TY - JOUR
T1 - Methotrexate/6-mercaptopurine maintenance therapy influences the risk of a second malignant neoplasm after childhood acute lymphoblastic leukemia: results from the NOPHO ALL-92 study
AU - Schmiegelow, Kjeld
AU - Al-Modhwahi, Ibrahim
AU - Andersen, Mette Klarskov
AU - Behrendtz, Mikael
AU - Forestier, Erik
AU - Hasle, Henrik
AU - Heyman, Mats
AU - Kristinsson, Jon
AU - Nersting, Jacob
AU - Nygaard, Randi
AU - Svendsen, Anne Louise
AU - Vettenranta, Kim
AU - Weinshilboum, Richard
AU - Nordic Society for Paediatric Haematology and Oncology
N1 - Keywords: 6-Mercaptopurine; Administration, Oral; Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Combined Modality Therapy; Cranial Irradiation; Female; Follow-Up Studies; Humans; Immunoenzyme Techniques; Infant; Karyotyping; Male; Methotrexate; Methyltransferases; Neoplasms, Second Primary; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Remission Induction; Risk Factors; Stem Cell Transplantation; Survival Rate; Treatment Outcome
PY - 2009
Y1 - 2009
N2 - Among 1614 children with acute lymphoblastic leukemia (ALL) treated with the Nordic Society for Paediatric Haematology and Oncology (NOPHO) ALL-92 protocol, 20 patients developed a second malignant neoplasm (SMN) with a cumulative risk of 1.6% at 12 years from the diagnosis of ALL. Nine of the 16 acute myeloid leukemias or myelodysplastic syndromes had monosomy 7 (n = 7) or 7q deletions (n = 2). In Cox multivariate analysis, longer duration of oral 6-mercaptopurine (6MP)/methotrexate (MTX) maintenance therapy (P = .02; longest for standard-risk patients) and presence of high hyperdiploidy (P = .07) were related to increased risk of SMN. Thiopurine methyltransferase (TPMT) methylates 6MP and its metabolites, and thus reduces cellular levels of cytotoxic 6-thioguanine nucleotides. Of 524 patients who had erythrocyte TPMT activity measured, the median TPMT activity in 9 patients developing an SMN was significantly lower than in the 515 that did not develop an SMN (median, 12.1 vs 18.1 IU/mL; P = .02). Among 427 TPMT wild-type patients for whom the 6MP dose was registered, those who developed SMN received higher average 6MP doses than the remaining patients (69.7 vs 60.4 mg/m2; P = .03). This study indicates that the duration and intensity of 6MP/MTX maintenance therapy of childhood ALL may influence the risk of SMNs in childhood ALL.
AB - Among 1614 children with acute lymphoblastic leukemia (ALL) treated with the Nordic Society for Paediatric Haematology and Oncology (NOPHO) ALL-92 protocol, 20 patients developed a second malignant neoplasm (SMN) with a cumulative risk of 1.6% at 12 years from the diagnosis of ALL. Nine of the 16 acute myeloid leukemias or myelodysplastic syndromes had monosomy 7 (n = 7) or 7q deletions (n = 2). In Cox multivariate analysis, longer duration of oral 6-mercaptopurine (6MP)/methotrexate (MTX) maintenance therapy (P = .02; longest for standard-risk patients) and presence of high hyperdiploidy (P = .07) were related to increased risk of SMN. Thiopurine methyltransferase (TPMT) methylates 6MP and its metabolites, and thus reduces cellular levels of cytotoxic 6-thioguanine nucleotides. Of 524 patients who had erythrocyte TPMT activity measured, the median TPMT activity in 9 patients developing an SMN was significantly lower than in the 515 that did not develop an SMN (median, 12.1 vs 18.1 IU/mL; P = .02). Among 427 TPMT wild-type patients for whom the 6MP dose was registered, those who developed SMN received higher average 6MP doses than the remaining patients (69.7 vs 60.4 mg/m2; P = .03). This study indicates that the duration and intensity of 6MP/MTX maintenance therapy of childhood ALL may influence the risk of SMNs in childhood ALL.
U2 - 10.1182/blood-2008-11-187880
DO - 10.1182/blood-2008-11-187880
M3 - Journal article
C2 - 19224761
SN - 0006-4971
VL - 113
SP - 6077
EP - 6084
JO - Blood
JF - Blood
IS - 24
ER -