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Clinical Trial
. 2006 Dec 1;108(12):3654-61.
doi: 10.1182/blood-2006-03-009233. Epub 2006 Aug 15.

Clinical implications of FLT3 mutations in pediatric AML

Soheil Meshinchi  1 , Todd A Alonzo, Derek L Stirewalt, Michel Zwaan, Martin Zimmerman, Dirk Reinhardt, Gertjan J L Kaspers, Nyla A Heerema, Robert Gerbing, Beverly J Lange, Jerald P Radich
Affiliations
Clinical Trial

Clinical implications of FLT3 mutations in pediatric AML

Soheil Meshinchi et al. Blood. .

Abstract

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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Figures

Figure 1.
Figure 1.
Prevalence of FLT3/ITD and FLT3/ALM by age categories and by karyotype. (A) Prevalence of FLT3 mutations is presented for different age categories. Bars inside the box represent correspondence to the prevalence of FLT3 mutations in adults 18 to 55 years and older than 55 years as previously published. (B) Prevalence of FLT3 mutations is presented for each cytogenetic category. *Statistically significant difference compared with FLT3/WT.
Figure 2.
Figure 2.
Actuarial progression-free survival from study entry for patients with FLT3/ITD, FLT3/ALM, or FLT3/WT.
Figure 3.
Figure 3.
Clinical significance of FLT3/ITD by FLT3/ITD-AR. (A) Example of ITD-AR determination by Genescan analysis. The top panel is the agarose gel resolution of PCR product from a normal marrow (lane 1) and specimens from 3 patients with FLT3/ITD (lanes 2-4). The lower panels show the result of the Genescan analysis and ITD-AR determination. (B) Actuarial progression-free survival from study entry for patients with FLT3/ITD based on allelic ratio by tertiles. (C) Actuarial PFS from study entry for patients with high ITD-AR (ITD-AR > 0.4) compared with those with FLT3/WT.
Figure 4.
Figure 4.
Evaluation of prognostic significance of ITD-AR threshold of 0.4 in BFM SG and Dutch DCOG cohort. Overall survival for patients with FLT3/ITD with ITD-AR of greater than 0.4 versus 0.4 is compared with those without FL3/ITD.
Figure 5.
Figure 5.
Efficacy of allogeneic SCT in FLT3/ITD-positive AML. (A) Relapse risk (solid lines) and overall survival (shaded lines) in recipients of MFD SC transplant with and without FLT3/ITD. (B) Relapse risk (solid lines) and overall survival (shaded lines) in patients with FLT3/ITD treated with consolidation chemotherapy versus MFD SCT.
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