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

C. Callens; S. Chevret; J. M. Cayuela; B. Cassinat; E. Raffoux; S. de Botton; X. Thomas; A. Guerci; N. Fegueux; A. Pigneux; A. M. Stoppa; T. Lamy; F. Rigal-Huguet; A. Vekhoff; S. Meyer-Monard; A. Ferrand; M. Sanz; C. Chomienne; P. Fenaux; Herve Dombret; Caillès; Desablens; Gardembas; Hunault; Ifrah; Martin; Corront; Dor; Sutton; Pulik; Lepeu; Renoux; Deconinck; Ades; Gardin; Casassus; Fenaux; Pigneux; Boiron; Reiffers; Abgrall; Berthou; Reman; Leporrier; Deveaux; Salles; Revel de Revel; Nedellec; Plagne; Legros; Travade; Audhuy; Decaudin; Dutel; Pautas; Cordonnier; Reyes; Caillot; Guy; Cahn; Sotto; Durand; Solal-Celigny; Tertian; Morel; Nelken; Botton de Botton; Turlure; Bordessoule; Thomas; Archimbaud; Bastion; Michallet; Fière; Coiffier; Philippe; Stoppa; Bouabdallah; Vey; Blaise; Benothman; Allard; Christian; Margueritte; Fegueux; Donadio Rossi Donadio; Ojeda; Henon; Guerci; Witz; Harousseau; Pesce; Gratecos; Cassuto; Schoenwald; Dreyfus; Vilmer; Marie; Vekhoff

doi:10.1038/sj.leu.2403790

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

C. Callens, S. Chevret, J. M. Cayuela, B. Cassinat, E. Raffoux, S. de Botton, X. Thomas, A. Guerci, N. Fegueux, A. Pigneux, A. M. Stoppa, T. Lamy, F. Rigal-Huguet, A. Vekhoff, S. Meyer-Monard, A. Ferrand, M. Sanz, C. Chomienne, P. Fenaux, Herve DombretCaillès, Desablens, Gardembas, Hunault, Ifrah, Martin, Corront, Dor, Sutton, Pulik, Lepeu, Renoux, Deconinck, Ades, Gardin, Casassus, Fenaux, Pigneux, Boiron, Reiffers, Abgrall, Berthou, Reman, Leporrier, Deveaux, Salles, Revel de Revel, Nedellec, Plagne, Legros, Travade, Audhuy, Decaudin, Dutel, Pautas, Cordonnier, Reyes, Caillot, Guy, Cahn, Sotto, Durand, Solal-Celigny, Tertian, Morel, Nelken, Botton de Botton, Turlure, Bordessoule, Thomas, Archimbaud, Bastion, Michallet, Fière, Coiffier, Philippe, Stoppa, Bouabdallah, Vey, Blaise, Benothman, Allard, Christian, Margueritte, Fegueux, Donadio Rossi Donadio, Ojeda, Henon, Guerci, Witz, Harousseau, Pesce, Gratecos, Cassuto, Schoenwald, Dreyfus, Vilmer, Marie, Vekhoff

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Résumé

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.

langue originale	Anglais
Pages (de - à)	1153-1160
Nombre de pages	8
journal	Leukemia
Volume	19
Numéro de publication	7
Les DOIs	https://doi.org/10.1038/sj.leu.2403790
état	Publié - 1 janv. 2005
Modification externe	Oui

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10.1038/sj.leu.2403790

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Callens, C., Chevret, S., Cayuela, J. M., Cassinat, B., Raffoux, E., de Botton, S., Thomas, X., Guerci, A., Fegueux, N., Pigneux, A., Stoppa, A. M., Lamy, T., Rigal-Huguet, F., Vekhoff, A., Meyer-Monard, S., Ferrand, A., Sanz, M., Chomienne, C., Fenaux, P., ... Vekhoff (2005). 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(7), 1153-1160. https://doi.org/10.1038/sj.leu.2403790

@article{2d981643ec8141219ed6051ba024d368,

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

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.",

keywords = "Acute promyelocytic leukemia, FLT3, Prognosis, Ras",

author = "C. Callens and S. Chevret and Cayuela, {J. M.} and B. Cassinat and E. Raffoux and {de Botton}, S. and X. Thomas and A. Guerci and N. Fegueux and A. Pigneux and Stoppa, {A. M.} and T. Lamy and F. Rigal-Huguet and A. Vekhoff and S. Meyer-Monard and A. Ferrand and M. Sanz and C. Chomienne and P. Fenaux and Herve Dombret and Caill{\`e}s and Desablens and Gardembas and Hunault and Ifrah and Martin and Corront and Dor and Sutton and Pulik and Lepeu and Renoux and Deconinck and Ades and Gardin and Casassus and Fenaux and Pigneux and Boiron and Reiffers and Abgrall and Berthou and Reman and Leporrier and Deveaux and Salles and {de Revel}, Revel and Nedellec and Plagne and Legros and Travade and Audhuy and Decaudin and Dutel and Pautas and Cordonnier and Reyes and Caillot and Guy and Cahn and Sotto and Durand and Solal-Celigny and Tertian and Morel and Nelken and {de Botton}, Botton and Turlure and Bordessoule and Thomas and Archimbaud and Bastion and Michallet and Fi{\`e}re and Coiffier and Philippe and Stoppa and Bouabdallah and Vey and Blaise and Benothman and Allard and Christian and Margueritte and Fegueux and {Rossi Donadio}, Donadio and Ojeda and Henon and Guerci and Witz and Harousseau and Pesce and Gratecos and Cassuto and Schoenwald and Dreyfus and Vilmer and Marie and Vekhoff",

