Severe 6-mercaptopurine-induced hematotoxicity in childhood an ALL patient with homozygous NUDT15 missence variants.

Thiopurine S-methyltransferase (TPMT) and nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) variants are considered to be genes responsible for severe myelotoxicity induced by 6-mercaptopurine (6MP). We report a 4-year-old girl with acute lymphoblastic leukemia, who developed the complication of severe 6MP-induced myelotoxicity due to homozygous NUDT15 variant alleles. In early consolidation therapy containing 6MP, her course was complicated by severe neutropenia (Grade 4) and chemotherapy had to be discontinued for 33 days. The 6MP dose was subsequently adjusted based on the white blood cell count. The ratios of the prescribed 6MP dose over the protocol dose in early consolidation, central nervous system (CNS) prophylaxis, re-induction, interim maintenance and maintenance therapy were 63%, 27%, 4%, 26% and 7%, respectively. Suspension of therapy was required during early consolidation, CNS prophylaxis and interim maintenance therapy. We investigated candidate genes for 6MP-associated myelotoxicity and found homozygous NUDT15 variant alleles and a heterozygous inosine triphosphate pyrophosphatase (ITPA) variant allele. In patients with homozygous NUDT15 variants, drastic reduction (less than 10%) of the 6MP dose from the protocol dose might be required not only during maintenance therapy, but also during other treatment courses containing 6MP. Screening of candidate genes at diagnosis is recommended in order to avoid serious adverse events.