Midostaurin shapes macroclonal and microclonal evolution of FLT3-mutated acute myeloid leukemia
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 molecula...
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Elsevier
2025-01-01
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| Series: | Blood Advances |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2473952924006165 |
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| author | Romane Joudinaud Augustin Boudry Laurène Fenwarth Sandrine Geffroy Mikaël Salson Hervé Dombret Céline Berthon Arnaud Pigneux Delphine Lebon Pierre Peterlin Simon Bouzy Pascale Flandrin-Gresta Emmanuelle Tavernier Martin Carre Sylvie Tondeur Lamya Haddaoui Raphael Itzykson Sarah Bertoli Audrey Bidet Eric Delabesse Mathilde Hunault Christian Récher Claude Preudhomme Nicolas Duployez Pierre-Yves Dumas |
| author_facet | Romane Joudinaud Augustin Boudry Laurène Fenwarth Sandrine Geffroy Mikaël Salson Hervé Dombret Céline Berthon Arnaud Pigneux Delphine Lebon Pierre Peterlin Simon Bouzy Pascale Flandrin-Gresta Emmanuelle Tavernier Martin Carre Sylvie Tondeur Lamya Haddaoui Raphael Itzykson Sarah Bertoli Audrey Bidet Eric Delabesse Mathilde Hunault Christian Récher Claude Preudhomme Nicolas Duployez Pierre-Yves Dumas |
| author_sort | Romane Joudinaud |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-01a94cc50f2545dcb831b74580d7449d |
| institution | Kabale University |
| issn | 2473-9529 |
| language | English |
| publishDate | 2025-01-01 |
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| series | Blood Advances |
| spelling | doaj-art-01a94cc50f2545dcb831b74580d7449d2025-01-18T05:04:58ZengElsevierBlood Advances2473-95292025-01-0192365374Midostaurin shapes macroclonal and microclonal evolution of FLT3-mutated acute myeloid leukemiaRomane Joudinaud0Augustin Boudry1Laurène Fenwarth2Sandrine Geffroy3Mikaël Salson4Hervé Dombret5Céline Berthon6Arnaud Pigneux7Delphine Lebon8Pierre Peterlin9Simon Bouzy10Pascale Flandrin-Gresta11Emmanuelle Tavernier12Martin Carre13Sylvie Tondeur14Lamya Haddaoui15Raphael Itzykson16Sarah Bertoli17Audrey Bidet18Eric Delabesse19Mathilde Hunault20Christian Récher21Claude Preudhomme22Nicolas Duployez23Pierre-Yves Dumas24INSERM UMR1277, Centre National de la Recherche Scientifique UMR9020-CANTHER, Lille University Hospital, Université de Lille, Lille, France; Hematology Laboratory, Centre Hospitalier Universitaire de Lille, Lille, FranceHematology Laboratory, Centre Hospitalier Universitaire de Lille, Lille, France; ULR 2694 Metrics, Centre Hospitalier Universitaire de Lille, Université de Lille, Lille, FranceINSERM UMR1277, Centre National de la Recherche Scientifique UMR9020-CANTHER, Lille University Hospital, Université de Lille, Lille, France; Hematology Laboratory, Centre Hospitalier Universitaire de Lille, Lille, FranceINSERM UMR1277, Centre National de la Recherche Scientifique UMR9020-CANTHER, Lille University Hospital, Université de Lille, Lille, France; Hematology Laboratory, Centre Hospitalier Universitaire de Lille, Lille, FranceUMR 9189 Cristal, Centrale Lille, Centre National de la Recherche Scientifique, Université de Lille, Lille, FranceDépartement Hématologie et Immunologie, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Paris, FranceINSERM UMR1277, Centre National de la Recherche Scientifique UMR9020-CANTHER, Lille University Hospital, Université de Lille, Lille, France; Hematology Department, Centre Hospitalier Universitaire Lille, Lille, FranceService d’Hématologie Clinique et de Thérapie Cellulaire, Centre Hospitalier Universitaire Bordeaux, Bordeaux, FranceHematology Department, Centre Hospitalier Universitaire Amiens-Picardie, Amiens, FranceService d'hématologie clinique, Nantes University Hospital, Nantes, FranceHematology