Midostaurin shapes macroclonal and microclonal evolution of FLT3-mutated acute myeloid leukemia - Université de Picardie Jules Verne
Article Dans Une Revue Blood Advances Année : 2024

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

1 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
2 LilNCog - Lille Neurosciences & Cognition - U 1172
3 CRIStAL - Centre de Recherche en Informatique, Signal et Automatique de Lille - UMR 9189
4 BONSAI - Bioinformatics and Sequence Analysis
5 IRSL - Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine ; ex- Institut Universitaire Hématologie-IUH)
6 AP-HP - Hopital Saint-Louis [AP-HP]
7 Hôpital Claude Huriez [Lille]
8 SMS - Service des Maladies du Sang [CHU Lille]
9 CHU Bordeaux
10 CHU Amiens-Picardie
11 HEMATIM - HEMATIM - Hématopoïèse et immunologie - UR UPJV 4666
12 CHU Nantes - Centre Hospitalier Universitaire de Nantes = Nantes University Hospital
13 CRCI2NA - Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes-Angers
14 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Pontchaillou]
15 CHU ST-E - Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne]
16 Institut de Cancérologie de la Loire Lucien Neuwirth
17 CHUGA - Centre Hospitalier Universitaire [CHU Grenoble]
18 IC UM3 (UMR 8104 / U1016) - Institut Cochin
19 GenCellDis (U944 / UMR7212) - Génomes, biologie cellulaire et thérapeutiques
20 IUCT Oncopole - UMR 1037 - Institut Universitaire du Cancer de Toulouse - Oncopole
21 CRCT - Centre de Recherches en Cancérologie de Toulouse
22 Service d'Hématologie Biologique [CHU Bordeaux]
23 Service Hématologie - IUCT-Oncopole [CHU Toulouse]
Arnaud Pigneux
  • Fonction : Auteur
Lamya Haddaoui
  • Fonction : Auteur
Mathilde Hunault
Christan Récher
Claude Preudhomme
Nicolas Duployez
Pierre-Yves Dumas

Résumé

Despite the use of midostaurin (MIDO) with intensive chemotherapy (ICT) as the front-line treatment for FLT3-mutated acute myeloid leukemia (AML), complete remission rates are close to 60-70%, and relapses occur in over 40% of cases. Here we studied the molecular mechanisms underlying refractory/relapsed (R/R) situation in FLT3-mutated AML patients. We conducted a retrospective and multicenter study involving 150 patients with R/R AML harboring FLT3-ITD (n=130) and/or FLT3-TKD (n=26) at diagnosis assessed by standard methods. Patients were treated in front-line 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 co-mutations 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] < 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 compared with patients not receiving MIDO (68% vs. 87.5%, P=0.011). In patients receiving ICT + MIDO, detection of multiple FLT3-ITD clones (referred to as "clonal interference") was associated with a higher FLT3-ITD persistence rate at R/R disease (multiple clones: 88% vs. single clones: 57%, P=0.049). Considering both treatment groups, if only 24% of FLT3-ITD microclones detected at diagnosis were retained at relapse, 43% of them became macroclones. Together, these results identify parameters influencing the fitness of FLT3-ITD clones and highlight the importance of using sensitive techniques for FLT3­-ITD screening in clinical practice.

Domaines

Hématologie
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Dates et versions

hal-04752501 , version 1 (24-10-2024)

Identifiants

Citer

Romane Joudinaud, Augustin Boudry, Laurène Fenwarth, Sandrine Geffroy, Mikaël Salson, et al.. Midostaurin shapes macroclonal and microclonal evolution of FLT3-mutated acute myeloid leukemia. Blood Advances, 2024, ⟨10.1182/bloodadvances.2024014672⟩. ⟨hal-04752501⟩
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