Infants with acute lymphoblastic leukemia: no evidence for high methotrexate resistance

Abstract

CORRESPONDENCEInfants with acute lymphoblastic leukemia: no evidence for high methotrexate resistance Leukemia (2002) 16, 949-951. DOI: 10.1038/sj/leu/2402491 TO THE EDITORThe antifolate methotrexate (MTX) has contributed significantly to the great improvement in overall survival and central nervous system prophylaxis in patients with acute lymphoblastic leukemia (ALL) in the past 50 years. After transport into the cell, MTX is polyglutamylated with multiple glutamate residues to MTX-polyglutamates (MTXPGs), which have superior intracellular retention. Cellular resistance to MTX might contribute to treatment failure in childhood ALL. C/preB-lineage ALL (у1 year) has a favorable prognosis and is in vitro more sensitive to MTX in the TSIA (short exposure) than T-lineage ALL. 1 C/preB ALL also have more efficient accumulation of (long chain) MTX-PGs compared to T-ALL and acute myeloid leukemia. [2][3][4] ALL diagnosed in infants less than 1 year of age is closely associated with a number of biological features, especially MLL gene (at chromosome 11q23) rearrangements and the proB (CD10-negative precursor B) immunophenotype, and still have a poor outcome. 5 So far, little is known of the pharmacodynamics of MTX in infants with ALL, and the relationship thereof with the other biological characteristics frequent in infant ALL. The question then arises whether the poor prognosis of infants with ALL is associated with cellular resistance to MTX.Lymphoblasts isolated from bone marrow or peripheral blood of 47 infants Ͻ1 year with newly diagnosed, untreated ALL from the Dutch Childhood Leukemia Study Group (DCLSG), the German COALL study group, the Berlin-Frankfurt-Mü nster (BFM) Study Group and the Pediatric Oncology Group cell bank (POG) were used for this portion of the study. The distribution of important clinical parameters within the infants showed a high association with the proB immunophenotype and translocations involving the MLL gene (11q23, determined by karyotype, RT-PCR, and/or Southern blotting), and significantly higher white blood cell counts at presentation, features typical of infants with ALL. Since MTX cytotoxicity on primary ALL cells cannot be measured with the MTT assay, we used the thymidylate synthase (TS) inhibition assay (TSIA), which correlates strongly with IC 50 values for MTX obtained for cell lines in the MTT assay. 1 These data were expressed as the concentration of MTX necessary to inhibit 50% of the TS activity (TSI 50 ), compared to the controls incubated without MTX. A large range of TSI 50 values for MTX was observed for both the short (3 h, followed by 18 h drug-free) and continuous (21 h) exposure conditions. Infant ALL cells did not differ in MTX sensitivity from those of a reference group of 109 common(c)/preB ALL patients older than 1 year, with overlapping ranges and similar median TSI 50 values (Table 1, Figure 1a and b). The total in vitro accumulation of MTX and the pharmacologically important long-chain polyglutamates (MTX-PG 4-6 , analyzed by HPLC) 4 did not differ signifi...

In vitro drug-resistance profile in infant acute lymphoblastic leukemia in relation to age, MLL rearrangements and immunophenotype

“…24 However, using the in situ thymidylate synthase inhibition assay, we have no evidence for high resistance to methotrexate in infant ALL. 25 These results confirm our earlier findings in a small number of infants o1 year of age. 7 Importantly, we also confirmed in this larger series that infant ALL cells are highly sensitive to AraC, and, in addition, showed that the same was true for 2-CdA.…”

Influence of wild-type MLL on glucocorticoid sensitivity and response to DNA-damage in pediatric acute lymphoblastic leukemia

“…In contrast however, no protective effect of MLL -knockdown was seen for ARAC or MTX in the present study. Whilst one might expect that suppression of DNA-damage response pathways should increase resistance to both of these agents, it is interesting to note that, unlike GCs, elevated resistance to neither of these drugs is associated with MLL -rearrangement [32,33]; infants in fact are known to be generally more sensitive to ARAC [8,32]. There may therefore be some unexplained insult specificity in the role of MLL in mediating responses to DNA-damage.…”

Pharmacokinetics of high‐dose methotrexate in infants treated for acute lymphoblastic leukemia

“…For methotrexate (MTX), however, no difference in drug resistance was found 6. Variation in drug disposition with age might be another factor, since important changes in body composition and in the drug eliminating capacity of liver and kidneys take place during the first year of life.…”