We reported that children with B-progenitor-cell acute lymphoblastic leukemia (BpALL) treated in the early 1980s whose lymphoblasts accumulated high levels of methotrexate (MTX) and of methotrexate polyglutamates (MTXPGs) in vitro had an improved 5-year event-free survival (EFS) (65% (standard error (s.e.) 12%) vs 22% (s.e. 9%)). We repeated this study in children with BpALL treated in the early 1990s. The major change in treatment was the addition of 12 24-h infusions of 1 g/M 2 MTX with leucovorin rescue (IDMTX). In 87 children treated on Pediatric Oncology Group (POG) study 9005 and POG 9006, the 5-year EFS for those whose lymphoblasts accumulated high levels of MTX and MTXPGs (79.2%, s.e. 8.3%) was not significantly different from that of patients with lesser accumulation of MTX and MTXPGs (77.7%, s.e. 5.4%). These findings support the notion that higher dose MTX therapy has contributed to increased cure, particularly for patients whose lymphoblasts accumulate the drug less well.

No abstract

Levels of accumulation of methotrexate polyglutamates were measured in vitro in lymphoblasts obtained at diagnosis from children with B-progenitor cell acute lymphoblastic leukemia (pro-B ALL). They were compared to numerical and structural chromosomal abnormalities present in these leukemic cells. In a series of 95 patients, the percent with high lymphoblast methotrexate polyglutamate levels increased with the increase in modal number of total chromosomes (p<0.001). Thus, lymphoblast methotrexate polyglutamate accumulation appeared to be closely linked to the extent of hyperdiploidy in childhood pro-B ALL. Lymphoblasts from 35 (88%) of the 40 children with hyperdiploid (>50 chromosomes) and 23 (88%) of 26 with hyperdiploid (DNA Index >1.16) pro-B ALL accumulated high levels of methotrexate polyglutamate, suggesting that they were more sensitive to methotrexate cytotoxicity. While children with hyperdiploid (DNA Index >1.16) pro-B ALL have a good prognosis, those with trisomies of both chromosomes 4 and 10, almost all of whom are hyperdiploid, have an even better outcome. There was no significant difference in methotrexate polyglutamate levels in lymphoblasts from 19 children with and 21 without trisomies of both chromosomes 4 and 10 (p = 0.25). The improved response to multi-agent chemotherapy conferred by the presence of trisomies of both chromosomes 4 and 10 in such patients may be due to increased sensitivity of their lymphoblasts to one or more anti-leukemic agents in addition to methotrexate.