Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation

Fecha de publicación: 03/08/2017

Autores de IIS La Fe

Miguel Ángel Sanz Alonso

Autor

Participantes ajenos a IIS La Fe

Stone, RM
Mandrekar, SJ
Sanford, BL
Laumann, K
Geyer, S
Bloomfield, CD
Thiede, C
Prior, TW
Döhner K
Marcucci, G
Lo-Coco, F
Klisovic, RB
Wei, A
Sierra, J
Brandwein, JM
de Witte, T
Niederwieser, D
Appelbaum, FR
Medeiros, BC
Tallman, MS
Krauter, J
Schlenk, RF
Ganser, A
Serve, H
Ehninger, G
Amadori, S
Larson, RA
Döhner H

Grupos

Hematología y Hemoterapia

Investigador Principal

Javier De La Rubia Comos

Abstract

BACKGROUND Patients with acute myeloid leukemia (AML) and a FLT3 mutation have poor outcomes. We conducted a phase 3 trial to determine whether the addition of midostaurin - an oral multitargeted kinase inhibitor that is active in patients with a FLT3 mutation - to standard chemotherapy would prolong overall survival in this population. METHODS We screened 3277 patients, 18 to 59 years of age, who had newly diagnosed AML for FLT3 mutations. Patients were randomly assigned to receive standard chemotherapy (induction therapy with daunorubicin and cytarabine and consolidation therapy with high-dose cytarabine) plus either midostaurin or placebo; those who were in remission after consolidation therapy entered a maintenance phase in which they received either midostaurin or placebo. Randomization was stratified according to subtype of FLT3 mutation: point mutation in the tyrosine kinase domain (TKD) or internal tandem duplication (ITD) mutation with either a high ratio (> 0.7) or a low ratio (0.05 to 0.7) of mutant to wild-type alleles (ITD [high] and ITD [low], respectively). Allogeneic transplantation was allowed. The primary end point was overall survival. RESULTS A total of 717 patients underwent randomization; 360 were assigned to the midostaurin group, and 357 to the placebo group. The FLT3 subtype was ITD (high) in 214 patients, ITD (low) in 341 patients, and TKD in 162 patients. The treatment groups were well balanced with respect to age, race, FLT3 subtype, cytogenetic risk, and blood counts but not with respect to sex (51.7% in the midostaurin group vs. 59.4% in the placebo group were women, P = 0.04). Overall survival was significantly longer in the midostaurin group than in the placebo group (hazard ratio for death, 0.78; one-sided P = 0.009), as was event-free survival (hazard ratio for event or death, 0.78; one-sided P = 0.002). In both the primary analysis and an analysis in which data for patients who underwent transplantation were censored, the benefit of midostaurin was consistent across all FLT3 subtypes. The rate of severe adverse events was similar in the two groups. CONCLUSIONS The addition of the multitargeted kinase inhibitor midostaurin to standard chemotherapy significantly prolonged overall and event-free survival among patients with AML and a FLT3 mutation. (Funded by the National Cancer Institute and Novartis; ClinicalTrials.gov number, NCT00651261.)

Datos de la publicación

ISSN/ISSNe:: 0028-4793, 1533-4406
Tipo:: Article
Páginas:: 454-464
DOI:: 10.1056/NEJMoa1614359
Factor de Impacto:: 19,476 SCImago ℠
Cuartil:: Q1 SCImago ℠

Documentos

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Métricas

Filiaciones

Stone, RM:: Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave,D-2053, Boston, MA 02115 USA
Mandrekar, SJ:: Mayo Clin, Div Biomed Stat & Informat, Rochester, MN USA

Mayo Clin, Alliance Stat & Data Ctr, Rochester, MN USA
Sanford, BL:: Duke Univ, Alliance Stat & Data Ctr, Durham, NC USA
Laumann, K:: Mayo Clin, Div Biomed Stat & Informat, Rochester, MN USA

Mayo Clin, Alliance Stat & Data Ctr, Rochester, MN USA
Geyer, S:: Mayo Clin, Alliance Stat & Data Ctr, Rochester, MN USA

