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Long FLT3 internal tandem duplications and reduced PML-RARα expression at diagnosis characterize a high-risk subgroup of acute promyelocytic leukemia patients

AuthorsChillón, M. del Carmen; Santamaría, Carlos; García-Sanz, Ramón; San Miguel, Jesús F. ; González, Marcos
KeywordsAcute promyelocytic leukemia
FLT3-ITD size
PML-RARα level
Issue Date4-Feb-2010
PublisherFerrata Storti Foundation
CitationHaematologica 95(5): 745-751 (2010)
Abstract[Background]: Internal tandem duplications of the FLT3 gene (FLT3-ITDs) are frequent in patients with acute promyelocytic leukemia (APL), however its clinical impact remains controversial. [Design and Methods]: We analyzed the prognostic significance of FLT3-ITD mutant level and size, as well as FLT3-D835 point mutations, PML-RARα expression and other predictive factors in 129 APL patients at diagnosis enrolled on the Spanish LPA96 (n=43) or LPA99 (n=86) PETHEMA trials. [Results]: FLT3-ITDs and D835 mutations were detected in 21% and 9% of patients, respectively. Patients with increased ITD mutant/wild-type ratio or longer ITD size displayed shorter 5-year relapse-free survival (RFS) (P=0.048 and P<0.0001, respectively). However, patients with D835 mutations did not show differences in RFS or overall survival (OS). Moreover, patients with initial normalized copy number (NCN) of PML-RARα transcripts less than the 25th percentile had adverse clinical features and shorter 5-year RFS (P<0.0001) and OS (P=0.004) compared to patients with higher NCN. Patients with low NCN showed increased incidence of ITDs (P=0.001), with higher ratios (P<0.0001) and/or longer sizes (P=0.007). Multivariate analysis showed that long FLT3-ITD (P=0.001), low PML-RARα levels (P=0.004) and elevated WBC counts (>10×109/L) (P=0.018) were independent predictors for shorter RFS. We identified a subgroup of patients with high WBC, long FLT3-ITD and low NCN of transcripts that showed an extremely bad prognosis (5-year RFS 23.4%, P<0.0001). [Conclusions]: In conclusion, FLT3-ITD size and PML-RARα transcript levels at diagnosis could contribute to improve the risk stratification in APL.
Description7 páginas, 2 figuras, 2 tablas.-- This is an open-access paper.-- et al.
Publisher version (URL)http://dx.doi.org/10.3324/haematol.2009.015073
Appears in Collections:(IBMCC) Artículos
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