Oral chronic GVHD in children—treatment with topical tacrolimus ointment

Abstract

Oral chronic graft versus host disease (GVHD) frequently presents as lichen-type changes, hyperkeratotic plaques, pseudomembranes, or decreased oral range of motion in patients with sclerotic features of skin GVHD and is often associated with significant limitations of oral food intake and a generally decreased quality of life. Decreased oral intake is especially problematic in children with already reduced caloric uptake due to chronic gastrointestinal GVHD. Systemic tacrolimus is well established and efficacious for prophylaxis and treatment of acute and chronic GVHD and topical tacrolimus has shown activity in chronic GVHD skin lesions. We therefore initiated a pilot study to investigate the safety and efficacy of topical tacrolimus ointment in pediatric stem cell transplant recipients with debilitating oral chronic GVHD. Two patients (6 and 13 years) with β-thalassemia were included in the study at 179 and 382 days post transplant respectively. Both suffered from progressive onset, moderate to severe chronic GVHD with involvement of the oral mucosa exhibiting lichen-type changes alongside pain, erythema and small ulcerations of the oral mucosa. One patient additionally presented with progressive sclerosis of the lips limiting opening of the oral cavity. In both patients oral lesions had been refractory to systemic GVHD treatment (cyclosporine 3 and 2 mg/kg respectively). After exclusion of infectious causes for oral lesions, tacrolimus ointment 0.1% (Protopic®, Fujisawa Healthcare) was applied twice daily using a sterile gauze that was inserted into both buccal pouches and left in place for 20 minutes without rinsing the mouth afterwards. At a follow up of 24 and 14 weeks respectively, the only side effect observed was a slight burning discomfort after the first application in one patient. Tacrolimus was absorbed in both patients as exhibited by tacrolimus plasma levels up to 4.2 and 5.6 ng/ml respectively. Pain, erythematous lesions and ulcerations disappeared within 4 weeks of treatment in both. Lichenoid changes markedly improved in both and range of oral opening normalized in the patient affected. Systemic immunosuppression was tapered during treatment with topical tacrolimus in both patients. We conclude that topical application of tacrolimus ointment holds promise as a safe and efficacious treatment for oral chronic GVHD in children. These findings deserve to be affirmed in a larger prospective evaluation. Oral chronic graft versus host disease (GVHD) frequently presents as lichen-type changes, hyperkeratotic plaques, pseudomembranes, or decreased oral range of motion in patients with sclerotic features of skin GVHD and is often associated with significant limitations of oral food intake and a generally decreased quality of life. Decreased oral intake is especially problematic in children with already reduced caloric uptake due to chronic gastrointestinal GVHD. Systemic tacrolimus is well established and efficacious for prophylaxis and treatment of acute and chronic GVHD and topical tacrolimus has shown activity in chronic GVHD skin lesions. We therefore initiated a pilot study to investigate the safety and efficacy of topical tacrolimus ointment in pediatric stem cell transplant recipients with debilitating oral chronic GVHD. Two patients (6 and 13 years) with β-thalassemia were included in the study at 179 and 382 days post transplant respectively. Both suffered from progressive onset, moderate to severe chronic GVHD with involvement of the oral mucosa exhibiting lichen-type changes alongside pain, erythema and small ulcerations of the oral mucosa. One patient additionally presented with progressive sclerosis of the lips limiting opening of the oral cavity. In both patients oral lesions had been refractory to systemic GVHD treatment (cyclosporine 3 and 2 mg/kg respectively). After exclusion of infectious causes for oral lesions, tacrolimus ointment 0.1% (Protopic®, Fujisawa Healthcare) was applied twice daily using a sterile gauze that was inserted into both buccal pouches and left in place for 20 minutes without rinsing the mouth afterwards. At a follow up of 24 and 14 weeks respectively, the only side effect observed was a slight burning discomfort after the first application in one patient. Tacrolimus was absorbed in both patients as exhibited by tacrolimus plasma levels up to 4.2 and 5.6 ng/ml respectively. Pain, erythematous lesions and ulcerations disappeared within 4 weeks of treatment in both. Lichenoid changes markedly improved in both and range of oral opening normalized in the patient affected. Systemic immunosuppression was tapered during treatment with topical tacrolimus in both patients. We conclude that topical application of tacrolimus ointment holds promise as a safe and efficacious treatment for oral chronic GVHD in children. These findings deserve to be affirmed in a larger prospective evaluation.