Accumulation of methotrexate polyglutamates, ploidy and trisomies of both chromosomes 4 and 10 in lymphoblasts from children with B-progenitor cell acute lymphoblastic leukemia: a pediatric oncology group study

Levels of accumulation of methotrexate polyglutamates were measured in vitr o in lymphoblasts obtained at diagnosis from children with B-progenitor cel l 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 c hromosomes (p < 0.001). Thus, lymphoblast methotrexate polyglutamate accumu lation appeared to be closely linked to the extent of hyperdiploidy in chil dhood pro-B ALL, Lymphoblasts from 35 (88 %) of the 40 children with hyperd iploid (> 50 chromosomes) and 23 (88 %) of 26 with hyperdiploid (DNA Index > 1.16) pro-B ALL accumulated high levels of methotrexate polyglutamate, su ggesting that they were more sensitive to methotrexate cytotoxicity. While children with hyperdiploid (DNA Index > 1.16) pro-B ALL have a good prognos is, those with trisomies of both chromosomes 4 and 10, almost all of whom a re hyperdiploid, have an even better outcome. There was no significant diff erence in methotrexate polyglutamate levels in lymphoblasts from 19 childre n with and 21 without trisomies of both chromosomes 4 and 10 (p = 0.25). Th e improved response to multi-agent chemotherapy conferred by the presence o f trisomies of both chromosomes 4 and 10 in such patients may be due to inc reased sensitivity of their lymphoblasts to one or more anti-leukemic agent s in addition to methotrexate.