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

• Published in: Blood Vol. 113; no. 24; pp. 6077 - 6084
• Main Authors: Schmiegelow, Kjeld, Al-Modhwahi, Ibrahim, Andersen, Mette Klarskov, Behrendtz, Mikael, Forestier, Erik, Hasle, Henrik, Heyman, Mats, Kristinsson, Jon, Nersting, Jacob, Nygaard, Randi, Svendsen, Anne Louise, Vettenranta, Kim, Weinshilboum, Richard
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 11.06.2009; Americain Society of Hematology; American Society of Hematology
• Series: Clinical Trials and Observations
• Subjects: 6-Mercaptopurine; Administration; administration & dosage; Administration, Oral; Adolescent; adverse effects; Antineoplastic Combined Chemotherapy Protocols; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Biological and medical sciences; chemically induced; Child; Child, Preschool; Clinical Trials and Observations; Combined Modality Therapy; Cranial Irradiation; diagnosis; drug therapy; Drug toxicity and drugs side effects treatment; Female; Follow-Up Studies; Hematologic and hematopoietic diseases; Humans; Immunoenzyme Techniques; Infant; Karyotyping; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; MEDICIN; Medicin och hälsovetenskap; MEDICINE; Mercaptopurine - administration & dosage; Mercaptopurine - adverse effects; metabolism; Methotrexate; Methotrexate - administration & dosage; Methotrexate - adverse effects; Methyltransferases; Methyltransferases - metabolism; Miscellaneous (drug allergy, mutagens, teratogens...); Neoplasms; Neoplasms, Second Primary - chemically induced; Neoplasms, Second Primary - diagnosis; Neoplasms, Second Primary - metabolism; Oral; pathology; Pediatrics; Pediatrik; Pharmacology. Drug treatments; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology; Precursor Cell Lymphoblastic Leukemia-Lymphoma - radiotherapy; Preschool; Prognosis; radiotherapy; Remission Induction; Risk Factors; Second Primary; Stem Cell Transplantation; Survival Rate; Treatment Outcome; Human; Antineoplastic agent; Purine derivatives; Hematology; Toxicity; Thiopurine derivatives; Malignant hemopathy; Malignant tumor; Antifolate; Chemotherapy; Treatment; Antimetabolic; Second cancer; Lymphoproliferative syndrome; Maintenance treatment; Risk factor; Complication; Acute lymphocytic leukemia; Methotrexate; Child; Cancer; Mercaptopurine
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2008-11-187880

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.