Midostaurin shapes macroclonal and microclonal evolution of <i>FLT3</i>-mutated acute myeloid leukemia

Despite the use of midostaurin (MIDO) with intensive chemotherapy (ICT) as frontline treatment for Fms-like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia (AML), complete remission rates are close to 60% to 70%, and relapses occur in >40% of cases. Here, we studied the molecular mechanisms underlying refractory/relapsed (R/R) disease in patients with FLT3-mutated AML. We conducted a retrospective and multicenter study involving 150 patients with R/R AML harboring FLT3-internal tandem duplication (ITD) (n = 130) and/or FLT3-tyrosine kinase domain mutation (n = 26) at diagnosis assessed by standard methods. Patients were treated with ICT + MIDO (n = 54) or ICT alone (n = 96) according to the diagnosis date and label of MIDO. The evolution of FLT3 clones and comutations was analyzed in paired diagnosis-R/R samples by targeted high-throughput sequencing. Using a dedicated algorithm for FLT3-ITD detection, 189 FLT3-ITD microclones (allelic ratio [AR] of <0.05) and 225 macroclones (AR ≥ 0.05) were detected at both time points. At R/R disease, the rate of FLT3-ITD persistence was lower in patients treated with ICT + MIDO than in patients not receiving MIDO (68% vs 87.5%; P = .011). In patients receiving ICT + MIDO, detection of multiple FLT3-ITD clones was associated with a higher FLT3-ITD persistence rate at R/R disease (multiple clones: 88% vs single clones: 57%; P = .049). If only 24% of FLT3-ITD microclones detected at diagnosis were retained at relapse, 43% became macroclones. Together, these results identify parameters influencing the fitness of FLT3-ITD clones.

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Publication Details

Journal
Blood Advances
Published
2024-10-17
DOI
https://doi.org/10.1182/bloodadvances.2024014672
Citations
4
Primary Topic
Acute Myeloid Leukemia Research
Type
article
Field-Weighted Citation Impact
1.82
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article

Midostaurin shapes macroclonal and microclonal evolution of FLT3-mutated acute myeloid leukemia

Arnaud Pigneux, Audrey Bidet, Raphaël Itzykson, Mathilde Hunault et al.
4 citations
Blood Advances
Acute Myeloid Leukemia Research
1.82
article

Midostaurin shapes macroclonal and microclonal evolution of FLT3-mutated acute myeloid leukemia

Arnaud Pigneux, Audrey Bidet, Raphaël Itzykson, Mathilde Hunault, Emmanuelle Tavernier, Éric Delabesse, Christian Récher, Augustin Boudry, Claude Preudhomme, Pierre‐Yves Dumas, Pierre Péterlin, Laurène Fenwarth, Hervé Dombret, Sarah Bertoli, Delphine Lebon, Romane Joudinaud, Sandrine Geffroy, Lamya Haddaoui, Simon Bouzy, Céline Berthon, Nicolas Duployez, Martin Carré, Pascale Flandrin‐Gresta, Mikaël Salson, Sylvie Tondeur
article en
4 citations

Abstract

Despite the use of midostaurin (MIDO) with intensive chemotherapy (ICT) as frontline treatment for Fms-like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia (AML), complete remission rates are close to 60% to 70%, and relapses occur in >40% of cases. Here, we studied the molecular mechanisms underlying refractory/relapsed (R/R) disease in patients with FLT3-mutated AML. We conducted a retrospective and multicenter study involving 150 patients with R/R AML harboring FLT3-internal tandem duplication (ITD) (n = 130) and/or FLT3-tyrosine kinase domain mutation (n = 26) at diagnosis assessed by standard methods. Patients were treated with ICT + MIDO (n = 54) or ICT alone (n = 96) according to the diagnosis date and label of MIDO. The evolution of FLT3 clones and comutations was analyzed in paired diagnosis-R/R samples by targeted high-throughput sequencing. Using a dedicated algorithm for FLT3-ITD detection, 189 FLT3-ITD microclones (allelic ratio [AR] of <0.05) and 225 macroclones (AR ≥ 0.05) were detected at both time points. At R/R disease, the rate of FLT3-ITD persistence was lower in patients treated with ICT + MIDO than in patients not receiving MIDO (68% vs 87.5%; P = .011). In patients receiving ICT + MIDO, detection of multiple FLT3-ITD clones was associated with a higher FLT3-ITD persistence rate at R/R disease (multiple clones: 88% vs single clones: 57%; P = .049). If only 24% of FLT3-ITD microclones detected at diagnosis were retained at relapse, 43% became macroclones. Together, these results identify parameters influencing the fitness of FLT3-ITD clones.

Blood AdvancesVol. 9(2)
Centre National de la Recherche Scientifique (FR), Université Toulouse III - Paul Sabatier (FR), Inserm (FR), Université Fédérale de Toulouse Midi-Pyrénées (FR), Université Paris Cité (FR), Université de Lille (FR), Centre Hospitalier Universitaire de Grenoble (FR), Centre Hospitalier Universitaire de Bordeaux (FR), Centre Hospitalier Universitaire de Lille (FR), Centre Hospitalier Universitaire de Nantes (FR), Centre Hospitalier Universitaire de Toulouse (FR), Sorbonne Université (FR), Centre de Recherches en Cancérologie de Toulouse (FR), Lille’s Cardiology Hospital (FR), Sorbonne Paris Cité (FR), Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes Angers (FR), Centre Hospitalier Universitaire Amiens-Picardie (FR), Assistance Publique – Hôpitaux de Paris (FR), Institut universitaire du cancer de Toulouse Oncopole (FR), Laboratoire de Thermique et Energie de Nantes (FR), Institute Cancer De La Loire Lucien Neuwirth (FR), Centre Hospitalier Universitaire d'Angers (FR), Pitié-Salpêtrière Hospital (FR), Centre d'Investigation Clinique de Nantes (FR), Hôpital Saint-Louis (FR), Centre Hospitalier Universitaire de Rennes (FR), Centre Hospitalier Universitaire de Saint-Étienne (FR), École Centrale de Lille (FR), Université Grenoble Alpes (FR), Nantes Université (FR)
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Acute Myeloid Leukemia Research
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