1. ¹Department of Pediatrics, Lund University Hospital, Lund, Sweden
2. ²Department of Clinical Pharmacology, Lund University Hospital, Lund, Sweden
3. ³Department of Cancer Epidemiology, Lund University Hospital, Lund, Sweden
4. ⁴Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland
5. ⁵Department of Pediatrics, University Hospital of Trondheim, Trodheim, Norway
6. ⁶Pediatric Clinic, University Hospital of Copenhagen, Copenhagen, Denmark

Correspondence: Dr TVch Skärby, Departments of Clinical Pharmacology and Pediatric Oncology, Lund University Hospital, Lund SE 221 85, Sweden. E-mail: tor.skarby@med.lu.se

Received 14 June 2006; Revised 8 August 2006; Accepted 9 August 2006; Published online 21 September 2006.

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.