PMID: 11037849

Issn Print: 0192-8562

Publication Date: 2000/09/01


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PROGNOSTIC FACTORS IN ACUTE LYMPHOBLASTIC LEUKEMIA

Paul S. Gaynon

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Excerpt

Much ink has been spilled in our professional journals describing the purely descriptive prognostic significance of age and white blood cell count (1), “lymphomatous features”(2), blast morphology (3), immunophenotype (4), ploidy (5), and chromosomal translocations (6) in childhood acute lymphoblastic leukemia (ALL). Some factors have appeared only to fall again into disfavor while retaining their prognostic significance, like lymphomatous features and FAB morphology. Other factors, like trisomy 6 (7), t(1;19) (8), coexpression of myeloid-associated surface antigens (9,10), and T-lineage disease (11), seem to have lost prognostic significance during the course of time. Whereas these factors may help us to determine whether patients are at greater or lesser risk of relapse, and to decide whether to pursue more or less aggressive therapy, they provide little insight into the mechanisms of treatment failure.
The reproducible prognostic significance of resistance has been repeatedly demonstrated in a variety of contexts, namely, in vitro sensitivity assays (12), day 7 peripheral blood blast count (13), day 7 through 14 marrow blast percentage (14), and now, measures of minimal residual disease at end of induction (15,16). This redundancy is more a sign of robustness than confusion or uncertainty. Little ink has flowed in examination of the molecular physiology of resistance (17). The presence or absence of a particular fusion mRNA provides little more insight into underlying biology than the nuclear/cytoplasmic ratio and number of nucleoli.
Intermediate dose methotrexate (MTX) with rescue is a common element in many contemporary regimens for childhood ALL. However, clear proof of its contribution is lacking. St. Jude Study Total X showed a clear advantage for a complex regimen including IDM relative to a second complex regimen excluding IDM (18), but this was not a clear test of IDM. Mahoney et al. found an advantage for IDM with rescue relative to oral MTX with rescue (19). Two Children's Cancer Group trials examined the role of IDM versus weekly oral MTX with no rescue. Children's Cancer Group 139 found no advantage for MTX 0.5 g/m2(20), and Children's Cancer Group 144 (21) found no advantage for MTX 33.6 g/m2 for patients at standard-risk. More recently, British and French investigators have also reported the results of trials testing IDM versus weekly oral MTX. United Kingdom ALL XI study found no advantage for MTX 6 to 8 g/m2 for patients at average-risk (22). French ALL 93 found no advantage for MTX 8 g/m2 for patients at intermediate-risk (23). Several have proposed that the clinical efficacy of MTX depends on a critical interaction between MTX and its antidote, 5-methyltetrahydrofolate (THF) (19,24).
In a previous edition of this Journal (J Pediatr Hematol Oncol 2000;22:221–6.) Mantadakis et al. actually explore the cellular pharmacodynamics of MTX and THF (25). Blasts obtained at the time of presentation in 16 patients who remained in first complete remission were compared with blasts obtained from four patients at relapse. The present authors could not substantiate earlier observations that MTX polyglutamation in blasts predicted outcome (26,27). Here, neither cellular uptake of MTX nor THF alone predicted outcome, but the ratio did! The authors suggest that such pharmacologic parameters may usefully supplement clinical and pathologic markers and allow better identification of patients at higher-risk for relapse.
The small sample size allows a degree of skepticism that the authors clearly acknowledge. Particular observations may be culled from a larger series and chosen for publication when a “statistically significant” finding is identified. Indices and ratios multiply the opportunities for comparisons. Formulation of a compelling, commonsensical “mechanism” provides additional help for publication even when post hoc. As the authors themselves suggest, further work is needed.
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