Photo courtesy of NIH
SAN DIEGO—Results of a phase 2 study suggest an oral mouth rinse formulation of the steroid clobetasol could provide short-term treatment of oral chronic graft-vs-host disease (cGVHD).
A majority of patients had a greater than 25% improvement in their cGVHD after using the clobetasol rinse, and patients reported improvements in oral health-related quality of life.
The rinse even proved effective in patients who had failed prior treatment with clobetasol ointment.
However, researchers found evidence to suggest the clobetasol rinse is not suitable for unmonitored, long-term use, as some patients experienced adrenal suppression.
Jacqueline W. Mays, DDS, PhD, of the National Institutes of Health (NIH) in Bethesda, Maryland, presented these findings at the 2016 ASH Annual Meeting (abstract 826).
Dr Mays noted that topical therapy for oral cGVHD is intended to spare patients from exposure to systemic immunosuppressive agents.
According to NIH consensus criteria, dexamethasone is recommended as the first-line topical therapy for these patients. However, clinical trial data suggest only 29% to 58% of patients respond to this therapy.
Second-line treatment is not well-established, but it typically consists of topical steroids in a gel or ointment formulation. Unfortunately, patient compliance is an issue with this type of treatment.
“If you can imagine trying to apply something in a petrolatum base to the inside of your very wet wall cavity, you can imagine that’s a challenge for a healthy individual, much less for a chronic graft-vs-host disease patient who often will have joint mobility and fine motor issues,” Dr Mays said.
“So this leads to frequent treatment failures of topical regimens, not only due to the drug agents but also due to patient compliance.”
Dr Mays noted that clobetasol is a superpotent synthetic glucocorticoid that has been used off-label in ointment form to treat refractory oral GVHD.
In an attempt to overcome the application challenges with this ointment and improve patient adherence to oral cGVHD treatment, Dr Mays and her colleagues decided to investigate a clobetasol 0.05% solution formulated as an oral rinse in an aqueous base.
The team tested the rinse in a phase 2 trial with an initial 2-week randomized, double-blind, placebo-controlled period.
Patient population
The trial enrolled and randomized 36 patients with oral cGVHD. The patients had an Oral Mucositis Rating Scale (OMRS) score of ≥20 with moderate erythema and/or ulceration. They also had stable or tapering systemic therapy during the 2 weeks prior to starting the study and for the duration of the blinded period.
The patients’ median age was 42 (range, 18-68), and 20 were male. Thirty-five patients received ablative conditioning, 18 received a related-donor transplant, 34 received a matched-donor transplant, and 30 received a peripheral blood stem cell graft.
The median time from cGVHD diagnosis to trial enrollment was 257 days (range, 15-3013). Thirty-six patients had mouth cGVHD, 21 had skin cGVHD, 26 had eye cGVHD, 14 had gastrointestinal cGVHD, 16 had liver cGVHD, 11 had lung cGVHD, and 10 had cGVHD of the joints and fascia.
Six patients had not received any prior oral topical therapy. The other 30 patients had a median of 2 prior oral topical therapies. Eleven patients had received prior clobetasol ointment.
Treatment
The patients were randomized to receive clobetasol or placebo rinse for 2 weeks (blinded period). After that, all patients received clobetasol rinse until they completed 28 days of treatment.
The patients were required to perform a 2-minute swish with 10 ml of clobetasol rinse 3 times daily and a once-daily swish with nystatin (100,000 u/ml) rinse for antifungal prophylaxis. The patients continued on systemic pneumocystis, antiviral, and antifungal prophylaxis, per NIH cGVHD guidelines.
Thirty-two of the patients completed treatment, using the clobetasol rinse for the full 28 days.
Four patients went off study before completing 28 days of treatment. One of these patients could not tolerate the rinse. This patient had gastrointestinal issues that were attributed (by the patient and the physician) to use of the study drug.
Two patients went off study because they could not make it to the NIH for follow-up visits, and 1 patient died. The death was unrelated to the study drug.
Safety
Dr Mays noted that small amounts of clobetasol were detectable in the bloodstream, but she and her colleagues found this was not directly correlated to patient serum cortisol levels.
However, the researchers did observe a significant drop in serum cortisol levels from baseline to day 28, suggesting the rinse has an adrenal impact.
On the other hand, the peripheral lymphocyte profile was unchanged by the use of clobetasol rinse, which suggests there were no significant systemic immunosuppressive effects.
Adverse events considered possibly or probably related to clobetasol rinse included herpes simplex virus reactivation (n=3, grade 2-3), oral candidiasis (n=3, grade 2), other oral viral infection (n=1, grade 2), facial edema (n=3, grade 1), and adrenal suppression (6 grade 1 and 1 grade 2).
Dr Mays noted that many of the patients came on the study with adrenal suppression, but the clobetasol rinse had an additional impact.
Efficacy
The study’s primary endpoint was change in oral cGVHD severity scale at day 28 compared to baseline. Complete response was defined as a score of 0 on the erythema and ulceration components. Partial response was defined as a 25% decrease in score.
Progression was defined as a 25% increase in initial score. Stable disease was defined as a status that does not meet the criteria for progression or response.
Ninety-one percent of patients had a greater than 25% improvement in oral cGVHD severity scale. Nineteen percent of patients had a complete response, 72% of patients had a partial response, and 9% had stable disease. None of the patients progressed.
Dr Mays noted that patients who failed treatment with prior clobetasol ointment responded similarly to the clobetasol rinse when compared with the full study cohort.
Among the 11 patients with prior clobetasol ointment, 18% had a complete response, 73% had a partial response, 9% had stable disease, and none progressed.
Clobetasol rinse significantly decreased the clinical OMRS score (P<0.0001) and improved cGVHD pathology diagnosis (P=0.0001).
Patients reported a significant improvement in oral health-based quality of life (P=0.0008) after completing treatment, as well as significant improvements in oral pain (P=0.017) and oral sensitivity (P=0.0081).
Though saliva production did not change significantly from baseline to day 28, patients reported a significant improvement in oral dryness (P=0.014).
The blinded period of the study showed that placebo treatment was not effective. There was a significant difference between the placebo and clobetasol groups with regard to improvement in OMRS score from baseline to day 14 (P=0.0031).
“We found clobetasol oral rinse to be both effective and safe for short-term treatment of oral mucosal cGVHD and hope that it will improve sparing of systemic immunosuppressants in this patient population,” Dr Mays said. “Its risk profile is generally not suitable for unmonitored, long-term use.”
