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


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.
Department of Hematology, University Hospital of Salamanca, Paseo San Vicente 58-182, Salamanca, 37007, Spain. chillon@usal.es
María Carmen
MC
Chillón
Carlos
C
Santamaría
Ramón
R
García-Sanz
Ana
A
Balanzategui
María Eugenia
ME
Sarasquete
Miguel
M
Alcoceba
Luis
L
Marín
María Dolores
MD
Caballero
María Belén
MB
Vidriales
Fernando
F
Ramos
Teresa
T
Bernal
Joaquín
J
Díaz-Mediavilla
Alfonso
A
García de Coca
María Jesús
MJ
Peñarrubia
José Antonio
JA
Queizán
Pilar
P
Giraldo
Jesús F
JF
San Miguel
Marcos
M
González
D000328:Adult; D014408:Biomarkers, Tumor / Q000235:genetics; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors* / Q000235:genetics*; D017354:Point Mutation / Q000235:genetics; D012307:Risk Factors; D020080:Tandem Repeat Sequences / Q000235:genetics*; D055815:Young Adult; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
D014408:Biomarkers, Tumor; D015514:Oncogene Proteins, Fusion; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3