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Multicenter Study
. 2025 Jan 28;9(2):365-374.
doi: 10.1182/bloodadvances.2024014672.

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

Romane Joudinaud  1   2 , Augustin Boudry  2   3 , Laurène Fenwarth  1   2 , Sandrine Geffroy  1   2 , Mikaël Salson  4 , Hervé Dombret  5 , Céline Berthon  1   6 , Arnaud Pigneux  7 , Delphine Lebon  8 , Pierre Peterlin  9 , Simon Bouzy  10 , Pascale Flandrin-Gresta  11 , Emmanuelle Tavernier  12 , Martin Carre  13 , Sylvie Tondeur  14 , Lamya Haddaoui  15 , Raphael Itzykson  5   16 , Sarah Bertoli  17 , Audrey Bidet  18 , Eric Delabesse  19 , Mathilde Hunault  20 , Christian Récher  17 , Claude Preudhomme  1   2 , Nicolas Duployez  1   2 , Pierre-Yves Dumas  7
Affiliations
Multicenter Study

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

Romane Joudinaud et al. Blood Adv. .

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.

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Conflict of interest statement

Conflict-of-interest disclosure: M.C. reports honoraria from AbbVie, Astellas, Jazz, and Bristol Myers Squibb. R.I. reports honoraria from Astellas and Daichii-Sankyo, and research support from Novartis. S. Bertoli declares a consulting or advisory role with Abbvie, Astellas, Bristol Myers Squibb-Celgene, Jazz Pharmaceuticals and Novartis; and received travel grants from Abbvie and Pfizer. C.R. reports consulting or advisory role with AbbVie, Amgen, Astellas, Bristol Myers Squibb, Boehringer, Jazz Pharmaceuticals, Johnson & Johnson, and Servier; received research funding from AbbVie, Amgen, Astellas, Bristol Myers Squibb, Iqvia, and Jazz Pharmaceuticals; and received support for attending meetings and/or travel from AbbVie, Novartis, and Servier. P.-Y.D. reports honoraria and research support to institution from Novartis, Servier, Bristol Myers Squibb, Astellas, and Daiichi-Sankyo; honoraria from AbbVie, Jazz Pharmaceuticals, and Janssen; and research support to institution from Roche. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Evolution of FLT3-ITD mutations between diagnosis and R/R disease. (A) FLT3-ITD status at R/R disease assessed by HTS, according to the treatment group and the type of progression. Left panel: only patients harboring FLT3-ITD macroclones at diagnosis are displayed. Only macroclones are taken into account to determine FLT3-ITD status at R/R disease. Right panel: patients harboring FLT3-ITD microclones and/or macroclones at diagnosis are displayed. Both macroclones and microclones are taken into account to determine FLT3-ITD status at R/R disease. (B) Patterns of evolution of FLT3-ITD microclones and macroclones between diagnosis and R/R disease, according to the number of FLT3-ITD clones detected at diagnosis (either a single clone or multiple clones) and the treatment group. Each square represents 1 patient. Patterns of evolution (from diagnosis to R/R disease) were assessed by HTS and defined as follows. Identical: clone A → clone A. Loss: clone A + clone B → clone A. Gain: clone A → clone A + clone B. Switch: clone A → clone B. Complex changes: clone A + clone B → clone B + clone C. Eradication: clone A → ⦰. ∗, <.05; ∗∗, <.01. Pts, patients.
Figure 2.
Figure 2.
Quantification of FLT3-ITD clones at diagnosis and relapse by HTS. (A) Σnorm-VAFs per sample at diagnosis and relapse, according to the treatment group. Only patients with a positive FLT3-ITD status by HTS at both diagnosis and relapse are displayed. (B) AR at diagnosis for lost and retained FLT3-ITD microclones and macroclones upon AML relapse, according to the treatment group. (C) Evolution of the AR of FLT3-ITD microclones detected at AML diagnosis. Each line features the evolution of a FLT3-ITD microclone between diagnosis and relapse. The threshold is positioned at an AR of 0.05. ∗, <.05; ∗∗∗, <.001. MUT, mutated; Pts, patients.
Figure 3.
Figure 3.
Evolution of gene mutations between diagnosis and R/R disease assessed by HTS. (A-B) Evolution of gene mutations between diagnosis and R/R disease, according to the type of progression: relapse (A) or refractory disease (B) and the treatment group. Genes are organized according to their functional class. Each column represents a single patient. For each patient, the evolution of the gene status is indicated by the color of the boxes. For each gene, the number (n) and percentage (%) of patients with mutated genes at each time point are displayed on the right of the figures. (C-D) Evolution of gene mutations among patients who experienced relapse (C) or refractory disease (D), according to the treatment group. Only patients harboring FLT3-ITD mutations at diagnosis as assessed by HTS are displayed. D, diagnosis; PM, point mutations; R, relapsed (left side) or refractory disease (right side).
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