Thiopurine methyltransferase polymorphisms and mercaptopurine tolerance in Turkish children with acute lymphoblastic leukemia

• Published in: Cancer chemotherapy and pharmacology 2011-11, Vol.68 (5), p.1155-1159
• Main Authors: Albayrak, Meryem, Konyssova, Uljan, Kaya, Zuhre, Gursel, Turkiz, Guntekin, Sezen, Percin, E. Ferda, Kocak, Ulker
• Format: Article
• Language: English
• Subjects: Antimetabolites, Antineoplastic - adverse effects; Antimetabolites, Antineoplastic - therapeutic use; Antineoplastic agents; Biological and medical sciences; Cancer Research; Child; Child, Preschool; Female; Hematologic and hematopoietic diseases; Humans; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Medicine; Medicine & Public Health; Mercaptopurine - adverse effects; Mercaptopurine - therapeutic use; Methyltransferases - genetics; Oncology; Original Article; Pharmacology. Drug treatments; Pharmacology/Toxicology; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma - enzymology; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Turkey
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-011-1599-7

Purpose Thiopurine methyltransferase (TPMT) enzyme is involved in the metabolism of 6-mercaptopurine (6-MP), a key component of acute lymphoblastic leukemia (ALL) treatment protocols in children. The aims of this study were to investigate the frequency of common genetic polymorphisms associated with low TPMT activity and correlations of polymorphic variants with 6-MP tolerance in a group of Turkish children with ALL. Methods Genotyping for G238C, A719G, and G460A mutations were performed by using NanoChip Technology. Adverse reactions during the first 6 months of maintenance therapy with oral 6-MP and methotrexate were retrospectively analyzed from patient’s files. Results Five (8.6%) of 58 children with ALL had a polymorphic TPMT allele: 4 (3.4%) were heterozygous for TPMT*3A (G460A and A719G), and one (0.9%) was heterozygous for TPMT*3C (A719G). No cases with TPMT*3B (G460A) or TPMT*2 (G238C) variants were identified. Children with TPMT*3A and *3C had significantly lower leukocyte and neutrophil counts and percentage of target 6-MP dosage, and longer periods with ≥grade 2 infections, ≥grade 2 liver toxicity, and chemotherapy interruptions than the children with wild-type TPMT during the first 24 weeks of maintenance therapy. Conclusions The frequency and distribution of common TPMT polymorphisms in Turkish children with ALL is similar to other Caucasian populations. Polymorphic variants were associated with excessive 6-MP toxicity supporting the suggestion that TPMT genotyping should be performed before institution of 6-MP therapy.