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

• Published in: Leukemia Vol. 20; no. 11; pp. 1955 - 1962
• Main Authors: SKARBY, T. V. Ch, ANDERSON, H, HELDRUP, J, KANERVA, J. A, SEIDEL, H, SCHMIEGELOW, K
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 01-11-2006; Nature Publishing Group
• Subjects: Acute lymphoblastic leukemia; Antimetabolites, Antineoplastic - administration & dosage; Biological and medical sciences; Bone marrow; Cancer and Oncology; Cancer och onkologi; Case-Control Studies; Child; Child, Preschool; Children; Clinical Medicine; Cohort analysis; Confidence intervals; Disease-Free Survival; Dosage; Drug dosages; Drug Interactions; Epidemiology; Female; General aspects; Hematologic and hematopoietic diseases; Hematology; Humans; Klinisk medicin; Leucovorin - administration & dosage; Leucovorin - adverse effects; Leukemia; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Logarithms; Lymphatic leukemia; Male; Medical and Health Sciences; Medical sciences; Medicin och hälsovetenskap; Methotrexate; Methotrexate - administration & dosage; Oncology; Patients; Pediatrics; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma - epidemiology; Public health. Hygiene; Public health. Hygiene-occupational medicine; Registries; Regression analysis; Risk; Risk Factors; Risk groups; Secondary Prevention; Statistical analysis; Vitamin B Complex - administration & dosage; Vitamin B Complex - adverse effects; Denmark; Sweden; Norway; Finland; Human; Antineoplastic agent; Relapse; Cure; Acute; Acute leukemia; Malignant hemopathy; Calcium folinate; Lymphoid neoplasm; Epidemiology; Antifolate; Treatment; Antimetabolic; Lymphoproliferative syndrome; Risk factor; relapse risk; childhood ALL; Acute lymphocytic leukemia; high-dose methotrexate; Methotrexate; leucovorin; High dose; Child
• ISSN: 0887-6924; 1476-5551; 1476-5551
• DOI: 10.1038/sj.leu.2404404

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.