BMSEHA15
Published online 4 February 2010
(Haematologica 2010, 10.3324/haematol.2009.015073)
Copyright © 2010 by Ferrata Storti Foundation
This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Google Scholar
Right arrow Articles by Chillón, M. C.
Right arrow Articles by González, M.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Chillón, M. C.
Right arrow Articles by González, M.

Article

Long FLT3 internal tandem duplications and reduced PML-RAR{alpha} expression at diagnosis characterize a high-risk subgroup of acute promyelocytic leukemia patients.

María Carmen Chillón1,2, Carlos Santamaría1,3, Ramón García-Sanz1,2,3, Ana Balanzategui1, María Eugenia Sarasquete1,2, Miguel Alcoceba1, Luis Marín1, María Dolores Caballero1, María Belén Vidriales1, Fernando Ramos4, Teresa Bernal5, Joaquín Díaz-Mediavilla6, Alfonso García de Coca7, María Jesús Peñarrubia8, José Antonio Queizán9, Pilar Giraldo10, Jesús F. San Miguel1,3, Marcos González1,2,3

1 Servicio de Hematología, Hospital Universitario de Salamanca, Salamanca, Spain
2 Unidad de Genómica, Servicio de Investigación, Hospital Universitario de Salamanca, Salamanca, Spain
3 Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca, Spain
4 Complejo Hospitalario de León and Ibiomed, Universidad de León, León, Spain
5 Hospital Central de Asturias, Oviedo, Spain
6 Hospital Clínico San Carlos, Madrid, Spain
7 Hospital Clínico de Valladolid, Valladolid, Spain
8 Hospital Río Hortega, Valladolid, Spain
9 Hospital General de Segovia, Segovia, Spain
10 Hospital Miguel Servet, Zaragoza, Spain

CORRESPONDENCE: María del Carmen Chillón Santos, PhD, Department of Hematology, University Hospital of Salamanca, Paseo San Vicente 58-182, Salamanca, 37007, Spain. Phone +34-923291384. Fax +34-923294624. E-mail: chillon{at}usal.es

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-RAR{alpha} 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-RAR{alpha} 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-RAR{alpha} levels (p=0.004) and elevated WBC counts (>10 x 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-RAR{alpha} transcripts levels at diagnosis could contribute to improve the risk stratification in APL.

Key words: acute promyelocytic leukemia, FLT3- ITD size, PML-RAR{alpha} level, prognosis.