Prognostic Impact of FLT3 ‐ ITD Microclones in AML : An EHA AML ‐Specialized Working Group Study

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 ‐ITD m ; AR < 0.05), whose clinical significance remains uncertain. Herein, we investigated diagnostic aspects and the prognostic impact of FLT3 ‐ITD m . 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 ‐ITD m , 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 ‐ITD m (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 ‐ITD m 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.

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Journal
American Journal of Hematology
Published
2026-11-01
DOI
https://doi.org/10.1002/ajh.70546
Primary Topic
Acute Myeloid Leukemia Research
Type
article
Field-Weighted Citation Impact
0.00

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article

Prognostic Impact of FLT3 ‐ ITD Microclones in AML : An EHA AML ‐Specialized Working Group Study

Richard James Dillon, Anna Candoni, Joana Brioso Infante, Matilde Boada et al.
6 links
American Journal of Hematology
Acute Myeloid Leukemia Research
article

Prognostic Impact of FLT3 ‐ ITD Microclones in AML : An EHA AML ‐Specialized Working Group Study

Richard James Dillon, Anna Candoni, Joana Brioso Infante, Matilde Boada, Annika Meid, Amanda Gilkes, Jorge Sierra, Brian J.P. Huntly, Daniela Späth, Giovanni Marsili, Calogero Vetro, Nigel H. Russell, Jacopo Nanni, Marta Sobas, Alfonso Piciocchi, Patrizia Chiusolo, Maria Rosaria Pascale, Konstanze Döhner, Mauro Di Ianni, Carmelo Gurnari, Maria Teresa Voso, Tiziana Ottone, Emiliano Fabiani, Ian Thomas, Lorenzo Brunetti, Nicola E. Potter, Guadalupe Oñate, Hartmut Döhner, Francesca Romano, Paola Ricci, Adriano Venditti, Sean James Johnson
article en

Abstract

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 ‐ITD m ; AR < 0.05), whose clinical significance remains uncertain. Herein, we investigated diagnostic aspects and the prognostic impact of FLT3 ‐ITD m . 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 ‐ITD m , 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 ‐ITD m (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 ‐ITD m 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.

American Journal of Hematology
University of Rome Tor Vergata (IT), University of Modena and Reggio Emilia (IT), Universitat Autònoma de Barcelona (ES), Cleveland Clinic (US), Universidad de la República de Uruguay (UY), King's College London (GB), Guy's and St Thomas' NHS Foundation Trust (GB), Wellcome/MRC Cambridge Stem Cell Institute (GB), University of Cambridge (GB), Hospital de Sant Pau (ES), Nicolaus Copernicus University (PL), Josep Carreras Leukaemia Research Institute (ES), AULSS 2 Marca Trevigiana (IT), IRCCS Azienda Ospedliero-Universitaria di Bologna Policlinico di Sant'Orsola (IT), Azienda Ospedaliero Universitaria Ospedali Riuniti (IT), Fondazione Gimema Onlus (IT), Collegium Medicum in Bydgoszcz (PL), Hospital de Santa Maria (PT), Hospital de Clínicas (UY), University Hospital Ulm (DE), Azienda Ospedaliero Universitaria Policlinico "G.Rodolico - San Marco" (IT), Cardiff University (GB), University of Bologna (IT)
Fondazione AIRC per la ricerca sul cancro ETS, European Hematology Association, Fondazione Italiana per la Ricerca sul Cancro
Good health and well-being
Openalex Percentile: Top 12%
Acute Myeloid Leukemia Research
DOIOpen Access PDFOpenAlex
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