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Thiopurine S‐methyltransferase (TPMT) polymorphisms in children with acute lymphoblastic leukemia, and the need for reduction or cessation of 6‐mercaptopurine doses during maintenance therapy: The Polish multicenter analysis
Author(s) -
PeregudPogorzelski Jarosław,
TeteraRudnicka Edyta,
Kurzawski Mateusz,
Brodkiewicz Andrzej,
Adrianowska Natalia,
Mlynarski Wojciech,
Januszkiewicz Danuta,
Drozdzik Marek
Publication year - 2011
Publication title -
pediatric blood and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.116
H-Index - 105
eISSN - 1545-5017
pISSN - 1545-5009
DOI - 10.1002/pbc.23013
Subject(s) - thiopurine methyltransferase , medicine , mercaptopurine , allele , genotype , allele frequency , neutropenia , gastroenterology , chemotherapy , genetics , biology , gene , azathioprine , disease
Background 6‐Mercaptopurine (6‐MP) is used for the treatment of pediatric acute lymphoblastic leukemia (ALL). Mutations in the TPMT gene may influence the efficacy and safety of 6‐MP treatment. This multicenter study investigated the association between TPMT genotype, 6‐MP dose adjustments, and the incidence of adverse effects in patients. Procedure A total of 203 ALL children were genotyped using PCR/allele‐specific amplification and PCR/RFLP. The control group consisted of 394 healthy volunteers. Results The TPMT*3A variant allele was found in 16 patients (15 TPMT*1/*3A , 1 TPMT*3A/*3A ) and the TPMT*3C (A719G) allele in 1 patient. No TPMT*2 (G238C) or TPMT*3B (G460A) alleles were detected in the study group. TPMT*3A , TPMT*1 (wild‐type), and TPMT*3C alleles were detected at frequencies of 3.94%, 95.81%, and 0.25%, respectively. The genotype and allele distributions were similar in the ALL and control groups. The 6‐MP dose was reduced more frequently in patients with TPMT*3A and TPMT*3C alleles, compared with wild‐type alleles ( P = 0.042). Reductions because of leucopenia with respiratory tract infection, or because of leucopenia, anemia and/or thrombocytopenia were four ( P = 0.007) and five ( P = 0.03) times more common, respectively. The groups differed with regard to the rates of 6‐MP dose reduction ( P = 0.028). 6‐MP was discontinued more often in patients with TPMT*3A and TPMT*3C alleles (14‐fold) as a result of leucopenia, anemia, and/or thrombocytopenia ( P = 0.004). Conclusions The results indicate that TPMT genotype influences the safety and efficacy of ALL treatment and genotype information may therefore be useful for optimizing 6‐MP therapy. Pediatr Blood Cancer 2011; 57: 578–582. © 2011 Wiley‐Liss, Inc.