1. ¹Department of Hematology, Hôpital Saint-Louis, Paris, France
2. ²Department of Biostatistics, Hôpital Saint-Louis, Paris, France
3. ³Department of Hematology of the Centre Hospitalier Universitaire of Lille, France
4. ⁴Department of Hematology of the Centre Hospitalier Universitaire of Lyon, France
5. ⁵Department of Hematology of the Centre Hospitalier Universitaire of Nancy, France
6. ⁶Department of Hematology of the Centre Hospitalier Universitaire of Montpellier, France
7. ⁷Department of Hematology of the Centre Hospitalier Universitaire of Bordeaux, France
8. ⁸Department of Hematology, Institut Paoli Calmettes, Marseille, France
9. ⁹Department of Hematology of the Centre Hospitalier Universitaire of Rennes, France
10. ¹⁰Department of Hematology of the Centre Hospitalier Universitaire of Toulouse, France
11. ¹¹Department of Hematology of the Centre Hospitalier Universitaire of Paris Hotel Dieu, France
12. ¹²Department of Hematology, University of Basel, Switzerland
13. ¹³Department of Hematology, Cliniques Universitaires St Luc, Bruxelles, Belgium
14. ¹⁴Department of Hematology, Hospital Universitario La Fe, Valencia, Spain
15. ¹⁵Department of Hematology Hôpital Avicenne, Bobigny, France

Correspondence: Professor H Dombret, Department of Hematology, Hôpital Saint-Louis, 1 Avenue Claude Vellefaux, 75010 Paris, France. Fax: +33 1 4249 9345; E-mail: herve.dombret@sls.ap-hop-paris.fr

Received 11 January 2005; Accepted 1 April 2005; Published online 12 May 2005.

Abstract

Internal tandem duplications (ITDs) of the FLT3 gene have been observed in about 35% of APL cases. If FLT3-ITD is associated with a worse outcome in patients with acute myeloid leukemia (AML) in general, its prognostic value in acute promyelocytic leukemia (APL) is still a matter of debate. We investigated incidence, associated clinical features, and prognostic implication of FLT3-ITD, but also FLT3-D835 point mutation and N-Ras or K-Ras mutations in 119 APL patients, all prospectively enrolled in the two consecutive APL-93 and APL-2000 trials. Mutation incidences were 38, 20, and 4%, for FLT3-ITD, FLT3-D835, and Ras, respectively. The presence of FLT3-ITD was associated with high white blood cell count, high Sanz index, M3-variant subtype, and V/S PML-RAR isoforms. Complete remission (CR), induction death, and death in CR rates were not affected by FLT3 or Ras mutations, as well as cumulative incidence of relapse. However, a trend for a shorter overall survival (P=0.09) was observed in FLT3-ITD patients, because of a very poor postrelapse survival (P=0.02). This feature, which has been also reported in patients with AML in general, is suggestive of an underlying genetic instability in FLT3-ITD patients, leading to the acquisition of additional unknown bad-prognosis gene mutations at relapse.