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Blood, 1 December 2006, Vol. 108, No. 12, pp. 3654-3661.
Prepublished online as a Blood First Edition Paper on August 15, 2006; DOI 10.1182/blood-2006-03-009233.


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Submitted March 31, 2006
Accepted July 24, 2006

Clinical implications of FLT3 mutations in pediatric AML

Soheil Meshinchi*, Todd A Alonzo, Derek L Stirewalt, Michel Zwaan, Martin Zimmerman, Dirk Reinhardt, Gertjan JL Kaspers, Nyla A Heerema, Robert Gerbing, Beverly J Lange, and Jerald P Radich

Fred Hutchinson Cancer Research Center, University of Washington Medical Center, Seattle, WA
University of Southern California Keck School of Medicine, Los Angeles, CA
Erasmus MC-Sophia Childrens Hospital, and Dutch Childhood Oncology Group, Rotterdam, Netherlands
AML-BFM Study Group, Munster, Germany
VU University Medical Center, and Dutch Childhood Oncology Group, Amsterdam, Netherlands
The Ohio State University, Columbus, Ohio
Children's Oncology Group, Arcadia, CA
Childrens Hospital of Philadelphia, Philadelphia, PA
Fred Hutchinson Cancer Research Institute, University of Washington Medical Center, Seattle, WA

* Corresponding author; email: smeshinc{at}fhcrc.org.

Activating mutations of the FLT3 gene occur due to an internal tandem duplication of the juxta-membrane domain (FLT3/ITD) or point mutation of the activation loop domain (FLT3/ALM). The presence of FLT3 mutations as well as the allelic ratio of FLT3/ITD (ITD-AR, mutant to wild type ratio)) may have prognostic significance. FLT3 mutation status of 630 children with de novo AML treated on CCG-2941/2961 was determined, and ITD-AR was determined for FLT3/ITD-positive patients. Clinical characteristics and outcomes for patients with FLT3/ALM, and FLT3/ITD at varying ITD-AR was determined and compared to those without FLT3 mutations (FLT3/WT). FLT3/ITD and FLT3/ALM were detected in 77 (12%) and 42 (6.7%) of the patients. Progression-free survival (PFS) was similar in patients with FLT3/ALM and FLT3/WT (51% vs. 55%, p=0.862). In contrast, PFS at 4 years from study entry for FLT3/ITD-positive patients was inferior to that of FLT3/WT patients (31% vs. 55%, p<0.001). PFS decreased with increasing FLT3/ITD-AR (p< 0.001), and those with ITD-AR >0.4 had a significantly worse PFS than those with lower ITD-AR (16% vs. 72%, p=0.001) or with FLT3/WT (55%, p<0.001). ITD-AR defines the prognostic significance in FLT3/ITD-positive AML and ITD-AR >0.4 is a significant, and independent prognostic factor for relapse in pediatric AML.


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