FLT3 internal tandem duplication in 234 children with acute myeloid leukemia: Prognostic significance and relation to cellular drug resistance

Christian M. Zwaan*, Soheil Meshinchi, Jerald P. Radich, Anjo J.P. Veerman, Dieuwke R. Huismans, Leonhard Munske, Martina Podleschny, Karel Hählen, Rob Pieters, Martin Zimmermann, Dirk Reinhardt, Jochen Harbott, Ursula Creutzig, Gertjan J.L. Kaspers, Frank Griesinger

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

FLT3 is a receptor tyrosine kinase involved in the proliferation and differentiation of hematopoietic stem cells. FLT3 internal tandem duplications (FLT3/ITDs) are reported in acute myeloid leukemia (AML) and predict poor clinical outcome. We found FLT3/ITDs in 11.5% of 234 children with de novo AML. FLT3/ITD-positive patients were significantly older and had higher percentages of normal cytogenetic findings or French-American-British (FAB) classification M1/M2 and lower percentages of 11q23 abnormalities or FAB MS. FLT3/ITD-positive patients had lower remission induction rates (70% vs 88%; P = .01) and lower 5-year probability rates of event-free survival (pEF) (29% vs 46%; P = .0046) and overall survival (32% vs 58%; P = .037). Patients with high ratios (higher than the median) between mutant and wild-type FLT3 had significantly worse 2-year EFS rates than FLT3/ITD-negative patients (pEFS 20% vs 61%, P = .037), whereas patients with ratios lower than the median did not (pEFS 44% vs 61%; P = .26). FLT3/ITD was the strongest independent predictor for pEFS, with an increase in relative risk for an event of 1.92 (P = .01). Using an MTT (methyl-thiazol-tetrazolium)-based assay, we studied cellular drug resistance on 15 FLT3/ITD-positive and 125 FLT3/ITD-negative AML samples, but we found no differences in cellular drug resistance that could explain the, poor outcomes in FLT3/ITD-positive patients, We conclude that FLT3/ITD is less common in pediatric than in adult AML. FLT3/ITD is a strong and independent adverse prognostic factor, and high ratios between mutant and WT-FLT3 further compromise prognosis. However, poor outcomes in FLT3/ITD-positive patients could not be attributed to increased in vitro cellular drug resistance.

Original languageEnglish
Pages (from-to)2387-2394
Number of pages8
JournalBlood
Volume102
Issue number7
DOIs
Publication statusPublished - 1 Oct 2003

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