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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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Submitted April 29, 2005
Accepted July 23, 2005
The relationship between FLT3 mutation status, biological 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, and David Grimwade*
Department of Haematology, University College London Hospitals, London, United Kingdom
Clinical Trials Unit, University of Birmingham, Birmingham, United Kingdom
Haematological Malignancy Diagnosis Service, Department of Haematology, Leeds General Infirmary, Leeds, United Kingdom
Department of Haematology, University of Cardiff, Cardiff, Wales, United Kingdom
Department of Medical & Molecular Genetics, King's College London, London, United Kingdom
Department of Haematology, University College London Hospitals, London, United Kingdom; Department of Medical & Molecular Genetics, King's College London, London, United Kingdom
* Corresponding author; email: david.grimwade{at}genetics.kcl.ac.uk.
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 cases of PML-RARA positive APL; 43% had a FLT3 mutation (65 ITD, 19 D835/I836, 4 ITD+D835/I836). Both mutations were associated with higher presenting leukocyte count (WBC); 75% cases with WBC  10 x 109L had mutant FLT3. FLT3/ITDs were correlated with M3v subtype (P.0001), bcr3 PML breakpoint (P< .0001) and expression of reciprocal RARA-PML transcripts (P.01). Microarray analysis revealed differences in expression profiles between cases with FLT3/ITDs, D835/I836 and wild-type FLT3. Cases 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 front-line therapy for APL.
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