Cannabis sativa contains numerous cannabinoids, with D9-tetrahydrocannabinol (THC) and cannabidiol (CBD) the primary cannabinoids of medical interest. Both THC and CBD possess potent anti-inflammatory and immunosuppressive properties, but THC has significant psychoactive properties. In a phase 2 study of CBD plus standard GVHD prophylaxis,, Yeshrun et al found low rates of grade II - IV acute GVHD, and compared with 101 historical control subjects given standard GVHD prophylaxis, the hazard ratio of developing grades II - IV acute GVHD was .3 (P =.0002)1. Also, Kalytera Therapeutics announced promising results in a Phase 2a study evaluating the safety and efficacy of CBD, for the treatment of acute Grade III-IV GVHD, including 9/ 10 responses, of which 7 were complete remission (CR)2. We report a case of steroid refractory eczematous GVHD successfully treated with a CBD-predominant medical cannabis product.
A 35 year old woman with T-cell Acute Lymphoblastic Leukemia (T-ALL) was treated on an MSKCC pediatric -inspired ALL protocol. She developed CNS involvement during induction therapy treated with intrathecal therapy with persistent CNS disease. She then received salvage therapy with HyperCVAD part B with high dose methotrexate, high dose cytarabine, with CR and underwent matched related donor (sister) stem cell transplant conditioned with Etoposide, TBI 1200 cGy. GvHD prophylaxis was Alemtuzumab, Tacrolimus. She developed a rash on day 126 post transplant involving face and scalp which spread to chest and back and within 1 week involved 100% of BSA with itching, facial and orbital swelling, ankle/feet swelling. Skin biopsy revealed an eczematous variant of GvHD which is considered to be very aggressive, difficult to control with immunosuppression3, and carries a poor prognosis. Phototherapy and steroid ointment was initiated with initial benefit and regression of rash but then rash and edema returned within 6 months. Ruxolitinib was given on expanded access protocol with no benefit. Systemic steroids were again initiated at 1 mg/kg/ day with minimal benefit. Insurance denied tociluzumab. Extracorporeal photopheresis was started with only minimal response and eventually ibrutinib was initiated. With steroids, photopheresis and ibrutinib she had marginal response but ongoing severe skin GvHD. She had numerous infectious complications including soft tissue skin infections requiring multiple admissions. At 16 months post transplant, the patient began a medical cannabis product manufactured by VIREO HEALTH, consisting of a high CBD:THC ratio (19:1) oral solution containing CBD 47.5mg/ml and THC 2.5mg/ml. A daily dose of 6 ml provided 285 mg CBD and 15mg THC daily comparable to the 300 mg CBD product in the Kalytera product. Toxicity was sleepiness; thus the patient took the dose in the evening. There was a definite response within 3 months, allowing discontinuation of ibrutinib and photopheresis. By 2 years post transplant, her skin issues had resolved with only mild itching and flakiness. She remains on this product at a dose of 6 ml daily.
This case adds to the developing evidence regarding the potential anti- inflammatory and immunosuppressive effects of medical cannabis and its activity for the treatment of active GVHD. Both THC and CBD are anti-inflammatory via CB2 receptors and THC inhibits T-lymphocyte expansion in a murine BMT model.1 The THC component may have contributed therapeutic benefit but also explains the toxicity and was dose limiting. Further studies are warranted to explore the role of medical cannabis, the optimal dose of CBD and THC, in the prevention and management of GVHD.
1 Yeshurun, Moshe, et al. "Cannabidiol for the Prevention of Graft-versus-Host-Disease after Allogeneic Hematopoietic Cell Transplantation: Results of a Phase II Study." Biology of Blood and Marrow Transplantation, vol. 21, no. 10, 2015, pp. 1770-1775., doi:10.1016/j.bbmt.2015.05.018.
2. Kalytera Therapeutics Announces Encouraging Results of a Phase 2a Clinical Study for the Treatment of Acute Graft versus Host Disease. Source: Kalytera Therapeutics, Inc.VANCOUVER, British Columbia, Feb. 22, 2017 (GLOBE NEWSWIRE)
3. Creamer D, Martyn-Simmons CL, Osborne G, et al. Eczematoid Graft-vs-Host Disease: A Novel Form of Chronic Cutaneous Graft-vs-Host Disease and Its Response to Psoralen-UV-A Therapy. Arch Dermatol.2007;143(9):1157-1162. doi:10.1001/archderm.143.9.1157
No relevant conflicts of interest to declare.
This is a medical cannabis product manufactured by VIREO HEALTH, consisting of a high CBD:THC ratio (19:1) oral solution containing CBD 47.5mg/ml and THC 2.5mg/ml. The drug was used to treat refractory graft versus host disease.
Asterisk with author names denotes non-ASH members.