Tongue graft-versus-host disease: remission with ruxolitinib

Background

Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is the only treatment for many benign and malignant haematological disorders. Graft-versus-host disease (GvHD) often occurs as a complication after allo-HSCT with poor outcome, especially in patients who do not have a response to first-line therapy, which usually consists of corticosteroids. It is a complex disease characterised by alloreactive donor T cells which are immunologically stimulated and attack the recipient’s healthy tissue rather than targeting tumour cells with the production of high levels of pro-inflammatory cytokines, some of which are mediated by the Janus kinases (JAK). JAK1/2 are intracellular signalling molecules involved in the activation of various immune cells, including T cells, which are crucial for the progression of GvHD.1 Most importantly, despite this regulation by JAKs, their inhibition appears to maintain a graft-versus-leukaemia response. Ruxolitinib, a selective JAK1 and JAK2 inhibitor, has shown efficiency in patients with glucocorticoid resistant GvHD.2

The clinical presentations of GvHD rather than the timing of symptoms after transplantation, define it as acute or chronic. The National Institutes of Health consensus suggested the identification of acute GvHD (aGvHD) with typical onset before day 100 and persistent, recurrent or delayed aGvHD (post day 100, often after cessation of immune suppression). A chronic GvHD (cGvHD) consists of classic chronic without aGvHD characteristics, and an overlap syndrome that shows both aGvHD and cGvHD.3

Case presentation

A man (age range 20–25) underwent an allo-HSCT from an unrelated HLA-matched donor for primary refractory Hodgkin’s lymphoma. He received myeloablative conditioning regimen including Carmustine TD 400 mg/mq (day −6), Fludarabine TD 100 mg/mq (days −7 to –6, −5 to –4) and Thiotepa TD 20 mg/kg (days −5 to –4). Graft infusion was performed on d0 of conditioning regimen (CD34⁺: 5.4×10⁶ cells/kg, CD3⁺: 163.5×10⁶ cells/kg). Prophylaxis against GvHD comprised of cyclosporine (5 mg/kg from day −3) and low dose alemtuzumab 30 mg (days −2 and –1), in accordance with the institutional evaluation and bioethics committee (No. 344/04.08.06 and 525/07.09.06).4 The patient was negative for cytomegalovirus (CMV) IgG, and the donor was positive. Engraftment occurred on days +16 and+7 for leucocytes and platelets, respectively. The early period after the transplant was without adverse events, and cyclosporine was interrupted on day +103. Due to high-risk disease, the patient received low-dose donor lymphocyte infusions ((DLI), 0.5 million CD3⁺cells/kg) according to an institutional protocol.5 6

On day +152 the patient developed diffuse erythema and poikiloderma consistent with a post-DLI skin GvHD (moderate cGvHD). He was treated with cyclosporine and corticosteroids, with complete resolution of the erythema, and his immunosuppressive treatment was interrupted on day +225. Forty-five days later, on day +270, the erythema and poikiloderma reappeared (moderate cGvHD) and immunosuppressive treatment with corticosteroids and cyclosporine was reinitiated. However, approximately 18 months post-allo-HSCT, while he was under immunosuppressive treatment with cyclosporine and low dose steroids, diffuse confluent whitish patches on the patient’s tongue were noted (figure 1A).

Investigations

Viral serology, bacterial and fungal cultures from the tongue lesions were all negative. A tongue lesion biopsy revealed lichenoid, hyperkeratotic tissue changes and intraepithelial T-cell infiltration, consistent with cGvHD. Periodic acid–Schiff and Grocott’s-Silver stains, for both living and dead fungal organisms, were negative.

Differential diagnosis

Clinically, especially due to the delayed lesion onset, differential diagnoses include: oral candidiasis and chronic hyperplastic candidiasis, pseudomembranous candidiasis, idiopathic white patch (leukoplakia), sublingual keratosis, lichen planus or lichenoid reaction, pseudomembranes, xerostomia and squamous cell carcinoma.7

Candida albicans is an opportunistic fungal infection that occurs in patients with systemic or topical predeterminants such as inadequate oral health, use of dentures and dry mouth. While systemic factors are antibiotics and corticosteroids (oral and inhaled), immune deficiency, diabetes, chemotherapy and radiotherapy. Therefore, it was the first and most common culprit to be excluded from the differential diagnosis.7 Pseudomembranous candidiasis (thrush) presents as thick whitish patches and can be removed with a gauge. However, this was not the case in our patient. Taken together, the negative: fungal cultures, periodic acid–Schiff and Grocott’s-Silver stains, oral, pseudomembranous and chronic hyperplastic candidiasis were ruled out. As far as dry mouth and xerostomia were concerned, our patient did not present with remarkable salivary gland dysfunction or reported change in the quantity or quality of his saliva, as per the specialist’s examination.

Treatment

Antibacterial and antifungal therapy were initiated to rule out the possible coexistence of candida, but it was ineffective. He was treated with mycophenolate mofetil for 6 months with minimal lesion improvement. Therefore, JAK inhibitor (ruxolitinib) treatment was commenced 24 months after allo-HSCT. A complete resolution of the tongue lesions was observed (figure 1B), and treatment was discontinued 5 months later (2 years and 5 months after allo-HSCT).

Outcome and follow-up

Currently, 5 years after allo-HSCT, the patient is in complete remission of the Hodgkin’s lymphoma, in excellent condition and in complete remission of his tongue GvHD without the need for any immunosuppressive treatment.