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Acute Non-Lymphocytic Leukemia

Prognostic implication of FLT3 and Ras gene mutations in patients with acute promyelocytic leukemia (APL): a retrospective study from the European APL Group

Leukemia volume 19, pages 1153–1160 (2005)Cite this article

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-RARα 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.

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Author information

Authors and Affiliations

  1. Department of Hematology, Hôpital Saint-Louis, Paris, France

    C Callens, J-M Cayuela, B Cassinat, E Raffoux, C Chomienne & H Dombret

  2. Department of Biostatistics, Hôpital Saint-Louis, Paris, France

    S Chevret

  3. Department of Hematology of the Centre Hospitalier Universitaire of Lille, France

    S de Botton

  4. Department of Hematology of the Centre Hospitalier Universitaire of Lyon, France

    X Thomas

  5. Department of Hematology of the Centre Hospitalier Universitaire of Nancy, France

    A Guerci

  6. Department of Hematology of the Centre Hospitalier Universitaire of Montpellier, France

    N Fegueux

  7. Department of Hematology of the Centre Hospitalier Universitaire of Bordeaux, France

    A Pigneux

  8. Department of Hematology, Institut Paoli Calmettes, Marseille, France

    A-M Stoppa

  9. Department of Hematology of the Centre Hospitalier Universitaire of Rennes, France

    T Lamy

  10. Department of Hematology of the Centre Hospitalier Universitaire of Toulouse, France

    F Rigal-Huguet

  11. Department of Hematology of the Centre Hospitalier Universitaire of Paris Hotel Dieu, France

    A Vekhoff

  12. Department of Hematology, University of Basel, Switzerland

    S Meyer-Monard

  13. Department of Hematology, Cliniques Universitaires St Luc, Bruxelles, Belgium

    A Ferrand

  14. Department of Hematology, Hospital Universitario La Fe, Valencia, Spain

    M Sanz

  15. Department of Hematology Hôpital Avicenne, Bobigny, France

    P Fenaux

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  1. C Callens
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for the European APL Group

Corresponding author

Correspondence to H Dombret.

Appendix A APL-93 and/or APL-2000 investigators

Appendix A APL-93 and/or APL-2000 investigators

French group: Caillères (Aix-en-Provence), Desablens (Amiens), Gardembas, Hunault, Ifrah (Angers), Martin, Corront (Annecy), Dor (Antibes), Sutton, Pulik (Argenteuil), Lepeu (Avignon), Renoux (Bayonne), Deconinck (Besancon), Ades, Gardin, Casassus, Fenaux (Bobigny), Pigneux, Boiron, Reiffers (Bordeaux), Abgrall, Berthou (Brest), Reman, Leporrier (Caen), Deveaux, Salles (Chalon-sur-Saone), de Revel, Nedellec (Clamart), Plagne, Legros, Travade (Clermont-Ferrand), Gardin (Clichy), Audhuy (Colmart), Decaudin, Dutel (Compiegne), Pautas, Cordonnier, Reyes (Creteil), Caillot, Guy (Dijon), Cahn, Sotto (Grenoble), Durand (Le Havre), Solal-Celigny (Le Mans), Tertian (Kremlin-Bicetre), Morel (Lens), Nelken, de Botton (Lille), Turlure, Bordessoule (Limoges), Thomas, Archimbaud, Bastion, Michallet, Fière, Coiffier, Philippe (Lyon), Stoppa, Bouabdallah, Vey, Blaise (Marseille), Benothman, Allard (Meaux), Christian (Metz), Margueritte, Fegueux, Rossi Donadio (Montpellier), Ojeda, Henon (Mulhouse), Guerci, Witz (Nancy), Harousseau (Nantes), Pesce, Gratecos, Cassuto (Nice), Schoenwald (Orleans), Dreyfus (Paris Cochin), Vilmer (Paris Robert-Debre), Marie, Vekhoff (Paris Hotel Dieu), Buzyn, Lefrère, Varet (Paris Necker), Vernant (Paris Pitie-Salpetriere), Isnard, Gorin, Najman (Paris Saint-Antoine), Dombret, Raffoux, Gisselbrecht, Marolleau, Baruchel, Degos (Paris Saint-Louis), Leverger (Paris Trousseau), Vaque, Quetin (Point-a-Pitre), Guilhot (Poitiers), Pignon (Reims), Grosbois, Lamy, Le Prisé (Rennes), Stamatoulas, Tilly (Rouen), Bourquard (Saint-Brieuc), Janvier (Saint-Cloud), Guyotat (Saint-Etienne), Maloisel (Strasbourg), Jaubert (Toulon), Huguet, Attal, Pris, Robert, Despax (Toulouse), Colombat (Tours), Simon, Pollet (Valenciennes), Castaigne (Versailles), Bourhis, Machover (Villejuif).

Spanish group: Villegas (Almeria), Zuazu (Barcelona), Torres Carrete, Deben (Juan Canalejo), Javier de la Serna, Odriozola, Gomez-Sanz (Madrid), Rayon (Oviedo), Besalduch (Palma de Mallorca), San Miguel (Salamanca), Condé (Santander), Perez Encinas (Santiago), Sanz, Martin, Montagud (Valencia), Palomera (Zaragoza).

German group: Soucek (Dresden), Strobel (Erlangen), Ganser (Frankfurt), Brennscheidt (Freiburg), Link (Hanover), Wandt (Nurnberg), Breitenbach (Stuttgart), Herrmann (Ulm).

Swiss group: Wernli, Bargetzi (Aarau), Meyer-Monard, Ticheli, Gratwohl (Basel), Pabst, Fey, Zenhäusern (Bern), Wuillemin, Gregor (Luzern), Hess, Hitz (St Gallen), Fehr, Jacky, Taverna (Zürich), Chapuis, Starobinski (Genève), Cavalli, Ghielmini (Bellinzona), Schapira, Grob, von Fliedner (Lausanne).

Belgian group: Meeus (Anvers), Ferrant (Brussels), Boulet (Mons), Bosly (Yvoir).

Dutch group: Daenen (Griningen), Muus (Nijmegen).

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Callens, C., Chevret, S., Cayuela, JM. et al. Prognostic implication of FLT3 and Ras gene mutations in patients with acute promyelocytic leukemia (APL): a retrospective study from the European APL Group. Leukemia 19, 1153–1160 (2005). https://doi.org/10.1038/sj.leu.2403790

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