BI45 A double-edged sword: life-threatening adverse effects of 6-mercaptopurine

Abstract

We report the case of a 35-year-old patient with severe chronic actinic dermatitis (CAD) and allergic contact dermatitis to chemical ultraviolet filters who developed life-threatening toxicity while receiving 6-mercaptopurine (6-MP) for refractory disease. The patient had not responded to multiple systemic therapies and initially demonstrated clinical improvement with azathioprine; however, treatment was complicated by neutropenic sepsis in 2019, necessitating cessation. In 2022, 6-MP was commenced and later combined with dupilumab in 2023, followed by subsequent therapeutic trials with tralokinumab and lebrikizumab. Escalation of 6-MP dosing to 75–100 mg on alternate days resulted in significant clinical improvement. The patient remained clinically stable on 6-MP for > 3 years, with no initial safety concerns. Levels of 6-thioguanine nucleotide (6-TGN) were monitored regularly and remained within the therapeutic range throughout this period. Over time, the patient developed a progressive reduction in lymphocyte count and was initially reluctant to reduce the dose. While receiving a reduced dose of 37.5 mg, the patient developed neutropenic sepsis associated with markedly deranged thiopurine metabolites, including 6-methylmercaptopurine nucleotides (6-MMPN) exceeding 20 000 pmol per 8 × 108 red blood cells and an elevated 6-TGN level of 749 pmol per 8 × 108 red blood cells. Genetic testing for variants affecting thiopurine metabolism, including TPMT and NUDT15, was normal. The patient exhibited classical features of severe thiopurine toxicity, including myelosuppression, gastrointestinal toxicity, mucocutaneous ulceration and hepatotoxicity. Prominent manifestations included painful oral ulceration, diarrhoea and profound cytopenias. During admission, the platelet count declined to 0.02 × 1012 cells L−1 and haemoglobin to 68 g L−1, requiring multiple blood and platelet transfusions. Clinical recovery was prolonged despite cessation of thiopurine therapy. Subsequently, the patient developed acute renal failure requiring haemodialysis and was diagnosed with microangiopathic haemolytic anaemia and atypical haemolytic uraemic syndrome, for which treatment with eculizumab was initiated. This case highlights the potential for severe, multisystem thiopurine toxicity even in patients with normal TPMT and NUDT15 activity, requiring heightened clinical vigilance and monitoring.