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Therapy

High leucovorin doses during high-dose methotrexate treatment may reduce the cure rate in childhood acute lymphoblastic leukemia

Leukemia volume 20, pages 1955–1962 (2006)Cite this article

Abstract

We explored the relationship between time to relapse and different exposure variables (serum methotrexate (S-MTX) 23, 36 and 42 h after start of administration, MTX elimination time and leucovorin (LV) dose) during high-dose MTX (HDM) treatment of 445 children with acute lymphoblastic leukemia. MTX was infused at 5 g/m2 (non-high risk) or 8 g/m2 (high risk) over 24 h, 2–9 times per patient. LV rescue dose was adjusted according to the S-MTX concentration. Time from end of the last HDM to relapse was analyzed by Cox regression analysis with the logarithms of S-MTX and LV dose as exposures. The combined results from all risk groups suggest that high LV dose is related to higher risk for relapse. Doubling of the LV dose increased the relapse risk by 22% (95% confidence interval 1–49%, P=0.037). High LV doses correlated with high MTX levels at 23, 36 and 42 h and longer elimination time. The results suggest that high doses of LV increase the risk for relapse despite the fact that they were correlated with high MTX levels and longer MTX elimination time. The choice of MTX and LV doses may be regarded as an intricate balance between effect and counter-effect.

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References

  1. Ackland S, Schilsky R . High-dose methotrexate: a critical reappraisal. J Clin Oncol 1987; 5: 2017–2031.

    Article  CAS  Google Scholar 

  2. Evans WE, Crom WR, Abromowitch M, Dodge R, Look AT, Bowman WP et al. Clinical pharmacodynamics of high-dose methotrexate in acute lymphocytic leukaemia. Identification of a relation between concentration and effect. N Engl J Med 1986; 314: 471–477.

    Article  CAS  Google Scholar 

  3. Borsi JD, Moe PJ . Systemic clearance of methotrexate in the prognosis of acute lymphoblastic leukemia in children. Cancer 1987; 60: 3020–3024.

    Article  CAS  Google Scholar 

  4. Camitta B, Mahoney D, Leventhal B, Lauer SJ, Shuster JJ, Adair S et al. Intensive intravenous methotrexate and mercaptopurine treatment of higher-risk non-T, non-B acute lymphocytic leukemia: a Pediatric Oncology Group Study. J Clin Oncol 1994; 12: 1383–1389.

    Article  CAS  Google Scholar 

  5. Seidel H, Nygaard R, Moe PJ, Jacobsen G, Lindqvist B, Slørdal L . On the prognostic value of systemic methotrexate clearance in childhood acute lymphocytic leukemia [see comments]. Leuk Res 1997; 21: 429–434.

    Article  CAS  Google Scholar 

  6. Evans WE, Relling MV, Rodman JH, Crom WR, Boyett JM, Pui CH . Conventional compared with individualized chemotherapy for childhood acute lymphoblastic leukemia. N Engl J Med 1998; 338: 499–505.

    Article  CAS  Google Scholar 

  7. Pinedo HM, Chabner BA . Role of drug concentration, duration of exposure, and endogenous metabolites in determining methotrexate cytotoxicity. Cancer Treat Rep 1977; 61: 709–715.

    CAS  PubMed  Google Scholar 

  8. Wolfrom C, Hartmann R, Fengler R, Bruhmuller S, Ingwersen A, Henze G . Randomized comparison of 36-hour intermediate-dose versus 4-hour high-dose methotrexate infusions for remission induction in relapsed childhood acute lymphoblastic leukemia [see comments]. J Clin Oncol 1993; 11: 827–833.

    Article  CAS  Google Scholar 

  9. Boarman DM, Baram J, Allegra CJ . Mechanism of leucovorin reversal of methotrexate cytotoxicity in human MCF-7 breast cancer cells. Biochem Pharmacol 1990; 40: 2651–2660.

    Article  CAS  Google Scholar 

  10. Koizumi S, Ueno Y, Ohno I, Ichihara T, Tamaru Y, Matsukawa H . Reversal of methotrexate cytotoxicity to human bone marrow cells and leukemic K562 cells by leucovorin: methotrexate polyglutamates formation as a possible important factor. Jap J Cancer Res 1990; 81: 1162–1167.

    Article  CAS  Google Scholar 

  11. Graf N, Jost W, Muller J, Keller HE, Sitzmann FC . [The effect of methotrexate pharmacokinetics and of leucovorin rescue on the prognosis of osteosarcoma]. Klinische Padiatrie 1990; 202: 340–346.

    Article  CAS  Google Scholar 

  12. Borsi JD, Wesenberg F, Stokland T, Moe PJ . How much is too much? Folinic acid rescue dose in children with acute lymphoblastic leukaemia. Eur J Cancer 1991; 27: 1006–1009.

