Blast cell methotrexate-polyglutamate accumulation in vivo differs by lineage, ploidy, and methotrexate dose in acute lymphoblastic leukemia.
High-dose methotrexate (HDMTX) is a component of most treatment protocols for childhood acute lymphoblastic leukemia (ALL), yet recent studies of receptor-mediated transport and saturable polyglutamylation have questioned its rationale. To investigate this in vivo, methotrexate and its active polyglutamated metabolites (MTX-PG) were measured in bone marrow blasts obtained from 101 children randomized to single-agent therapy with either HDMTX (1 g/m2 per 24 h i.v., n = 47) or low-dose MTX (LDMTX, 30 mg/m2 by mouth every 6 h x 6, n = 54), before remission induction therapy. Blast concentrations of total MTX-PGs (median 460 vs 1380 pmol/10(9) cells) and of long-chain MTX-glu4-6 were both significantly higher after HDMTX (P < 0.001). With either treatment, MTX-PGs were significantly higher in B-lineage blasts than in T-lineage blasts (LDMTX P = 0.001, HDMTX P = 0.03). In a multiple regression analysis of B-lineage ALL, blast MTX-PG was significantly related to MTX dose (or plasma MTX concentration), lymphoblast ploidy (hyperdiploid > nonhyperdiploid), and percentage S-phase. This is the first evidence that HDMTX achieves higher MTX-PG concentrations in ALL blasts in vivo, establishing a rationale for HDMTX in the treatment of childhood ALL, especially T-lineage or nonhyperdiploid B-lineage ALL, disease characteristics associated with a poor prognosis on conventional therapy.
Synold
T W
TW
Hematology-Oncology, Department, St. Jude Children's Research Hospital, Memphis, Tennessee.
Relling
M V
MV
Boyett
J M
JM
Rivera
G K
GK
Sandlund
J T
JT
Mahmoud
H
H
Crist
W M
WM
Pui
C H
CH
Evans
W E
WE
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D011003:Ploidies; D011099:Polyglutamic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000378:metabolism*
D011099:Polyglutamic Acid; C014085:methotrexate polyglutamate; D008727:Methotrexate