Flt3 internal tandem duplication and P-glycoprotein functionality in 171 patients with acute myeloid leukemia.
OBJECTIVE
Patients with adult acute myeloid leukemia (AML) with intermediate cytogenetics remain a heterogeneous group with highly variable individual prognoses. New molecular markers could help to refine cytogenetic stratification.


METHODS
We assessed P-glycoprotein (Pgp) activity and Flt3 internal tandem duplication (ITD+) because of their known prognostic value and because they might lead to targeted therapy. We did a multivariate analysis on 171 patients with adult AML treated in the European Organization for Research and Treatment of Cancer protocols.


RESULTS
ITD+ and high Pgp activity (Pgp+) were found in 26 of 171 (15%) and 55 of 171 (32%) of all patients, respectively. ITD and Pgp activities were negative in 94 of 171 (55%, Pgp-ITD- group), mutually exclusive in 73 of 171 (43%, Pgp-ITD+ and Pgp+ITD- groups), and only 4 of 171 (2%, Pgp+ITD+ group) patients were positive for both. In multivariate analyses, Pgp+ITD+ (P < 0.0001) and age (P = 0.0022) were independent prognostic factors for the achievement of complete remission (CR). Overall survival (OS), CR achievement (P < 0.0001), WHO performance status (P = 0.0007), and Pgp+ITD+ status (P = 0.0014) were also independent prognostic factors. In 95 patients with intermediate cytogenetics, the CR rates of ITD+ patients were 40% versus 62% for ITD- (P = 0.099) and 41% versus 67% (P = 0.014) for Pgp+ versus Pgp- patients. In the Pgp-ITD- group (41 of 95), CR rates were 70% versus 44% for others (P = 0.012), OS achieved 48% versus 16% (P < 0.0001) and disease-free survival was 56% versus 27% (P = 0.024), respectively. Furthermore, the OS curves of the intermediate cytogenetics-Pgp-ITD- group were not significantly different from the favorable cytogenetic group.


CONCLUSIONS
Flt3/ITD and Pgp activity are independent and additive prognostic factors which provide a powerful risk classification that can be routinely used to stratify the treatment of patients with intermediate cytogenetic AML. ITD+ and Pgp+ patients should be considered for targeted therapy.
Marzac
Christophe
C
Université Pierre et Marie Curie-Paris 6, UMRS 736, Les Cordeliers, INSERM, Paris F-75006, France.
Teyssandier
I
I
Calendini
Ors'Anton
O
Perrot
Jean-Yves
JY
Faussat
Anne-Marie
AM
Tang
Ruoping
R
Casadevall
Nicole
N
Marie
Jean-Pierre
JP
Legrand
Ollivier
O
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism*; D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020732:Cytogenetic Analysis; D005500:Follow-Up Studies; D020440:Gene Duplication; D006801:Humans; D007951:Leukemia, Myeloid / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D008875:Middle Aged; D015999:Multivariate Analysis; D011379:Prognosis; D012074:Remission Induction; D012307:Risk Factors; D015996:Survival Rate; D020080:Tandem Repeat Sequences; D016896:Treatment Outcome; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
D018435:ATP Binding Cassette Transporter, Subfamily B; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3