Pediatric Drugs

, Volume 13, Issue 3, pp 193–196

Folate Fortification and Survival of Children with Acute Lymphoblastic Leukemia

  • Deborah A. Kennedy
  • Sandy Grupp
  • Mark Greenberg
  • Gideon Koren
Original Research Article


Background: The antifolate drug methotrexate is a mainstay of treatment for children diagnosed with acute lymphoblastic leukemia (ALL). There have been concerns regarding the impact of folate fortification on the efficacy of methotrexate therapy and hence treatment outcomes of ALL.

Objective: The objective of this study was to evaluate whether folate fortification has been associated with a higher incidence of adverse outcomes in children with ALL.

Methods: In a retrospective, population-based study, using data from the Pediatric Oncology Group of Ontario (POGO), Ontario, Canada, and the WHO, we examined yearly and population-adjusted mortality rates in Canada, the US, and several European countries.

Results: Our analysis demonstrates that there has been a decreasing trend in ALL mortality numbers and rates between 1999 and 2005 in the US and Canada, in a similar degree to those in European countries where folate fortification is not implemented.

Conclusion: These data suggest that folate fortification does not appear to have caused an increase in therapeutic failures in children with ALL.


  1. 1.
    Wilson RD, Johnson JA, Wyatt P, et al. Pre-conceptional vitamin/folic acid supplementation 2007: the use of folic acid in combination with a multivitamin supplement for the prevention of neural tube defects and other congenital anomalies. J Obstet Gynaecol Can 2007 Dec; 29(12): 1003–26PubMedGoogle Scholar
  2. 2.
    Pfeiffer CM, Johnson CL, Jain RB, et al. Trends in blood folate and vitamin B-12 concentrations in the United States, 1988–2004. Am J Clin Nutr 2007 Sep; 86(3): 718–27PubMedGoogle Scholar
  3. 3.
    Wald NJ, Law MR, Morris JK, et al. Quantifying the effect of folic acid. Lancet 2001 Dec 15; 358(9298): 2069–73PubMedCrossRefGoogle Scholar
  4. 4.
    Leukemia facts and statistics [online]. Available from URL: [Accessed 2010 Jul 7]
  5. 5.
    Factsheet: childhood cancer [online]. Available from URL: [Accessed 2010 Jul 7]
  6. 6.
    Canadian Cancer Society’s Steering Committee: Canadian cancer statistics 2008. Toronto (ON): Canadian Cancer Society, 2008Google Scholar
  7. 7.
    Pui CH, Robison LL, Look AT. Acute lymphoblastic leukaemia. Lancet 2008 Mar 22; 371(9617): 1030–43PubMedCrossRefGoogle Scholar
  8. 8.
    Petra BG, Janez J, Vita D. Gene-gene interactions in the folate metabolic pathway influence the risk for acute lymphoblastic leukemia in children. Leuk Lymphoma 2007 Apr; 48(4): 786–92PubMedCrossRefGoogle Scholar
  9. 9.
    Cunningham L, Aplenc R. Pharmacogenetics of acute lymphoblastic leukemia treatment response. Expert Opin Pharmacother 2007 Oct; 8(15): 2519–31PubMedCrossRefGoogle Scholar
  10. 10.
    Dulucq S, St-Onge G, Gagne V, et al. DNA variants in the dihydrofolate reductase gene and outcome in childhood ALL. Blood 2008 Apr 1; 111(7): 3692–700PubMedCrossRefGoogle Scholar
  11. 11.
    de Jonge R, Hooijberg JH, van Zelst BD, et al. Effect of polymorphisms in folate-related genes on in vitro methotrexate sensitivity in pediatric acute lymphoblastic leukemia. Blood 2005 Jul 15; 106(2): 717–20PubMedCrossRefGoogle Scholar
  12. 12.
    Sterba J, Dusek L, Demlova R, et al. Pretreatment plasma folate modulates the pharmacodynamic effect of high-dose methotrexate in children with acute lymphoblastic leukemia and non-Hodgkin lymphoma: “folate overrescue” concept revisited. Clin Chem 2006 Apr; 52(4): 692–700PubMedCrossRefGoogle Scholar
  13. 13.
    Skarby TV, Anderson H, Heldrup J, et al. High leucovorin doses during high-dose methotrexate treatment may reduce the cure rate in childhood acute lymphoblastic leukemia. Leukemia 2006 Nov; 20(11): 1955–62PubMedCrossRefGoogle Scholar
  14. 14.
    POGO. Pediatric Oncology Group of Ontario database. Toronto (ON): Pediatric Oncology Group of Ontario, 2006Google Scholar
  15. 15.
    World Health Organization. Health statistics and health information systems: mortality data [online]. Available from URL: [Accessed 2010 May 27]
  16. 16.
    Greenberg ML, Barr RD, DiMonte B, et al. Childhood cancer registries in Ontario, Canada: lessons learned from a comparison of two registries. Int J Cancer 2003 May 20; 105(1): 88–91PubMedCrossRefGoogle Scholar
  17. 17.
    Agha M, DiMonte B, Greenberg M, et al. Incidence trends and projections for childhood cancer in Ontario. Int J Cancer 2006 Jun 1; 118(11): 2809–15PubMedCrossRefGoogle Scholar
  18. 18.
    World Health Organization. International classification of diseases, 10th ed. [online]. Available from URL: [Accessed 2010 Feb 17]
  19. 19.
    World Health Organization. WHO Statistical Information System (WHOSIS): download the detailed data files of the WHO Mortality Database [online]. Available from URL: [Accessed 2010 Oct 18]
  20. 20.
    Te Poele EM, de Bont ES, Marike Boezen H, et al. Dexamethasone in the maintenance phase of acute lymphoblastic leukaemia treatment: is the risk of lethal infections too high? Eur J Cancer 2007 Nov; 43(17): 2532–6PubMedCrossRefGoogle Scholar
  21. 21.
    Hahn-Ast C, Glasmacher A, Mückter S, et al. Overall survival and fungal infection-related mortality in patients with invasive fungal infection and neutropenia after myelosuppressive chemotherapy in a tertiary care centre from 1995 to 2006. J Antimicrob Chemother 2010; 65: 761–8PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2011

Authors and Affiliations

  • Deborah A. Kennedy
    • 1
    • 2
  • Sandy Grupp
    • 1
  • Mark Greenberg
    • 3
    • 4
  • Gideon Koren
    • 1
    • 2
  1. 1.The Motherisk ProgramThe Hospital for Sick ChildrenTorontoCanada
  2. 2.Leslie Dan Faculty of PharmacyUniversity of TorontoTorontoCanada
  3. 3.Pediatric Oncology Group of Ontario (POGO)TorontoCanada
  4. 4.Department of Pediatrics, Faculty of MedicineUniversity of TorontoTorontoCanada
  5. 5.Division of Clinical Pharmacology/ToxicologyHospital for Sick ChildrenTorontoCanada

Personalised recommendations