Ohio State Univ, Comprehens Canc Ctr, Columbus, OH 43210 USA
Bloomfield, CD:: Ohio State Univ, Comprehens Canc Ctr, Columbus, OH 43210 USA
Thiede, C:: Tech Univ Dresden, Univ Klinikum Carl Gustav Carus, Med Klin & Poliklin 1, Dresden, Germany
Prior, TW:: Ohio State Univ, Comprehens Canc Ctr, Columbus, OH 43210 USA
Marcucci, G:: Ohio State Univ, Comprehens Canc Ctr, Columbus, OH 43210 USA
Lo-Coco, F:: Univ Tor Vergata, Dept Biomed & Prevent, Rome, Italy
Klisovic, RB:: Ohio State Univ, Comprehens Canc Ctr, Columbus, OH 43210 USA
Wei, A:: Alfred Hosp, Dept Clin Haematol, Melbourne, Vic, Australia

Monash Univ, Melbourne, Vic, Australia
Sierra, J:: Autonomous Univ Barcelona, Dept Hematol, Hosp Santa Creu & St Pau, Barcelona, Spain
Sanz, MA:: Univ Valencia, Dept Med, Dept Hematol, Hosp Univ Fe, Valencia, Spain
Brandwein, JM:: Princess Margaret Hosp, Dept Med Oncol & Hematol, Toronto, ON, Canada
de Witte, T:: Radboud Univ Nijmegen, Med Ctr, Radboud Inst Mol Studies, Nijmegen, Netherlands
Niederwieser, D:: Univ Leipzig, Hematol & Oncol, Leipzig, Germany
Appelbaum, FR:: Fred Hutchinson Canc Res Ctr, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA
Medeiros, BC:: Stanford Univ, Stanford Comprehens Canc Ctr, Div Hematol Oncol, Stanford, CA 94305 USA
Tallman, MS:: Mem Sloan Kettering Canc Ctr, Dept Med, Leukemia Serv, 1275 York Ave, New York, NY 10021 USA

Weill Cornell Med Coll, New York, NY USA
Krauter, J:: Hannover Med Sch, Dept Hematol Hemostasis Oncol & Stem Cell Transpl, Hannover, Germany
Schlenk, RF:: Univ Hosp Ulm, Dept Internal Med 3, Ulm, Germany
Ganser, A:: Hannover Med Sch, Dept Hematol Hemostasis Oncol & Stem Cell Transpl, Hannover, Germany
Serve, H:: Goethe Univ Hosp Frankfurt, Dept Med 2, Hematol Oncol, Frankfurt, Germany
Ehninger, G:: Tech Univ Dresden, Univ Klinikum Carl Gustav Carus, Med Klin & Poliklin 1, Dresden, Germany
Amadori, S:: Univ Tor Vergata, Dept Biomed & Prevent, Rome, Italy
Larson, RA:: Univ Chicago, Dept Med, 5841 S Maryland Ave, Chicago, IL 60637 USA

Campos de estudio

Proyectos asociados

RED DE INVESTIGACION COOPERATIVA DE CANCER

RD06/0020/0031 . INSTITUTO DE SALUD CARLOS III; FUNDACIÓN PARA LA INVESTIGACIÓN DEL HOSPITAL UNIVERSITARIO LA FE DE LA COMUNIDAD VALENCIANA . 2006

PROYECTO CAIBER

CAI08/01/0061 . INSTITUTO DE SALUD CARLOS III; FUNDACIÓN PARA LA INVESTIGACIÓN DEL HOSPITAL UNIVERSITARIO LA FE DE LA COMUNIDAD VALENCIANA . 2009

CREACION Y MEJORA DE INFRAESTRUCTURAS EN MEDICINA REGENERATIVA

Investigador Principal: FUNDACIÓN PARA LA INVESTIGACIÓN DEL HOSPITAL UNIVERSITARIO LA FE DE LA COMUNIDAD VALENCIANA

PLE2009-0141 ACI-PLAN E . MINISTERIO DE CIENCIA E INNOVACION; FUNDACIÓN PARA LA INVESTIGACIÓN DEL HOSPITAL UNIVERSITARIO LA FE DE LA COMUNIDAD VALENCIANA . 2009