Thiopurine methyltransferase activity is related to the risk of relapse of childhood acute lymphoblastic leukemia: results from the NOPHO ALL-92 study

• Published in: Leukemia Vol. 23; no. 3; pp. 557 - 564
• Main Authors: Schmiegelow, K, Forestier, E, Kristinsson, J, Söderhäll, S, Vettenranta, K, Weinshilboum, R, Wesenberg, F
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-03-2009; Nature Publishing Group
• Subjects: Acute lymphoblastic leukemia; Acute lymphocytic leukemia; Antimetabolites, Antineoplastic - administration & dosage; Antimetabolites, Antineoplastic - pharmacokinetics; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Biotransformation - drug effects; Cancer; Cancer Research; Child; Child, Preschool; Children; Critical Care Medicine; DNA Damage; Erythrocytes; Female; Genetic aspects; genetic polymorphisms; Genotype; Health risks; Hematologic and hematopoietic diseases; Hematology; Humans; Inactivation, Metabolic - genetics; Infant; Intensive; Internal Medicine; Leukemia; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphatic leukemia; Male; Medical sciences; Medicin och hälsovetenskap; Medicine; Medicine & Public Health; Mercaptopurine - administration & dosage; Mercaptopurine - pharmacokinetics; Methylation; Methyltransferase; Methyltransferases; Methyltransferases - analysis; Methyltransferases - genetics; Methyltransferases - physiology; Myelosuppression; Neoplasm Proteins - analysis; Neoplasm Proteins - genetics; Neoplasm Proteins - physiology; Neoplasms, Second Primary - enzymology; Neoplasms, Second Primary - epidemiology; Neoplasms, Second Primary - genetics; Nucleotides; Oncology; original-article; Pharmacokinetics; Physiological aspects; Polymorphism, Genetic; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - enzymology; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - epidemiology; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - enzymology; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - epidemiology; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Recurrence; Regression analysis; relapse rate; Risk; Risk factors; Scandinavian and Nordic Countries - epidemiology; second malignant neoplasm; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Statistical analysis; Thioguanine; Thioguanine - administration & dosage; Thioguanine - pharmacokinetics; thiopurine methyltransferase; Thiopurine S-methyltransferase; Denmark; thiopurine methyltransferase; genetic polymorphisms; acute lymphoblastic leukemia; second malignant neoplasm; relapse rate; Relapse; Genetic variability; Enzymatic activity; Lymphoproliferative syndrome; Genetics; Thiopurine S-methyltransferase; Acute lymphocytic leukemia; Child; Human; Hematology; Enzyme; Transferases; Genotype; Malignant hemopathy; Malignant tumor; Methyltransferases; Second cancer; Risk factor; Cancer; Polymorphism
• ISSN: 0887-6924; 1476-5551; 1476-5551
• DOI: 10.1038/leu.2008.316

Myelotoxicity during thiopurine therapy is enhanced in patients, who because of single nucleotide polymorphisms have decreased activity of the enzyme thiopurine methyltransferase (TPMT) and thus more thiopurine converted into 6-thioguanine nucleotides. Of 601 children with acute lymphoblastic leukemia (ALL) who were treated by the NOPHO ALL-92 protocol, 117 had TPMT genotype determined, whereas for 484 patients only erythrocyte TPMT activity was available. The latter were classified as heterozygous, if TPMT activity was <14 IU/ml, or deficient (<1.0 IU/ml). 526 patients had TPMT wild type, 73 were presumed heterozygous, and two were TPMT deficient. Risk of relapse was higher for the 526 TPMT wild type patients than for the remaining 75 patients (18 vs 7%,
P
=0.03). In cox multivariate regression analysis, sex (male worse;
P
=0.06), age (higher age worse,
P
=0.02), and TPMT activity (wild type worse;
P
=0.02) were related to risk of relapse. Despite a lower probability of relapse, patients in the low TPMT activity group did not have superior survival (
P
=0.82), possibly because of an excess of secondary cancers among these 75 patients (
P
=0.07). These data suggest that children with ALL and TPMT wild type might have their cure rate improved, if the pharmacokinetics/-dynamics of TPMT low-activity patients could be mimicked without a concurrent excessive risk of second cancers.