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. 2009 Jun 11;113(24):6077-84.
doi: 10.1182/blood-2008-11-187880. Epub 2009 Feb 17.

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

Kjeld Schmiegelow  1 , 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
Collaborators, Affiliations

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

Kjeld Schmiegelow et al. Blood. .

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.

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Figures

Figure 1
Figure 1
Flow chart of patient inclusion or exclusion. Patients (n = 545) participated in the randomized MTX/6MP maintenance therapy study or they developed SMNs and had their data on maintenance therapy 6MP/MTX dosage and blood counts retrieved. Data on both 6MP/MTX doses and blood counts were not available for all the 545 patients. TPMT phenotyping (n = 524) or genotyping or both were available for 609 patients.
Figure 2
Figure 2
Cumulative risk of a second malignant neoplasm (SMN) by risk group for patients who did not receive a transplant in first remission. Standard risk (SR) was 2.4% ± 0.7%, intermediate risk (IR) was 1.2% ± 0.7%, and higher risk (HR) was 0.3% ± 0.3% (P = .007). ALL indicates acute lymphoblastic leukemia.
Figure 3
Figure 3
Red blood cell thiopurine methyltransferase activity (TPMT) for patients who developed a second malignant neoplasm compared with patients who did not. Nine patients developed a SMN (right) compared with 515 patients who did not (left). Each dot represents 1 patient (median, 12.1 vs 18.1 IU/mL; P = .02).
See this image and copyright information in PMC

Comment in

  • Maintenance loses its innocence.
    Pulsipher MA. Pulsipher MA. Blood. 2009 Jun 11;113(24):6041-2. doi: 10.1182/blood-2009-03-210500. Blood. 2009. PMID: 19520809 No abstract available.
  • On the malignant potential of thiopurine therapy.
    de Boer NK, van Asseldonk DP, van Bodegraven AA. de Boer NK, et al. Blood. 2009 Jun 11;113(24):6258; author reply 6258-9. doi: 10.1182/blood-2009-03-208413. Blood. 2009. PMID: 19520817 No abstract available.

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