical Center, Petah-Tikva, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. Electronic address: moshe.yeshurun@gmail.com.
authors.forename: Moshe
authors.initials: M
authors.lastname: Yeshurun
authors.affiliation: Bone Marrow Transplantation Unit, Institute of Hematology, Davidoff Center, Beilinson Hospital, Rabin Medical Center, Petah-Tikva, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Ofer
authors.initials: O
authors.lastname: Shpilberg
authors.affiliation: Bone Marrow Transplantation Unit, Institute of Hematology, Davidoff Center, Beilinson Hospital, Rabin Medical Center, Petah-Tikva, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Corina
authors.initials: C
authors.lastname: Herscovici
authors.affiliation: Bone Marrow Transplantation Unit, Institute of Hematology, Davidoff Center, Beilinson Hospital, Rabin Medical Center, Petah-Tikva, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Liat
authors.initials: L
authors.lastname: Shargian
authors.affiliation: Bone Marrow Transplantation Unit, Institute of Hematology, Davidoff Center, Beilinson Hospital, Rabin Medical Center, Petah-Tikva, Israel.
authors.forename: Juliet
authors.initials: J
authors.lastname: Dreyer
authors.affiliation: Bone Marrow Transplantation Unit, Institute of Hematology, Davidoff Center, Beilinson Hospital, Rabin Medical Center, Petah-Tikva, Israel.
authors.forename: Anat
authors.initials: A
authors.lastname: Peck
authors.affiliation: Tissue Typing Laboratory, Rabin Medical Center, Petah-Tikva, Israel.
authors.forename: Moshe
authors.initials: M
authors.lastname: Israeli
authors.affiliation: Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; Felsenstein Medical Research Center, Beilinson Hospital, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Maly
authors.initials: M
authors.lastname: Levy-Assaraf
authors.affiliation: Pharmacy Services, Rabin Medical Center, Petah-Tikva, Israel.
authors.forename: Tsipora
authors.initials: T
authors.lastname: Gruenewald
authors.affiliation: Institute for Drug Research, Medical Faculty, Hebrew University, Jerusalem, Israel.
authors.forename: Raphael
authors.initials: R
authors.lastname: Mechoulam
authors.affiliation: Bone Marrow Transplantation Unit, Institute of Hematology, Davidoff Center, Beilinson Hospital, Rabin Medical Center, Petah-Tikva, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Pia
authors.initials: P
authors.lastname: Raanani
authors.affiliation: Bone Marrow Transplantation Unit, Institute of Hematology, Davidoff Center, Beilinson Hospital, Rabin Medical Center, Petah-Tikva, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Ron
authors.initials: R
authors.lastname: Ram
mesh_terms: D000328:Adult; D000368:Aged; D064591:Allografts; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D002185:Cannabidiol / Q000627:therapeutic use*; D016572:Cyclosporine / Q000627:therapeutic use; D005260:Female; D006085:Graft Survival; D006086:Graft vs Host Disease / Q000453:epidemiology / Q000517:prevention & control*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D015994:Incidence; D007239:Infections / Q000453:epidemiology; D053208:Kaplan-Meier Estimate; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use; D008875:Middle Aged; D011446:Prospective Studies; D055815:Young Adult
chemical_list: D000893:Anti-Inflammatory Agents; D007166:Immunosuppressive Agents; D002185:Cannabidiol; D016572:Cyclosporine; D008727:Methotrexate
keywords: Allogeneic hematopoietic cell transplantation; Cannabidiol; Cannabis sativa; Graft-versus-host disease; Prophylaxis