Glucocorticoid-Induced Proliferation and Differentiation of Untreated Pediatric AML Cells

Abstract 4873

The aim of the present study was to contribute to a more rational use of glucocorticoids (GC) in pediatric AML, by studying the relationship between in vitro GC responsiveness of AML cells, cell biological features and prognosis in 116 pediatric AML patients treated with GC-containing protocols (AML-BFM-87/93, DCOG-ANLL 87/93). In vitro GC resistance and GC-induced proliferation were determined by the 4-days MTT assay, GC-induced differentiation by morphology. Resistance to prednisolone (PRD) was expressed as the LC50 value, the concentration lethal to 50% of leukemic cells. Fifteen percent of the AML samples were somewhat sensitive to GCs (LC50<150 ug/ml), with an overrepresentation in that subgroup of FAB type M1 samples. Six out of 14 AML FAB type M1 samples were somewhat sensitive as compared to only 11 out of 101 non-FAB type M1 samples (p=0.002). However, none of the AML samples were highly sensitive to GC (LC50 < 0.1 ug/ml), in contrast to what is commonly observed in ALL cells (Kaspers et al., Blood 1998). Moreover, GC-induced AML cell proliferation was observed in 26% of samples, more frequently in FAB type M5 (p=0.01). Patients whose AML cells proliferated in vitro upon GC exposure had a lower 10-year event-free survival (32 % SE 5.5% versus 49% SE 8.5%, p=0.04). Such a difference was not found for patients with or without spontaneous proliferation. GC-induced differentiation was not observed in vitro. Multivariate analysis including BFM risk-group classification, FLT3 internal tandem duplications (FLT3/ITD) and GC induced proliferation, showed that only FLT3/ITD was an independent prognostic factor (P = 0.01). In conclusion, GCs are rarely highly cytotoxic towards AML cells, but do induce proliferation in a significant part of AML samples. That phenomenon is undesirable, and it is associated, though not independently, with a worse treatment outcome. We thus advice to use GC as antileukemic or anti-emetic drug with great reluctance in pediatric AML.