Abstract
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.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
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): 1003–26
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): 718–27
Wald NJ, Law MR, Morris JK, et al. Quantifying the effect of folic acid. Lancet 2001 Dec 15; 358(9298): 2069–73
Leukemia facts and statistics [online]. Available from URL: http://www.leukemia-lymphoma.org/all_page?item_id=9346#_incidencebyage [Accessed 2010 Jul 7]
Factsheet: childhood cancer [online]. Available from URL: http://www.cancer.gov/cancertopics/factsheet/Sites-Types/childhood [Accessed 2010 Jul 7]
Canadian Cancer Society’s Steering Committee: Canadian cancer statistics 2008. Toronto (ON): Canadian Cancer Society, 2008
Pui CH, Robison LL, Look AT. Acute lymphoblastic leukaemia. Lancet 2008 Mar 22; 371(9617): 1030–43
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): 786–92
Cunningham L, Aplenc R. Pharmacogenetics of acute lymphoblastic leukemia treatment response. Expert Opin Pharmacother 2007 Oct; 8(15): 2519–31
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): 3692–700
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): 717–20
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): 692–700
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): 1955–62
POGO. Pediatric Oncology Group of Ontario database. Toronto (ON): Pediatric Oncology Group of Ontario, 2006
World Health Organization. Health statistics and health information systems: mortality data [online]. Available from URL: http://www.who.int/healthinfo/statistics/mortality/en/index.html [Accessed 2010 May 27]
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): 88–91
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): 2809–15
World Health Organization. International classification of diseases, 10th ed. [online]. Available from URL: http://apps.who.int/classifications/apps/icd/icd10online [Accessed 2010 Feb 17]
World Health Organization. WHO Statistical Information System (WHOSIS): download the detailed data files of the WHO Mortality Database [online]. Available from URL: http://www.who.int/whosis/mort/download/en/index.html [Accessed 2010 Oct 18]
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): 2532–6
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: 761–8
Acknowledgements
No sources of funding were used to conduct this study or prepare this manuscript. Deborah Kennedy is supported by a career development grant from the SickKids Foundation. Mark Greenberg holds the POGO Chair in Childhood Cancer Control at the University of Toronto. Gideon Koren holds the Research Leadership for Better Pharmacotherapy During Pregnancy and Breastfeeding (The Hospital for Sick Children) and the Ivey Chair in Molecular Toxicology (University of Western Ontario). Sandy Grupp has no conflicts of interest to declare that are directly relevant to the content of this study.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kennedy, D.A., Grupp, S., Greenberg, M. et al. Folate Fortification and Survival of Children with Acute Lymphoblastic Leukemia. Pediatr-Drugs 13, 193–196 (2011). https://doi.org/10.2165/11588130-000000000-00000
Published:
Issue Date:
DOI: https://doi.org/10.2165/11588130-000000000-00000