Journal
BLOOD
Volume 113, Issue 24, Pages 6077-6084Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2008-11-187880
Keywords
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Categories
Funding
- Danish Childhood Cancer Foundation
- University Hospital Rigshospitalet
- Children's Cancer Foundation of Sweden [53/91, 62/94, 72/96, 98/59, 04/002]
- Danish Cancer Society [91-048, 92-017, 93-017, 95-100-28]
- Lundbeck Foundation [38/99]
- NovoNordisk Foundation
- Home Secretary Research Grant for Individualised Therapy
- Danish Research Council for Health and Disease
- Nordic Cancer Union [56-9257, 56-100-039102]
- Otto Christensen Foundation
- United States National Institutes of Health (NIH) [R01-GM28157, U01 GM61388]
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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/m(2); 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. (Blood. 2009; 113: 6077-6084)
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