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

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.

Prospective analysis of TEL/AML1-positive patients treated on Dana-Farber Cancer Institute Consortium Protocol 95-01

“…Such decreases have led to one speculation that these patients may be better treated by the increased doses of methotrexate used in these protocols. 24 In the present report, there was no difference in EFS among patients who were TEL/AML1-positive with respect to the type of asparaginase preparation received. Erwinia asparaginase has a shorter half-life than E coli asparaginase and has been associated with higher relapse rates when used instead of E coli asparaginase.…”

Resistance to antifolates

“…In the case of the TEL-AML1 translocation, associated with an excellent clinical outcome, the level of MTX polyglutamates was lower, and hyperdiploidy was rare, in lymphoblasts from patients with, as compared to those without, this translocation (Whitehead et al, 2001). The excellent survival of patients with trisomy of chromosomes 4 and 10 was not associated with augmentation of the accumulation of MTX polyglutamates (Whitehead et al, 1998b). This lack of sole dependence of treatment outcome on polyglutamation of MTX is not unexpected, since all regimens contain antineoplastics in addition to MTX.…”

“…For instance, children with B-progenitor ALL with less than 50 chromosomes and translocations of the short arm of chromosome 12 have low-level accumulation of MTX polyglutamates and long-term survival (Whitehead et al, 1998a). In the case of the TEL-AML1 translocation, associated with an excellent clinical outcome, the level of MTX polyglutamates was lower, and hyperdiploidy was rare, in lymphoblasts from patients with, as compared to those without, this translocation (Whitehead et al, 2001).…”

“…For instance, RFC expression is far greater in hyperdiploid than nonhyperdiploid pre-B-or B-lineage lymphoblasts in ALL (Whitehead et al, 1992(Whitehead et al, , 1998bZhang et al, 1998;Belkov et al, 1999); but there was no difference in the expression between nonhyperdiploid B-versus T-lineage lymphoblasts (Belkov et al, 1999). RFC message (Zhang et al, 1998;Belkov et al, 1999) and MTX polyglutamate accumulation (Belkov et al, 1999) correlated with the number of copies of chromosome 21.…”

High leucovorin doses during high-dose methotrexate treatment may reduce the cure rate in childhood acute lymphoblastic leukemia

“…Thus, it is well known that high-hyperdiploid ALL has a high propensity and that T-cell disease has a low propensity for MTX polyglutamation. [18][19][20][21] High-hyperdiploid ALL is characterized by a median age of 3-4 years and a low white cell count at Leucovorin, methotrexate and relapse risk in childhood ALL TVCh Skärby et al diagnosis, and would thus preferentially be grouped as SR patients, whereas all T-cell patients were classified in the HR/ VHR group. Thus, it is possible that low S-MTX concentration would be most crucial in the SR group, whereas high LV doses would be most deleterious in the HR group.…”