Management of Chronic Oral GVHD in Patient with High-Risk AML and Mixed Chimerism

Diagnosis and Treatment

A 45-year-old female has a history of acute myeloid leukemia with a complex cytogenetic karyotype that is in remission after induction therapy with 7+3 (cytarabine and idarubicin) and conditioning with high-dose cytarabine/ara-C (HiDAC). She underwent an allogeneic stem cell transplantation using a matched unrelated male donor with peripheral blood stem cells. 

She received GVHD prophylaxis consisting of post-transplant cyclophosphamide on days +3 and +4, and tacrolimus and mycophenolate mofetil from day +5 through day +35. 

Management of Acute GVHD

The patient’s initial post-transplant course was relatively unremarkable with expected cytopenias and gastrointestinal toxicity with nausea and vomiting and transfusion needs. 

Around day +35, she developed a faint maculopapular rash on the anterior chest and upper back, which was <25% body surface area and grade 1 acute GVHD. The rash was treated with topical triamcinolone 0.1% cream up to three times daily. Additionally, she was found to have elevated liver function tests (i.e., AST and ALT). Ursodiol was started with some improvement. 

Workup at 100 days post-transplant included a bone marrow biopsy, which continued to reveal remission from AML; however, she was found to have mixed chimerism (FISH XY) on bone marrow biopsy with four cells with female karyotype (196/200 XY, four cells XX). Due to high-risk disease and mixed chimerism, tacrolimus was tapered quickly between day 100 and day 120, decreasing incrementally while monitoring over 2 weeks. 

Following the discontinuation of tacrolimus, day +135 post-transplant, the patient expressed in clinic that a week prior she had developed dry mouth, which then progressed to redness inside her mouth and pain with acidic or spicy foods in the last few days. She reported a “spider web–like covering in her mouth.” The patient denied additional symptoms at that time, including diarrhea, skin rash, or jaundice. She was evaluated in the clinic and found to have erythema on the bilateral buccal mucosa with diffuse lichenoid changes and a shallow ulcer on the left side. She also had bilateral ridge lines across the buccal mucosa. She described the presence of small blisters that appear in her mouth after eating, last a few hours, and then resolve.  

Lab workup revealed the following: 

Labs revealed mild pancytopenia (mild leukopenia, anemia, and thrombocytopenia) not requiring any intervention, which is common for this timeframe post-transplant. Neutrophil count was normal. The patient did not have recurrence of any transaminitis and had no hyperbilirubinemia. The most significant of the lab findings was the FISH XY, which revealed that the patient’s female cells were persisting in 4/200 of the cells examined, which put her at a higher risk for relapsed disease.  

Management of Chronic Oral GVHD

The patient was given a prescription for dexamethasone 0.5 mg/5 mL elixir and instructions to swish and spit up to four times daily for up to 5 minutes if tolerated.^1,2 She was reevaluated in 1 week and found to have some minor improvements in the appearance of the mucosal erythema and decrease in size of the left buccal mucosal ulceration. Additionally, her sensitivity to foods had lessened, although she had chosen to abstain from acidic and spicy foods recently.  

After 2 weeks on dexamethasone swish and spit, the patient was found to have an area of white on the tongue resembling oral candidiasis/thrush. She was given nystatin 100,000 units/mL and instructed to use 5 mL after meals and before bedtime until resolution of the white patch on the tongue. Her oral GVHD symptoms continued to improve from a sensitivity perspective, but she continued to have a sore spot on the left buccal mucosa where her ulceration had improved but not resolved. The decision was made to switch from dexamethasone to clobetasol 0.05% gel four times daily.³ The patient had improvement of her symptoms over the following 2-3 weeks and remained on this medication for a few months until it was successfully tapered to as-needed use. 

Discussion

Oral involvement of chronic GVHD often begins with dry mouth (xerostomia), erythema of the mucosa, lichenoid changes, mucoceles, or ulceration of the mucosa. Sensitivity to spicy and acidic foods is also common. Some patients also develop a difficulty in opening the mouth or painful swallowing.  

Because this patient had high-risk disease and mixed chimerism, caution was taken to avoid high-dose steroids and systemic treatment, as she responded to topical agents and did not have additional organ involvement. However, if she had additional organ involvement or more severe symptoms, it would have been reasonable to cautiously consider steroids at 0.5 mg/kg per day and then potentially ruxolitinib or ibrutinib if she became steroid dependent or refractory. If the patient failed two systemic treatments, belumosudil could also be considered.  

For a high-risk patient, special care should be taken to weigh the risks and benefits of systemic immunosuppression for oral GVHD. Triamcinolone (as Kenalog in Orabase), which is a topical paste, could also be considered in this case. Some patients have also used topical tacrolimus orally with less success.³ Many compounding pharmacies are able to combine clobetasol or dexamethasone with nystatin, but they are available separately as well. In patients with moderate to severe oral GVHD symptoms, systemic treatment is recommended by the NIH Consensus Criteria.⁴

Patients with oral involvement of GVHD are also at risk for dental cavities due to the decrease in saliva production (dry mouth/xerostomia), which is common in this process. They should be seen on a regular basis by a dentist and maintain good hygiene with a soft toothbrush and non-alcohol–based mouth rinse. Abnormal mucosal lesions should be considered for biopsy, as immunocompromised patients are also at risk for secondary malignancies.  

References

1. Elsaadany BA, et al. Efficacy and safety of topical corticosteroids for management of oral chronic graft versus host disease. Int J Dent. 2017;2017:1908768.  
2. Sava A, et al. Topical corticosteroids a viable solution for oral graft versus host disease? A systematic insight on randomized clinical trials. Medicina (Kaunas). 2020;56:349.  
3. Noce CW, et al. Randomized double-blind clinical trial comparing clobetasol and dexamethasone for the topical treatment of symptomatic oral chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2014;20:1163-1168. 
4. Jagasia MH, et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report. Biol Blood Marrow Transplant. 2015;21:389-401.e1.