S4907 Severe Myelotoxicity After Azathioprine in a Hispanic Patient With NUDT15 Variant: Support for Risk-Based Genetic Screening

Introduction: Azathioprine is a commonly used immunosuppressant to treat inflammatory bowel disease. It is converted to various active metabolites-6-thioguanine nucleotide (6-TGN) and 6-methylmercaptopurine and exerts an antiproliferative effect. Higher 6-TGN levels are generally associated with increased risk of myelosuppression. The active metabolites are converted to inactivated forms by enzymes including thiopurine methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15). Individuals with reduced NUDT15 activity are at risk for severe bone marrow suppression. Case Description/Methods: A 54-year-old Hispanic woman with ileo-colonic and perianal Crohn’s disease was started on Infliximab and Azathioprine. Her TPMT activity was 25.2 IU/mL (normal 22-44 IU/mL), along with a normal complete blood cell count and liver enzyme levels. She was started on azathioprine 250 mg daily (2.3 mg/kg; recommended dose 2-2.5 mg/kg). Three weeks after starting azathioprine, she presented to the emergency department with fever, malaise and oral ulcerations. Lab workup revealed a pancytopenia (leukocyte count 1,100/μL, absolute neutrophil count 6/μL, platelets 56,000/μL, and hemoglobin at 10.7 g/dL). AST and ALT were mildly elevated (54 and 63 U/L respectively). Azathioprine was discontinued. She was treated for neutropenic fever with cefepime, received Filgrastim to stimulate bone marrow production and was discharged after 2 weeks with an improved leukocyte count, absolute neutrophil count and platelets. Azathioprine metabolite labs displayed an elevated 6-methylmercaptopurine (13,441, normal <5700 pmol/8 × 108 RBC) and low 6-TGN (59, normal 230-400 pmol/8 × 108 RBC). Genetic testing revealed at least 1 deleterious NUDT15 allele and no variant alleles in the TPMT gene. Discussion: While TPMT testing is more established and commonly done before azathioprine, routine NUDT15 genotyping is not yet standard practice. NUDT15 deficiency is a more common cause of thiopurine-related myelosuppression in Asians and Hispanics. Studies have shown that individuals with reduced NUDT15 activity may exhibit lower total 6-TGN levels but higher levels of the more cytotoxic metabolite, 6-TGTP, which is not measured in routine 6-TGN assays. This case underscores the importance of incorporating NUDT15 screening prior to thiopurine initiation, particularly in populations with a higher prevalence of NUDT15 variants. Disclosure: Sponsored by the Bruce L. Miller & M. Joyce Miller Memorial & Visiting Professorship.