Biology, Nantes University Hospital, Nantes, FranceHematology Laboratory, University Hospital of Saint-Etienne, Saint-Etienne, FranceDépartement d'hématologie clinique, Centre Hospitalier Universitaire de Saint-Étienne, Saint-Priest-en-Jarez, FranceDépartement d'hématologie, Centre Hospitalier Universitaire de Grenoble, Grenoble, FranceLaboratoire de Génétique des hémopathies, Institut de Biologie et Pathologie, Centre Hospitalier Universitaire Grenoble, Grenoble, FranceFrench Innovative Leukemia Organization Tumor Bank, Pitié-Salpêtrière Hospital, Paris, FranceDépartement Hématologie et Immunologie, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Paris, France; Génomes, Biologie Cellulaire et Thérapeutique U944, INSERM, Centre National de la Recherche Scientifique, Université Paris Cité, Paris, FranceService d’Hématologie, Institut Universitaire du Cancer de Toulouse Oncopole, Centre Hospitalier Universitaire Toulouse, Université Toulouse III Paul Sabatier, Toulouse, FranceLaboratoire d’Hématologie Biologique, Centre Hospitalier Universitaire Bordeaux, Bordeaux, FranceLaboratoire d'Hématologie Biologique, Institut Universitaire du Cancer de Toulouse Oncopole, Centre Hospitalier Universitaire de Toulouse, Toulouse, FranceDépartement des Maladies du Sang, Centre Hospitalier Universitaire 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, FranceService d’Hématologie, Institut Universitaire du Cancer de Toulouse Oncopole, Centre Hospitalier Universitaire Toulouse, Université Toulouse III Paul Sabatier, Toulouse, FranceINSERM UMR1277, Centre National de la Recherche Scientifique UMR9020-CANTHER, Lille University Hospital, Université de Lille, Lille, France; Hematology Laboratory, Centre Hospitalier Universitaire de Lille, Lille, FranceINSERM UMR1277, Centre National de la Recherche Scientifique UMR9020-CANTHER, Lille University Hospital, Université de Lille, Lille, France; Hematology Laboratory, Centre Hospitalier Universitaire de Lille, Lille, FranceService d’Hématologie Clinique et de Thérapie Cellulaire, Centre Hospitalier Universitaire Bordeaux, Bordeaux, France; Correspondence: Pierre-Yves Dumas, Hématologie Clinique et Thérapie Cellulaire, Centre Hospitalier Universitaire Bordeaux, 1 avenue Magellan, Hôpital du Haut-Lévèque, F-33000 Bordeaux, France;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.http://www.sciencedirect.com/science/article/pii/S2473952924006165 |
| spellingShingle | Romane Joudinaud Augustin Boudry Laurène Fenwarth Sandrine Geffroy Mikaël Salson Hervé Dombret Céline Berthon Arnaud Pigneux Delphine Lebon Pierre Peterlin Simon Bouzy Pascale Flandrin-Gresta Emmanuelle Tavernier Martin Carre Sylvie Tondeur Lamya Haddaoui Raphael Itzykson Sarah Bertoli Audrey Bidet Eric Delabesse Mathilde Hunault Christian Récher Claude Preudhomme Nicolas Duployez Pierre-Yves Dumas Midostaurin shapes macroclonal and microclonal evolution of FLT3-mutated acute myeloid leukemia Blood Advances |
| title | Midostaurin shapes macroclonal and microclonal evolution of FLT3-mutated acute myeloid leukemia |
| title_full | Midostaurin shapes macroclonal and microclonal evolution of FLT3-mutated acute myeloid leukemia |
| title_fullStr | Midostaurin shapes macroclonal and microclonal evolution of FLT3-mutated acute myeloid leukemia |
| title_full_unstemmed | Midostaurin shapes macroclonal and microclonal evolution of FLT3-mutated acute myeloid leukemia |
| title_short | Midostaurin shapes macroclonal and microclonal evolution of FLT3-mutated acute myeloid leukemia |
| title_sort | midostaurin shapes macroclonal and microclonal evolution of flt3 mutated acute myeloid leukemia |
| url | http://www.sciencedirect.com/science/article/pii/S2473952924006165 |
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