    Article  CAS  Google Scholar 

  13. Sterba J, Dusek L, Demlova R, Valik D . 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; 52: 692–700 [E-pub 2006 Feb 2].

    Article  CAS  Google Scholar 

  14. Gustafsson G, Schmiegelow K, Forestier E, Clausen N, Glomstein A, Jonmundsson G et al. Improving outcome through two decades in childhood ALL in the Nordic countries: the impact of high-dose methotrexate in the reduction of CNS irradiation. Leukemia 2000; 14: 2267–2275.

    Article  CAS  Google Scholar 

  15. Schmiegelow K, Björk O, Glomstein A, Gustafsson G, Keiding N, Kristinsson J et al. Intensification of mercaptopurine/methotrexate maintenance chemotherapy may increase the risk of relapse for some children with acute lymphoblastic leukemia. J Clin Oncol 2003; 21: 1332–1339.

    Article  CAS  Google Scholar 

  16. Nygaard U, Schmiegelow K . Dose reduction of coadministered 6-mercaptopurine decreases myelotoxicity following high-dose methotrexate in childhood leukemia. Leukemia 2003; 17: 1344–1348.

    Article  CAS  Google Scholar 

  17. Farber S, Diamond LK, Mercer RD, Sylvester RF, Wolff JA . Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid (aminopterin). N Engl J Med 1948; 238: 787–793.

    Article  CAS  Google Scholar 

  18. Kager L, Cheok M, Yang W, Zaza G, Cheng Q, Panetta JC et al. Folate pathway gene expression differs in subtypes of acute lymphoblastic leukemia and influences methotrexate pharmacodynamics. J Clin Invest 2005; 115: 110–117.

    Article  CAS  Google Scholar 

  19. Whitehead VM, Payment C, Cooley L, Lauer SJ, Mahoney DH, Shuster JJ et al. The association of the TEL-AML1 chromosomal translocation with the accumulation of methotrexate polyglutamates in lymphoblasts and with ploidy in childhood B-progenitor cell acute lymphoblastic leukemia: a Pediatric Oncology Group Study. Leukemia 2001; 15: 1081–1088.

    Article  CAS  Google Scholar 

  20. Whitehead VM, Vuchich MJ, Cooley LD, Lauer SJ, Mahoney DH, Shuster JJ et al. Accumulation of methotrexate polyglutamates, ploidy and trisomies of both chromosomes 4 and 10 in lymphoblasts from children with B-progenitor cell acute lymphoblastic leukemia: a Pediatric Oncology Group Study. Leuk Lymphoma 1998; 31: 507–519.

    Article  CAS  Google Scholar 

  21. Whitehead VM, Vuchich MJ, Lauer SJ, Mahoney D, Carroll AJ, Shuster JJ et al. Accumulation of high levels of methotrexate polyglutamates in lymphoblasts from children with hyperdiploid (greater than 50 chromosomes) B-lineage acute lymphoblastic leukemia: a Pediatric Oncology Group Study. Blood 1992; 80: 1316–1323.

    CAS  Google Scholar 

  22. Cohen IJ . Defining the appropriate dosage of folinic acid after high-dose methotrexate for childhood acute lymphatic leukemia that will prevent neurotoxicity without rescuing malignant cells in the central nervous system [see comment]. J Pediatric Hematol/Oncol 2004; 26: 156–163.

    Article  Google Scholar 

  23. Mantadakis E, Smith AK, Kamen BA . Ratio of methotrexate to folate uptake by lymphoblasts in children with B-lineage acute lymphoblastic leukemia: a pilot study. J Pediatric Hematol/Oncol 2000; 22: 221–226.

    Article  CAS  Google Scholar 

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Acknowledgements

This study has received financial support from the Children's Cancer Foundation of Sweden, the Swedish Cancer Society, Crafoord's, B Kamprad's, Gyllenstiern's Krapperup and the Lund University Hospital Foundations.

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Authors and Affiliations

  1. Department of Pediatrics, Lund University Hospital, Lund, Sweden

    T V Ch Skärby & J Heldrup

  2. Department of Clinical Pharmacology, Lund University Hospital, Lund, Sweden

    T V Ch Skärby

  3. Department of Cancer Epidemiology, Lund University Hospital, Lund, Sweden

    H Anderson

  4. Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland

    J A Kanerva

  5. Department of Pediatrics, University Hospital of Trondheim, Trodheim, Norway

    H Seidel

  6. Pediatric Clinic, University Hospital of Copenhagen, Copenhagen, Denmark

    K Schmiegelow

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  1. T V Ch Skärby
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  2. H Anderson
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  5. H Seidel
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  6. K Schmiegelow
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on behalf of the Nordic Society of Paediatric Haematology and Oncology (NOPHO)

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Correspondence to T V Ch Skärby.

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Skärby, T., 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 20, 1955–1962 (2006). https://doi.org/10.1038/sj.leu.2404404

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