Prognostic impact of FLT3 ‐ ITD microclones in AML : An EHA AML ‐specialized working group study

Gurnari, Carmelo, Ottone, Tiziana, Piciocchi, Alfonso, Späth, Daniela, Meid, Annika, Marsili, Giovanni, Fabiani, Emiliano, Romano, Francesca, Pascale, Maria Rosaria, Ricci, Paola, Chiusolo, Patrizia, Ianni, Mauro Di, Sobas, Marta, Brunetti, Lorenzo, Oñate, Guadalupe, Infante, Joana Brioso, Nanni, Jacopo, Vetro, Calogero, Boada, Matilde, Candoni, Anna, Sierra, Jorge, Potter, Nicola, Gilkes, Amanda, Johnson, Sean James, Thomas, Ian, Huntly, Brian, Venditti, Adriano, Russell, Nigel, Dillon, Richard, Döhner, Hartmut, Döhner, Konstanze and Voso, Maria Teresa 2026. Prognostic impact of FLT3 ‐ ITD microclones in AML : An EHA AML ‐specialized working group study. American Journal of Hematology 10.1002/ajh.70546

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Abstract

The 2022 ELN recommendations reclassified fms-like tyrosine kinase-3 (FLT3)-ITD mutated acute myeloid leukemia (AML) as intermediate-risk, irrespective of allelic ratio (AR), and designated capillary electrophoresis (CE) as the preferred detection method. However, CE requires substantial expertise, particularly to identify FLT3-ITD microclones (FLT3-ITDm; AR < 0.05), whose clinical significance remains uncertain. Herein, we investigated diagnostic aspects and the prognostic impact of FLT3-ITDm. An initial methodological study performed on 48 FLT3-ITD+ samples, with AR 0.001–6.00, showed overall concordance between CE and next-generation sequencing (NGS) results (p < 0.001), with only three microclones (AR: 0.002, 0.001, and 0.008) identified by CE and not by NGS. We next analyzed 658 AML patients diagnosed with a FLT3-ITD+ AML (n = 446 with AR ≥ 0.05, and n = 212 with a microclone) between 2017 and 2022. Patients with FLT3-ITDm, as compared to patients with AR ≥ 0.05, were older, more often had secondary-type AML, and displayed a higher prevalence of myelodysplasia-related gene mutations, while NPM1-mutation frequency was similar in the two groups. Complete remission rates were lower in FLT3-ITDm (74%) than in patients with AR ≥ 0.05 (88%) treated with intensive chemotherapy without FLT3-inhibitors (FLT3i). In the intensively treated subgroup, multivariate analyses demonstrated that age, NPM1 mutation, and allogeneic stem cell transplantation, rather than FLT3-ITD AR, were independent predictors of disease-free survival. At relapse, 15 of 33 (45%) evaluable patients remained FLT3-ITD+, with 10 expanding the original microclone. In conclusion, FLT3-ITDm are associated with older age, secondary AML, and with expansion of the FLT3-ITD clone upon relapse, thereby providing a rationale for the evaluation of FLT3i in randomized clinical trials.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Schools > Medicine Research Institutes & Centres > Centre for Trials Research (CNTRR)
Publisher:	Wiley
ISSN:	0361-8609
Last Modified:	10 Nov 2026 11:30
URI:	https://orca.cardiff.ac.uk/id/eprint/190801

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