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Comparative Study
. 2010 May;95(5):745-51.
doi: 10.3324/haematol.2009.015073. Epub 2010 Feb 4.

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

María Carmen Chillón  1 , Carlos Santamaría, Ramón García-Sanz, Ana Balanzategui, María Eugenia Sarasquete, Miguel Alcoceba, Luis Marín, María Dolores Caballero, María Belén Vidriales, Fernando Ramos, Teresa Bernal, Joaquín Díaz-Mediavilla, Alfonso García de Coca, María Jesús Peñarrubia, José Antonio Queizán, Pilar Giraldo, Jesús F San Miguel, Marcos González
Affiliations
Comparative Study

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

María Carmen Chillón et al. Haematologica. 2010 May.

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-RARalpha 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-RARalpha transcripts less than the 25(th) 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-RARalpha levels (P=0.004) and elevated WBC counts (>10x10(9)/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-RARalpha transcript levels at diagnosis could contribute to improve the risk stratification in APL.

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Figures

Figure 1.
Figure 1.
Kaplan-Meier analysis for RFS of APL patients regarding FLT3-ITD mutant/wild-type ratio (A) and ITD size (B), the median was selected for both cut-off values. Kaplan-Meier analysis comparing RFS (C) and OS (D) of APL patients according to PML-RARα expression levels at diagnosis. Only patients who survived beyond the 30th day are included in this analysis. To define low and high expression groups in the series, the 25th percentile of the NCN was selected as cut-off value.
Figure 2.
Figure 2.
RFS of APL patients according to FLT3-ITD size in addition to WBC counts. The median size was selected as cut-off value.
See this image and copyright information in PMC

References

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