Sativex Oromucosal Spray in Patients with Chronic Graft Versus Host Disease: Effect on Sclerodermal Features and Refractory Muscle Cramps

Introduction:

Chronic graft-versus-host disease (cGVHD) is a significant complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), affecting approximately 50% of recipients. Sclerodermatous involvement notably diminishes quality of life, especially when associated with neuromuscular complications such as muscle cramps. Although muscle cramps are a frequent issue in clinical practice related to cGVHD, their prevalence is rarely reported in literature. The relationship between muscle cramps and chronic GVHD, or their association with immunosuppression treatment, remains unclear.

Sativex, an oromucosal spray containing a 1:1 ratio of δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), is an endocannabinoid system modulator approved in several European countries for managing moderate to severe spasticity in multiple sclerosis patients resistant to standard treatments. Preliminary data suggest indicates potential benefits of targeting cannabinoid receptors in GVHD management.

Aim:

To preliminary assess the therapeutic potential of Sativex in cGVHD, focusing on sclerodermatous symptoms and muscle cramps.

Methods:

We conducted a retrospective analysis of 30 patients with cGVHD treated with Sativex between October 2015 and May 2024 in our center. All patients provided informed consent for the off-label use of Sativex. cGVHD was classified according to NIH 2014 criteria, with evaluations conducted by our center’s multidisciplinary team based on the 2014 Response Criteria Working Group report.

Results:

Median patient age was 53 years (range 18-71), with 50% receiving transplants from HLA-identical related donors. Twenty-six patients exhibited cutaneous and/or sclerodermatous involvement, with 14 also showing joint and/or fascial involvement. At Sativex initiation, 24 patients experienced muscle cramps refractory to pregabalin and/or baclofen. Median number of prior cGVHD treatments was 3 (range 1-9), with 93.33% patients receiving Sativex alongside other therapies.

Median follow-up duration was 49.5 months (range 1-112), with 8 patients still under treatment with Sativex at their last visit. Median treatment duration was 12 months (range 0-110), with a median dose of 3 daily puffs (range 1-5).

Among the 15 patients with sclerodermatous involvement, the Overall Response Rate (ORR) was low, with 4 achieving Partial Response within the first 3 months and none of them achieving Complete Response. Nevertheless, 13 of these patients (86.67%) reported subjective symptoms improvement.

Out of 24 patients with muscle cramps, 91.67% reported improvement, with complete resolution of cramps in 8 cases. Only 2 patients reported no improvement, both of them discontinuing treatment within the first month due to intolerance.

Twelve patients reported 18 adverse events (AEs), all grade 1 and mostly transient, including dysgeusia, dizziness, nausea and dry mouth. At last visit, 8 patients remained on treatment, being the main reasons for treatment discontinuation symptom resolution (8 patients), lack of improvement (2 patients) and intolerance (4 patients).

Conclusion:

Although the ORR with Sativex treatment was low, most patients reported improvement in chronic GVHD symptoms, with special attention on muscle cramps. This improvement, alongside a favorable AEs profile, makes this treatment an interesting strategy for this patient group. Further prospective studies are warranted to characterize the use of cannabinoids in patients with cGVHD.