Susceptibility to 6‐ MP toxicity conferred by a NUDT 15 variant in Japanese children with acute lymphoblastic leukaemia

• Published in: British journal of haematology 2015-10, Vol.171 (1), p.109-115
• Main Authors: Tanaka, Yoichi, Kato, Motohiro, Hasegawa, Daisuke, Urayama, Kevin Y., Nakadate, Hisaya, Kondoh, Kensuke, Nakamura, Kozue, Koh, Katsuyoshi, Komiyama, Takako, Manabe, Atsushi
• Format: Article
• Language: English
• ISSN: 0007-1048; 1365-2141
• DOI: 10.1111/bjh.13518

Genotyping of TPMT prior to 6‐mercaptopurine (6‐ MP ) administration in acute lymphoblastic leukaemia ( ALL ) patients has been integrated into clinical practice in some populations of European ancestry. However, the comparable rates of 6‐ MP myelotoxicity, but rarity of TPMT variants, in Asians suggest that major determinants have yet to be discovered in this population. We genotyped 92 Japanese paediatric ALL patients for NUDT 15 rs116855232, a 6‐ MP toxicity‐related locus discovered in Asians. Logistic regression and survival analysis were used to evaluate its association with leucopenia, hepatotoxicity, 6‐ MP dose reduction, therapy interruption and event‐free survival. The allele frequency of rs116855232 was 0·16, and leucopenia was more common in carriers of the T allele (odds ratio, 7·20; 95% confidence interval, 2·49–20·80; P  =   2·7 × 10 −4 ). As leucopenia results in 6‐ MP dose reduction, we observed average doses during maintenance therapy of 40·7, 29·3 and 8·8 mg/m 2 for patients with CC , CT and TT genotypes, respectively ( P  <   0·001). Hepatotoxicity was observed only in CC genotype patients. Event‐free survival did not significantly differ by NUDT 15 genotype. rs116855232 is an important determinant of 6‐ MP myelotoxicity in Japanese children with ALL and may represent the most robust toxicity‐related locus in Asians to date. Considerations for clinical application may be warranted.