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In Reply

Department of Paediatrics, Division of Haematology/Oncology; and the Department of Psychology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

Kimberly Kennedy

The Department of Psychology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

Ronnen Maze, Mark L. Greenberg, Sheila Weitzman, Johann K. Hitzler, Paul C. Nathan

Department of Paediatrics, Division of Haematology/Oncology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

We thank Dr Cohen for emphasizing the importance of adequate folinic acid rescue after the use of high-dose methotrexate in the management of childhood acute lymphoblastic leukemia for the prevention of neurotoxicity. It is important to recognize that neurotoxicity as defined in our study consisted of impairment of formally tested neurocognitive function after completion of therapy.¹ The identification of appropriate dosing levels of folinic acid for either of the doses of methotrexate used in our study was not the focus of our investigation. The folinic acid dose delivered did achieve sufficient concentrations in both the CSF and the brain substance to minimize neurotoxicity, but it is important to recognize that variability of achieved levels based on genetic polymorphism for the many enzymes involved in the disposition and excretion of methotrexate may also be relevant to the level of rescue needed. A recent article from Scandinavia² appears to give support to the contention that high folinic acid doses reduce the cure rate of childhood leukemia. Thus, the optimal dose of folinic acid that will prevent neurotoxicity without reducing the efficacy of methotrexate is unknown, and it is to be hoped that the pharmacogenomic studies underway at present will clarify this vexing issue. We are unable to comment at present on the cure rate for our patients without a separate analysis of the cohorts from which these patients were drawn.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The authors indicated no potential conflicts of interest.

ACKNOWLEDGMENTS

We are grateful for funding from the Hospital for Sick Children Leukemia/Lymphoma Group. Dr Mark Greenberg holds the Pediatric Oncology Group of Ontario Chair in Childhood Cancer Control at the University of Toronto.

REFERENCES

1. Spiegler BJ, Kennedy K, Maze R, et al: Comparison of long term neurocognitive outcomes in young children with acute lymphoblastic leukemia treated with cranial radiation or high-dose or very high-dose intravenous methotrexate. J Clin Oncol 24:3858-3864, 2006[Abstract/Free Full Text]

2. Skarby TV, Anderson H, Heldrup J, et al: High leukovorin doses during high-dose methotrexate treatment may reduce the cure rate in childhood acute lymphoblastic leukemia. Leukemia 20:1955-1962, 2006 [Epub 2006 Sep 21][CrossRef][Medline]

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Related Correspondence

• Comparison of Long-Term Neurocognitive Outcomes in Young Children With Acute Lymphatic Leukemia Treated With Cranial Radiation or High-Dose or Very High-Dose Intravenous Methotrexate
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  JCO 2007 25: 734-735 [Full Text]

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