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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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CLINICAL TRIALS AND OBSERVATIONS
Clinical implications of FLT3 mutations in pediatric AML
Soheil Meshinchi,
Todd A. Alonzo,
Derek L. Stirewalt,
Michel Zwaan,
Martin Zimmerman,
Dirk Reinhardt,
Gertjan J. L. Kaspers,
Nyla A. Heerema,
Robert Gerbing,
Beverly J. Lange, and
Jerald P. Radich
From the Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; the Department of Pediatrics, University of Washington Medical Center, Seattle; the University of Southern California Keck School of Medicine, Los Angeles; the Department of Pediatric Hematology/Oncology, Erasmus MC–Sophia Children's Hospital, Rotterdam, The Netherlands; the Dutch Childhood Oncology Group, Rotterdam, The Netherlands; the AML-BFM Study Group, Münster, Germany; the Department of Pediatric Hematology/Oncology, Vrije Universiteit (VU) University Medical Center, Amsterdam, The Netherlands; the Dutch Childhood Oncology Group, Amsterdam, The Netherlands; The Ohio State University, Columbus; the Children's Hospital of Philadelphia, PA; and the Children's Oncology Group, Arcadia, CA.
Activating mutations of the FLT3 gene occur because of 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–wild type ratio) may have prognostic significance. FLT3 mutation status of 630 children with de novo acute myeloid leukemia (AML) treated on CCG-2941 and -2961 was determined, and ITD-AR was calculated for patients with FLT3/ITD. Clinical characteristics and outcomes for patients with FLT3/ALM and FLT3/ITD at varying ITD-ARs was determined and compared with 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% versus 55%, P = .862). In contrast, PFS at 4 years from study entry for patients with FLT3/ITD was inferior to that of patients with FLT3/WT (31% versus 55%, P < .001). PFS decreased with increasing FLT3/ITD-AR (P < .001), and those with ITD-AR greater than 0.4 had a significantly worse PFS than those with lower ITD-AR (16% versus 72%, P = .001) or with FLT3/WT (55%, P < .001). ITD-AR defines the prognostic significance in FLT3/ITD-positive AML, and ITD-AR greater than 0.4 is a significant and independent prognostic factor for relapse in pediatric AML.
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