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Blood, 1 December 2005, Vol. 106, No. 12, pp. 3768-3776.
Prepublished online as a Blood First Edition Paper on August 16, 2005; DOI 10.1182/blood-2005-04-1746.
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CLINICAL TRIALS AND OBSERVATIONS
Relationship between FLT3 mutation status, biologic characteristics, and response to targeted therapy in acute promyelocytic leukemia
Rosemary E. Gale,
Robert Hills,
Arnold R. Pizzey,
Panagiotis D. Kottaridis,
David Swirsky,
Amanda F. Gilkes,
Elizabeth Nugent,
Kenneth I. Mills,
Keith Wheatley,
Ellen Solomon,
Alan K. Burnett,
David C. Linch,
David Grimwade, for the NCRI Adult Leukaemia Working Party
From the Department of Haematology, University College London Hospitals, London; Clinical Trials Unit, University of Birmingham; Haematological Malignancy Diagnosis Service, Department of Haematology, Leeds General Infirmary; Department of Haematology, University of Cardiff, Wales; and Department of Medical and Molecular Genetics, King's College London, United Kingdom.
The prognostic significance of FLT3 mutations in acute promyelocytic leukemia (APL) is not firmly established and is of particular interest given the opportunities for targeted therapies using FLT3 inhibitors. We studied 203 patients with PML-RARA–positive APL; 43% of the patients had an FLT3 mutation (65 internal tandem duplications [ITDs], 19 D835/I836, 4 ITD+D835/I836). Both mutations were associated with higher white blood cell (WBC) count at presentation; 75% of the patients with WBC counts of 10 x 109/L or greater had mutant FLT3. FLT3/ITDs were correlated with M3v subtype (P < .001), bcr3 PML breakpoint (P < .001), and expression of reciprocal RARA-PML transcripts (P = .01). Microarray analysis revealed differences in expression profiles among patients with FLT3/ITD, D835/I836, and wild-type FLT3. Patients with mutant FLT3 had a higher rate of induction death (19% vs 9%; P = .04, but no significant difference in relapse risk (28% vs 23%; P = .5) or overall survival (59% vs 67%; P = .2) at 5 years. In in vitro differentiation assays using primary APL blasts (n = 6), the FLT3 inhibitor CEP-701 had a greater effect on cell survival/proliferation in FLT3/ITD+ cells, but this inhibition was reduced in the presence of ATRA. Furthermore, in the presence of CEP-701, ATRA-induced differentiation was reduced in FLT3/ITD+ cells. These data carry implications for the use of FLT3 inhibitors as frontline therapy for APL.
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