Prognostic impact of <i>FLT3</i> -ITD microclones in young adults with acute myeloid leukemia treated with intensive chemotherapy
Abstract
Abstract FLT3 internal tandem duplications (FLT3-ITD) are major genetic events in acute myeloid leukemia (AML). Although the clinical impact of FLT3-ITD “macroclones” (allelic ratio [AR] ≥0.05) is well established, the significance of low-level FLT3-ITD subclones (“microclones”) remains uncertain. We conducted a post hoc analysis of 1733 patients with newly diagnosed AML enrolled in the Backbone Intergroup 1 trial (ClinicalTrials.gov identifier: NCT02416388). Using next-generation sequencing (NGS), we detected FLT3-ITD microclones (AR between 0.0004 and 0.05) in 17.4% of patients without FLT3-ITD macroclones. Microclones and macroclones (low and high AR) were independently associated with increased relapse risk (cause-specific hazard ratio, 1.50 [95% confidence interval (CI), 1.18-1.91]; 1.98 [1.50-2.62]; and 2.33 [1.69-3.22], respectively) after adjustment for age, white blood cell count, other gene mutations, midostaurin treatment, and allogeneic hematopoietic stem cell transplantation. At 2 years, the cumulative incidence of relapse reached 42.5% (95% CI, 37.0-47.9) in patients with macroclones, 45.1% (38.3-51.6) in patients with microclones, and 29.4% (26.6-32.3) in patients without FLT3-ITD. In NPM1-mutated AML, both microclones and macroclones were associated with higher levels of measurable residual disease (MRD) and increased relapse risk, without independent impact on overall survival after adjustment for MRD. An analysis of paired samples further revealed that 41.8% of relapses in patients with FLT3-ITD microclones at diagnosis were associated with a macroclone at relapse. These findings challenge current risk stratification models and support the integration of NGS-based FLT3-ITD detection into the diagnostic and prognostic workflow for AML. Prospective trials addressing the management of patients with FLT3-ITD microclones are warranted, as is their consideration in future European LeukemiaNet guidelines.
Article Details
Authors (45)
Nicolas Duployez
Unité Mixte de Recherche (UMR) 9020-UMR-S 1277-Canther-Cancer Heterogeneity, Plasticity and Resistance to Therapies, Institut de Recherche contre le Cancer de Lille, University of Lille, CNRS, Inserm, Centre Hospitalier Universitaire Lille, Lille, France
Romane Joudinaud
1Laboratory of Hematology, Centre Hospitalier Universitaire de Lille, Université de Lille, INSERM U1366, Lille, France
Augustin Boudry
1Laboratory of Hematology, Centre Hospitalier Universitaire de Lille, Université de Lille, INSERM U1366, Lille, France
Mathilde Hunault
2Department of Hematology, Centre Hospitalier Universitaire d’Angers, INSERM, Centre National de la Recherche Scientifique, Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes Angers, Fédération Hospitalo-Universitaire Grand Ouest Against Leukemia, Université d’Angers, Université de Nantes, Angers, France
Laurene Fenwarth
Unité Mixte de Recherche (UMR) 9020-UMR-S 1277-Canther-Cancer Heterogeneity, Plasticity and Resistance to Therapies, Institut de Recherche contre le Cancer de Lille, University of Lille, CNRS, Inserm, Centre Hospitalier Universitaire Lille, Lille, France
Emmanuelle Tavernier
Cécile Pautas
4Department of Hematology, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Créteil, France
Sarah Bertoli
Suzanne Tavitian
Emmanuel Raffoux
Marie-Anne Hospital
7Department of Hematology, Institut Paoli-Calmettes, Marseille, France
Tony Marchand
Maël Heiblig
9Department of Hematology, Centre Hospitalier Universitaire de Lyon, Lyon, France
Sylvain Chantepie
10Department of Hematology, Centre Hospitalier Universitaire de Caen, Caen, France
Martin Carré
Pierre Peterlin
12Department of Hematology, Centre Hospitalier Universitaire de Nantes, Nantes, France
Maria-Pilar Gallego-Hernanz
13Department of Hematology, Centre Hospitalier Universitaire de Poitiers, Poitiers, France
Romain Guieze
14Department of Hematology, Centre Hospitalier Universitaire de Clermont-Ferrand, Clermont-Ferrand, France
Célestine Simand
15Department of Hematology, Centre Hospitalier Universitaire de Strasbourg, Strasbourg, France
Pascal Turlure
16Department of Hematology, Centre Hospitalier Universitaire de Limoges, Limoges, France
Anne Huynh
5Department of Hematology, Centre Hospitalier Universitaire de Toulouse, Toulouse, France
Emilie Lemasle
17Department of Hematology, Centre Henri Becquerel, Rouen, France
Ludovic Gabellier
18Department of Hematology, Centre Hospitalier Universitaire de Montpellier, Montpellier, France
Juliette Lambert
19Department of Hematology, Centre Hospitalier Universitaire de Versailles, Versailles, France
Felipe Suarez
20Department of Hematology, Hôpital Necker, Paris, France
Samy Chraibi
21Department of Hematology, Centre Hospitalier Universitaire de Nîmes, Nîmes, France
Laurence Sanhes
22Department of Hematology, Centre Hospitalier de Perpignan, Perpignan, France
Karine Celli-Lebras
23Acute Leukemia French Intergroup Coordination, Paris, France
Ariane Mineur
24Acute Leukemia French Intergroup Coordination, Bordeaux, France
Claude Gardin
Hématologie Clinique, Hôpital Avicenne, AP-HP, Hôpitaux Universitaires Paris Seine Saint-Denis, Bobigny, France
Norbert Ifrah
2Department of Hematology, Centre Hospitalier Universitaire d’Angers, INSERM, Centre National de la Recherche Scientifique, Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes Angers, Fédération Hospitalo-Universitaire Grand Ouest Against Leukemia, Université d’Angers, Université de Nantes, Angers, France
Norbert Vey
7Department of Hematology, Institut Paoli-Calmettes, Marseille, France
Régis Peffault de Latour
Lucie Rigolot
26Laboratory of Hematology, Centre Hospitalier Universitaire de Toulouse, Toulouse, France
Isabelle Luquet
26Laboratory of Hematology, Centre Hospitalier Universitaire de Toulouse, Toulouse, France
Dominique Penther
27Laboratory of Genetics, Centre Henri Becquerel, Rouen, France
Raphaël Itzykson
6Department of Hematology, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Université Paris Cité, Paris, France
Éric Delabesse
26Laboratory of Hematology, Centre Hospitalier Universitaire de Toulouse, Toulouse, France
Jean-François Hamel
28Department of Biostatistics, Centre Hospitalier Universitaire d’Angers, Angers, France
Stéphane de Botton
Arnaud Pigneux
Hervé Dombret
Christian Récher
Claude Preudhomme
Unité Mixte de Recherche (UMR) 9020-UMR-S 1277-Canther-Cancer Heterogeneity, Plasticity and Resistance to Therapies, Institut de Recherche contre le Cancer de Lille, University of Lille, CNRS, Inserm, Centre Hospitalier Universitaire Lille, Lille, France
Pierre-Yves Dumas