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Flt3 Internal Tandem Duplication and P-Glycoprotein Functionality in 171 Patients with Acute Myeloid Leukemia

Authors' Affiliations: ¹ Université Pierre et Marie Curie-Paris 6, UMRS 736, Les Cordeliers, INSERM, UMR S 736, Paris F-75006, ² Service d'Hématologie Biologique, and ³ Département d'Hématologie Clinique, AP-HP, Hôpital Hôtel-Dieu, Paris, France

Requests for reprints: Ollivier Legrand, Département d'Hématologie et d'Oncologie Médicale, AP-HP, Hôpital Hôtel-Dieu, 75181 Paris cedex 04, France. Phone: 33-14234-8585; Fax: 33-14234-8406; E-mail: ollivier.legrand{at}htd.ap-hop-paris.fr.

Purpose: 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.

Experimental Design: 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.

Conclusion: 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.