ACCUMULATION OF METHOTREXATE POLYGLUTAMATES IN LYMPHOBLASTS IS A DETERMINANT OF ANTILEUKEMIC EFFECTS IN-VIVO - A RATIONALE FOR HIGH-DOSE METHOTREXATE

Methotrexate (MTX) is one of the most widely used drugs for the treatm ent of childhood acute lymphoblastic leukemia (ALL) and is commonly gi ven in high doses, However, the rationale for high-dose MTX (HDMTX) ha s been challenged recently, To determine whether higher MTX polyglutam ate (MTXPG) concentrations in ALL blasts translate into greater antile ukemic effects, 150 children with newly diagnosed ALL were randomized to initial treatment with either HDMTX (1,000 mg/m(2) intravenously ov er 24 h) or lower-dose MTX (30 mg/m(2) by mouth every 6 h x 6), ALL bl asts accumulated higher concentrations of MTXPG and long-chain MTXPG ( MTXPG(LC)) after HDMTX (P < 0.00001), Of 101 patients evaluable for pe ripheral blast cytoreduction, MTXPG concentrations were higher in pati ents whose blast count decreased within 24 h (P = 0.005) and in those who had no detectable circulating blasts within 4 days (P = 0.004), Th e extent of inhibition of de novo purine synthesis in ALL blasts was s ignificantly related to the blast concentration of MTXPG(LC) (IC95% = 483 pmol/l0(9) blasts), The percentage of patients with 44-h MTXPG, ex ceeding the IC95% was greater after HDMTX (81%) than LDMTX (46%, P < 0 .0001). These data indicate that higher blast concentrations of MTXPG are associated with greater antileukemic effects, establishing a stron g rationale for HDMTX in the treatment of childhood ALL.