Methotrexate polyglutamation may lack prognostic significance in children with B-cell precursor acute lymphoblastic...

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 (MTXPG(3-7)) by lymphoblasts was determined in 52 children newly diagnosed with BCP-ALL after incubation with 1 micromol/L [(3)H]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/10 cells) or of accumulated MTXPG (1450.0 +/- 919.4 vs. 617.4 +/- 482.7 pmol/10(9) 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 MTXPG(3-7)/10(9) cells was 80.0% +/- 7.3% versus 90.5% +/- 6.4% for those whose lymphoblasts accumulated less than 500 pmol MTXPG(3-7)/10(9) 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.