Prognostic impact of FLT3-ITD microclones in young adults with acute myeloid leukemia treated with intensive chemotherapy

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 1 733 patients with newly diagnosed AML enrolled in the BIG-1 trial (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 (sHR 1.50 [95% 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, 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. 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 ELN guidelines.

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Journal
Blood
Published
2026-05-21
DOI
https://doi.org/10.1182/blood.2025032829
Primary Topic
Acute Myeloid Leukemia Research
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article

Prognostic impact of FLT3-ITD microclones in young adults with acute myeloid leukemia treated with intensive chemotherapy

Laurence Sanhès, Maël Heiblig, Éric Delabesse, Isabelle Luquet et al.
Blood
Acute Myeloid Leukemia Research
article

Prognostic impact of FLT3-ITD microclones in young adults with acute myeloid leukemia treated with intensive chemotherapy

Laurence Sanhès, Maël Heiblig, Éric Delabesse, Isabelle Luquet, Augustin Boudry, Felipe Suarez, Sylvain Chantepie, Pierre Péterlin, Laurène Fenwarth, Pascal Turlure, Émilie Lemasle, Norbert Ifrah, Lucie Rigolot, Jean‐François Hamel‐Broza, Cécile Pautas, Samy Chraïbi, Norbert Vey, Karine Celli‐Lebras, Célestine Simand, Romane Joudinaud, Juliette Lambert, Ludovic Gabellier, Nicolas Duployez, Martin Carré, Tony Marchand, Suzanne Tavitian, Maria Pilar Gallego-Hernanz, Stephane de Botton, Mathilde Hunault, Claude Preudhomme, Dominique Penther, Hervé Dombret, Emmanuel Raffoux, Romain Guieze, Arnaud Pigneux, Ariane Mineur, Pierre-Yves Dumas, Anne Huynh, Christian Récher, Claude Gardin, Régis Peffault de Latour, Sarah Bertoli, Raphaël A. Itzykson, Emmanuelle Tavernier
article en

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 1 733 patients with newly diagnosed AML enrolled in the BIG-1 trial (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 (sHR 1.50 [95% 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, 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. 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 ELN guidelines.

Blood
Northwest African American Museum (US), Inserm (FR), Université Paris Cité (FR), Université de Lille (FR), Université Nantes Angers Le Mans (FR), Centre Hospitalier Universitaire de Grenoble (FR), Institut Gustave Roussy (FR), Centre Hospitalier Universitaire de Lille (FR), Centre Hospitalier Universitaire de Toulouse (FR), Centre de Recherches en Cancérologie de Toulouse (FR), Centre Hospitalier de Perpignan (FR), Lille’s Cardiology Hospital (FR), Centre Hospitalier Universitaire de Montpellier (FR), Acute Leukemia French Association (FR), Assistance Publique – Hôpitaux de Paris (FR), Institut universitaire du cancer de Toulouse Oncopole (FR), Hospices Civils de Lyon (FR), Laboratoire de Physique Nucléaire et de Hautes Énergies (FR), Bordeaux Population Health (FR), Centre Hospitalier Universitaire de Poitiers (FR), Institute Cancer De La Loire Lucien Neuwirth (FR), Centre Hospitalier Universitaire d'Angers (FR), Centre Hospitalier Universitaire de Limoges (FR), Hôpital Cardiologique du Haut-Lévêque (FR), Centre Hospitalier Universitaire de Clermont-Ferrand (FR), Hôpital Saint-Louis (FR), Institut National du Cancer (FR), Institut Paoli-Calmettes (FR), Centre Hospitalier Universitaire de Rennes (FR), Centre Hospitalier Universitaire de Saint-Étienne (FR), Centre Hospitalier de Versailles (FR), Centre Henri Becquerel (FR), Université de Strasbourg (FR), Nantes Université (FR), Université de Caen Normandie (FR)
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