Prevention of thiopurine-induced early leukopenia in a Korean pediatric patient with Crohn’s disease who turned out to possess homozygous mutations in NUDT15 R139C
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Homozygous mutations in NUDT15 R139C are known as the major factor associated with thiopurine-induced early leukopenia, particularly in Asian patients. Therefore, NUDT15 genotyping is currently recommended before thiopurine treatment to identify patients who are NUDT15 poor metabolizers and consider the use of an alternative immunomodulatory therapy. We report a case of a 12-year-old Korean girl with Crohn’s disease (CD), in whom thiopurine-induced leukopenia was prevented by initiation of azathioprine (AZA) therapy at a low dose (0.5 mg/kg/day) and early detection of significant hair loss and white blood cell (WBC) count decrease at 17 days from the start of AZA treatment. The WBC count dropped from 8,970/μL to 3,370/μL in 2 weeks, and AZA treatment was stopped because of concerns of potential leukopenia in the near future. Her WBC count recovered to 5,120/μL after 3 weeks. Gene analysis later revealed that she had a homozygous mutation in NUDT15 R139C, resulting in a poor metabolizing activity of NUDT15. In situations when NUDT15 genotyping is unavailable, initiation of AZA therapy at 0.5 mg/kg/day with close observation of hair loss and WBC counts within 2 weeks may be an alternative way to prevent thiopurine-induced early leukopenia in Asian children with CD.
Abstract
Homozygous mutations in NUDT15 R139C are known as the major factor associated with thiopurine-induced early leukopenia, particularly in Asian patients. Therefore, NUDT15 genotyping is currently recommended before thiopurine treatment to identify patients who are NUDT15 poor metabolizers and consider the use of an alternative immunomodulatory therapy. We report a case of a 12-year-old Korean girl with Crohn’s disease (CD), in whom thiopurine-induced leukopenia was prevented by initiation of azathioprine (AZA) therapy at a low dose (0.5 mg/kg/day) and early detection of significant hair loss and white blood cell (WBC) count decrease at 17 days from the start of AZA treatment. The WBC count dropped from 8,970/μL to 3,370/μL in 2 weeks, and AZA treatment was stopped because of concerns of potential leukopenia in the near future. Her WBC count recovered to 5,120/μL after 3 weeks. Gene analysis later revealed that she had a homozygous mutation in NUDT15 R139C, resulting in a poor metabolizing activity of NUDT15. In situations when NUDT15 genotyping is unavailable, initiation of AZA therapy at 0.5 mg/kg/day with close observation of hair loss and WBC counts within 2 weeks may be an alternative way to prevent thiopurine-induced early leukopenia in Asian children with CD.
참고문헌 (20)
- Rosen MJ, "Inflammatory bowel disease in children and adolescents", JAMA Pediatr, 169, pp.1053~1060 (2015)
- Benchimol EI, "Epidemiology of pediatric inflammatory bowel disease : a systematic review of international trends", Inflamm Bowel Dis, 17, pp.423~439 (2011)
- 홍석진, "Characteristics and Incidence Trends for Pediatric Inflammatory Bowel Disease in Daegu-Kyungpook Province in Korea: a Multi-Center Study", Journal of Korean Medical Science, 33(18), pp.1~8 (2018), 대한의학회
- Ben Kang, "Korean Children and Adolescents with Crohn's Disease Are More Likely to Present with Perianal Fistulizing Disease at Diagnosis Compared to Their European Counterparts", Pediatric Gastroenterology, Hepatology & Nutrition, 23(1), pp.49~62 (2020), 대한소아소화기영양학회[DOI]
- Kang B, "Mucosal healing in paediatric patients with moderate-to-severe luminal Crohn's disease under combined immunosuppression : escalation versus early treatment", J Crohns Colitis, 10, pp.1279~1286 (2016)
- Ben Kang, "Early Biologic Treatment in Pediatric Crohn’s Disease: Catchingthe Therapeutic Window of Opportunity in Early Disease by Treat-to-Target", Pediatric Gastroenterology, Hepatology & Nutrition, 21(1), pp.1~11 (2018), 대한소아소화기영양학회
- Ruemmele FM, "Consensus guidelines of ECCO", ESPGHAN on the medical management of pediatric Crohn's disease, 2014, pp.8, 1179~1207
- 김재학, "염증성 장질환 환자에서 Azathioprine", 6-Mercaptopurine 치료의 부작용: 빈도와 경과, 2008, pp.51(5), 291~297[DOI]
- 천지영, "Adverse Events Associated with Azathioprine Treatment in Korean Pediatric Inflammatory Bowel Disease Patients", Pediatric Gastroenterology, Hepatology & Nutrition, 16(3), pp.171~177 (2013), 대한소아소화기영양학회
- Yang SK, "A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia", Nat Genet, 46, pp.1017~1020 (2014)
- Lee YJ, "NUDT15 variant is the most common variant associated with thiopurine-induced early leukopenia and alopecia in Korean pediatric patients with Crohn's disease", Eur J Gastroenterol Hepatol, 28, pp.475~478 (2016)
- Kim HY, "Complete sequence-based screening of TPMT variants in the Korean population", Pharmacogenet Genomics, 25, pp.143~146 (2015)
- 이강문, "Use of Thiopurines in Inflammatory Bowel Disease: A Consensus Statement by the Korean Association for the Study of Intestinal Diseases (KASID)", Intestinal research, 13(3), pp.193~207 (2015), 대한장연구학회
- Asada A, "NUDT15 R139C-related thiopurine leukocytopenia is mediated by 6-thioguanine nucleotide-independent mechanism in Japanese patients with inflammatory bowel disease", J Gastroenterol, 51, pp.22~29 (2016)
- Zhu X, "NUDT15 polymorphisms are better than thiopurine S-methyltransferase as predictor of risk for thiopurine-induced leukopenia in Chinese patients with Crohn’s disease", Aliment Pharmacol Ther, 44, pp.967~975 (2016)
- Collie-Duguid ES, "The frequency and distribution of thiopurine methyltransferase alleles in Caucasian and Asian populations", Pharmacogenetics, 9, pp.37~42 (1999)
- Yang JJ, "Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia", J Clin Oncol, 33, pp.1235~1242 (2015)
- Kim HT, "NUDT15 genotype distributions in the Korean population", Pharmacogenet Genomics, 27, pp.197~200 (2017)
- Relling MV, "Clinical pharmacogenetics implementation consortium guideline for thiopurine dosing based on TPMT and NUDT15 genotypes : 2018 update", Clin Pharmacol Ther, 105, pp.1095~1105 (2019)
- Kakuta Y, "NUDT15 R139C causes thiopurine-induced early severe hair loss and leukopenia in Japanese patients with IBD", Pharmacogenomics J, 16, pp.280~285 (2016)