L'asparaginase and methotrexate combinations: clashes of empiric success and laboratory models?

In this issue of the journal Wacker and colleagues 1 present another analysis of the POG 8602 acute lymphoblastic leukemia (ALL) trial. There are already a number of prior publications detailing and comparing the outcomes of this 4-arm study. Owing to allergic reactions, nearly 76% of the 540 eligible patients switched from Escherichia coli to Erwinia asparaginase. Switching was associated with a younger age, white race, and standard risk ALL. However, multivariate analysis shows no correlation between the switch (or the timing of the switch) and event-free survival (EFS). Previous publications concerning this trial have shown that the 4 arms were equivalent. In contrast, other nonrandomized trials have suggested that the addition of asparaginase significantly improved EFS (Refs. 4, 5 in the Wacker et al article). The discussion in the current paper offers some explanations as to why the differences and what may be necessary to prove the value of this type of therapy. With the benefit of hindsight, what lessons have we learned? The 4 regimens in the POG 8602 trial were designed to test whether asparaginase or Cytosine Arabinoside (Ara-C) improved outcomes when added to a consolidation phase of therapy using an intermediate dose of MTX (1 g/m) given 6 times (weeks 7, 10, 13, 16, 19, and 22). EFS was 65% to 83% for different subgroups and there were no statistical differences between treatments. The next POG ALL protocols (9005/9006) changed the MTX dosing to every other week and increased the number of doses to 12. EFS for standard and higher risk subgroups was similar to the results for 8602 trials. Another regimen for standard risk patients in the 9005 trial used 180mg of MTX (30mg/m orally every 6h 6) without asparaginase every 2 weeks. EFS was also similar to those protocols using intermediate dose IV MTX. In the same time period, a pilot trial in Dallas-Fort Worth (DFW) evaluated divided dose oral MTX every other week, but in conjunction with asparaginase for 64 weeks (as opposed to MX alone). At last review, EFS at >7 years follow-up for both higher and standard risk patients in a second version of this protocol is 85% (personal communication). Moreover, another contemporary study showed that a major component of augmented therapy that improved survival in higher risk children was also a ‘‘Capizzi regimen. ’’ How do we reconcile laboratory data showing synergy or additive effects of MTX-asparaginase, the positive clinical correlations by some investigators, and the POG trials? The potential synergy of MTX-asparaginase was reported more than 30 years ago. The timing of drug administration was crucial. If asparaginase had trapped cells in G1 there could be less MTX uptake/metabolism and the S phase potency of the drug would be lost (ie, MTX was given too soon). However, as the cells treated with asparaginase recovered from the amino acid depletion, then there could be an increased uptake and effect of MTX (ie, if delivery timed correctly). On the basis of the empiric success, it is possible that the synergy seen with the MTXasparaginase in vitro is not relevant. That is, in patients each drug may kill cells the other could not, but there was no direct biochemical interaction. It is also possible that weekly asparaginase dosing after the MTX dose is not unreasonable, despite