year = "2005",

month = jan,

day = "1",

doi = "10.1038/sj.leu.2403790",

language = "English",

volume = "19",

pages = "1153--1160",

journal = "Leukemia",

issn = "0887-6924",

number = "7",

}

Callens, C, Chevret, S, Cayuela, JM, Cassinat, B, Raffoux, E, de Botton, S, Thomas, X, Guerci, A, Fegueux, N, Pigneux, A, Stoppa, AM, Lamy, T, Rigal-Huguet, F, Vekhoff, A, Meyer-Monard, S, Ferrand, A, Sanz, M, Chomienne, C, Fenaux, P, Dombret, H, Caillès, Desablens, Gardembas, Hunault, Ifrah, Martin, Corront, Dor, Sutton, Pulik, Lepeu, Renoux, Deconinck, Ades, Gardin, Casassus, Fenaux, Pigneux, Boiron, Reiffers, Abgrall, Berthou, Reman, Leporrier, Deveaux, Salles, de Revel, R, Nedellec, Plagne, Legros, Travade, Audhuy, Decaudin, Dutel, Pautas, Cordonnier, Reyes, Caillot, Guy, Cahn, Sotto, Durand, Solal-Celigny, Tertian, Morel, Nelken, de Botton, B, Turlure, Bordessoule, Thomas, Archimbaud, Bastion, Michallet, Fière, Coiffier, Philippe, Stoppa, Bouabdallah, Vey, Blaise, Benothman, Allard, Christian, Margueritte, Fegueux, Rossi Donadio, D, Ojeda, Henon, Guerci, Witz, Harousseau, Pesce, Gratecos, Cassuto, Schoenwald, Dreyfus, Vilmer, Marie & Vekhoff 2005, 'Prognostic implication of FLT3 and Ras gene mutations in patients with acute promyelocytic leukemia (APL): A retrospective study from the European APL Group', Leukemia, VOL. 19, Numéro 7, p. 1153-1160. https://doi.org/10.1038/sj.leu.2403790

TY - JOUR

T1 - Prognostic implication of FLT3 and Ras gene mutations in patients with acute promyelocytic leukemia (APL)

T2 - A retrospective study from the European APL Group

AU - Callens, C.

AU - Chevret, S.

AU - Cayuela, J. M.

AU - Cassinat, B.

AU - Raffoux, E.

AU - de Botton, S.

AU - Thomas, X.

AU - Guerci, A.

AU - Fegueux, N.

AU - Pigneux, A.

AU - Stoppa, A. M.

AU - Lamy, T.

AU - Rigal-Huguet, F.

AU - Vekhoff, A.

AU - Meyer-Monard, S.

AU - Ferrand, A.

AU - Sanz, M.

AU - Chomienne, C.

AU - Fenaux, P.

AU - Dombret, Herve

AU - Caillès,

AU - Desablens,

AU - Gardembas,

AU - Hunault,

AU - Ifrah,

AU - Martin,

AU - Corront,

AU - Dor,

AU - Sutton,

AU - Pulik,

AU - Lepeu,

AU - Renoux,

AU - Deconinck,

AU - Ades,

AU - Gardin,

AU - Casassus,

AU - Fenaux,

AU - Pigneux,

AU - Boiron,

AU - Reiffers,

AU - Abgrall,

AU - Berthou,

AU - Reman,

AU - Leporrier,

AU - Deveaux,

AU - Salles,

AU - de Revel, Revel

AU - Nedellec,

AU - Plagne,

AU - Legros,

AU - Travade,

AU - Audhuy,

AU - Decaudin,

AU - Dutel,

AU - Pautas,

AU - Cordonnier,

AU - Reyes,

AU - Caillot,

AU - Guy,

AU - Cahn,

AU - Sotto,

AU - Durand,

AU - Solal-Celigny,

AU - Tertian,

AU - Morel,

AU - Nelken,

AU - de Botton, Botton

AU - Turlure,

AU - Bordessoule,

AU - Thomas,

AU - Archimbaud,

AU - Bastion,

AU - Michallet,

AU - Fière,

AU - Coiffier,

AU - Philippe,

AU - Stoppa,

AU - Bouabdallah,

AU - Vey,

AU - Blaise,

AU - Benothman,

AU - Allard,

AU - Christian,

AU - Margueritte,

AU - Fegueux,

AU - Rossi Donadio, Donadio

AU - Ojeda,

AU - Henon,

AU - Guerci,

AU - Witz,

AU - Harousseau,

AU - Pesce,

AU - Gratecos,

AU - Cassuto,

AU - Schoenwald,

AU - Dreyfus,

AU - Vilmer,

AU - Marie,

AU - Vekhoff,

PY - 2005/1/1

Y1 - 2005/1/1

N2 - 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.

AB - 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.

KW - Acute promyelocytic leukemia

KW - FLT3

KW - Prognosis

KW - Ras

UR - http://www.scopus.com/inward/record.url?scp=21744440587&partnerID=8YFLogxK

U2 - 10.1038/sj.leu.2403790

DO - 10.1038/sj.leu.2403790

M3 - Article

C2 - 15889156

AN - SCOPUS:21744440587

SN - 0887-6924

VL - 19

SP - 1153

EP - 1160

JO - Leukemia

JF - Leukemia

IS - 7

ER -