PS1548 SAFETY AND EFFICACY OF CANNABIDIOL FOR SEVERE ACUTE GRAFT VERSUS HOST DISEASE - A PHASE I/II STUDY

Abstract

Background: Steroid refractory severe (grade 3–4) acute graft vs. host disease (GVHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic cell transplant (allo-HCT) and thus represents a major unmet medical need. Cannabidiol (CBD), a safe and non-psychotropic ingredient of marijuana, has been shown to exhibit potent immune-modulatory and anti-inflammatory properties in various inflammatory diseases including in GVHD setting, as reported by us in 2015. Aims: to examine the safety and efficacy of CBD for the treatment of steroid refractory severe acute GVHD Methods: We conducted a phase 1/2 prospective study (NCT 02392780). Upon recruitment, CBD was orally administered at a dose of 150 mg twice daily for up to 90 days. First line treatment consisting of cyclosporine or tacrolimus and high-dose methylprednisolone was continued, and tapered off slowly according to clinical response. Study endpoints included cumulative incidence of patients achieving either very good partial response (VGPR) or complete response (CR) and patients achieving partial response (PR) of their GVHD. Further endpoints included incidence of chronic GVHD and safety. Results: Between June 2014 and November 2016, 10 consecutive patients with severe acute GVHD following allo-HCT for hematological malignancy were enrolled (median age = 59, range, 31–70 years). Most patients had acute leukemia (9/10). All donors were HLA matched- sibling (5/10) or unrelated (5/10). Conditioning regimen was mostly myeloablative (8/10), with primary GVHD prophylaxis consisting of cyclosporine A and methotrexate (9/10). Acute GVHD occurred after donor lymphocyte infusion (DLI) for relapse of hematological malignancy in 4/10 patients: in 3/10 it appeared within day 100 of transplantation and in 3/10 during immunosuppression tapering off. Median duration between onset of GVHD and CBD initiation was 13 (range 5–52) days. Patients received CBD for a median of 84 days (range 11–258). Overall, CBD was well tolerated and no grade 3–4 toxicities were attributed to CBD. One patient (#10) developed severe sepsis 5 days from enrollment, and died 16 days later. Among the 9 evaluable patients, 8/9 responded to the treatment and achieved either CR (6/9) or VGPR (2/9). All responses were durable, apart from one patient (#2) who decided to stop treatment with a subsequent flare-up of fatal acute GvHD. In all responders (8/9), response to treatment was noted already one week after CBD initiation. Mean time to best response was 45.9 days with a median of 37 days (SD = 32.1, range 3–97). All responders could decrease substantially immunosuppressive treatment. None of the patients developed chronic GVHD while consuming CBD. Only one patient (#6) developed chronic GVHD, involving eye and mouth, after CBD cessation. Median follow up was 7 months (range 21 days - 46 months). At last follow up, 3 patients were alive, all in CR without acute or chronic GVHD at a median of 4.7 years post-transplant (range 4–6 years). Two patients died of relapse (#07 who was transplanted with refractory disease; #08 whose GvHD developed after relapse and DLI). Three patients died of late infectious complications (more than 6 months after enrollment).Summary/Conclusion: Considering the dismal prognosis of patients with severe refractory acute GVHD, the results of this study are encouraging, albeit with the limitation of our small sample size. Further prospective studies are warranted to confirm these preliminary results.