Methotrexate Polyglutamation May Lack Prognostic Significance in Children With B-Cell Precursor Acute Lymphoblastic Leukemia Treated With Intensive Oral Methotrexate

Abstract

The purpose of this study was to determine if a correlation exists between clinical outcome and accumulation and polyglutamation of methotrexate by lymphoblasts in vitro in children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL). The amount of accumulated methotrexate and of long-chain methotrexate polyglutamates (MTXPG3–7) by lymphoblasts was determined in 52 children newly diagnosed with BCP-ALL after incubation with 1 μmol/L [3H]MTX for 24 hours in vitro. All patients then received intensive multiagent chemotherapy that used divided-dose oral methotrexate during consolidation and intensive continuation and standard oral weekly methotrexate during maintenance. Eight patients had a bone marrow relapse at a median of 40.4 months (range 18.5–48.3 months) after diagnosis. The median follow-up for the remaining 44 patients is 69.0 months (range 22–92.8 months). There was no significant difference in the amount of accumulated methotrexate (1450.0 ± 896.3 vs. 640 ± 472.5 pmol/109 cells) or of accumulated MTXPG3–7 (1450.0 ± 919.4 vs. 617.4 ± 482.7 pmol/109 cells) (median ± semi-interquartile ranges) between patients who relapsed and those who remained in continuous complete remission. The estimated 5-year event-free survival rate for patients whose lymphoblasts accumulated more than 500 pmol MTXPG3–7/109 cells was 80.0% ± 7.3% versus 90.5% ± 6.4% for those whose lymphoblasts accumulated less than 500 pmol MTXPG3–7/109 cells. In the context of effective prolonged divided-dose oral methotrexate-based therapy in the treatment of BCP-ALL, methotrexate accumulation and polyglutamation no longer seem to have prognostic significance.