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.

Abstract

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.

• Authors: Kjeld Schmiegelow, Ibrahim Al-Modhwahi, Mette Klarskov Andersen, Mikael Behrendtz, Erik Forestier, Henrik Hasle, Mats Heyman, Jon Kristinsson, Jacob Nersting, Randi Nygaard, Anne Louise Svendsen, Kim Vettenranta, Richard Weinshilboum, Nordic Society for Paediatric Haematology and Oncology
• Journal: Blood (Blood) Vol. 113 Issue 24 Pg. 6077-84 (Jun 11 2009) ISSN: 1528-0020 [Electronic] United States
• PMID: 19224761 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Mercaptopurine
• Methyltransferases
• thiopurine methyltransferase
• Methotrexate

Topics

• Administration, Oral
• Adolescent
• Antineoplastic Combined Chemotherapy Protocols (adverse effects)
• Child
• Child, Preschool
• Combined Modality Therapy
• Cranial Irradiation
• Female
• Follow-Up Studies
• Humans
• Immunoenzyme Techniques
• Infant
• Karyotyping
• Male
• Mercaptopurine (administration & dosage, adverse effects)
• Methotrexate (administration & dosage, adverse effects)
• Methyltransferases (metabolism)
• Neoplasms, Second Primary (chemically induced, diagnosis, metabolism)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, pathology, radiotherapy)
• Prognosis
• Remission Induction
• Risk Factors
• Stem Cell Transplantation
• Survival Rate
• Treatment Outcome