Balancing benefit and burden: treatment intensification in paediatric KMT2A rearrangements acute myeloid leukaemia

KMT2A Rearrangements in Pediatric Intermediate-Risk Acute Myeloid Leukemia

Authors

  • Hend Fayez Department of Pediatric Oncology, Children’s Cancer Hospital Egypt (CCHE-57357), Cairo, Egypt
  • Mariam Elsherif Department of Pediatric Oncology, Children’s Cancer Hospital Egypt (CCHE-57357), Cairo, Egypt
  • Sherine Salem Department of Clinical Pathology, Children’s Cancer Hospital Egypt (CCHE-57357), Cairo, Egypt; Department of Clinical Pathology, National Cancer Institute, Cairo University, Cairo, Egypt
  • Nahla Elsharkawy Department of Clinical Pathology, Children’s Cancer Hospital Egypt (CCHE-57357), Cairo, Egypt; Department of Clinical Pathology, National Cancer Institute, Cairo University, Cairo, Egypt
  • Amr Elnashar Department of Research and Biostatistics, Children’s Cancer Hospital Egypt (CCHE-57357), Cairo, Egypt
  • Mohamed Kamal Department of Research and Biostatistics, Children’s Cancer Hospital Egypt (CCHE-57357), Cairo, Egypt
  • Reham Khedr Department of Pediatric Oncology, Children’s Cancer Hospital Egypt (CCHE-57357), Cairo, Egypt; Department of Pediatric Oncology, National Cancer Institute, Cairo University, Cairo, Egypt
  • Leslie Lehmann Pediatric Stem Cell Transplantation Unit, Dana-Farber Cancer Institute, Boston, MA, USA
  • Sonia Ahmed Department of Pediatric Oncology, Children’s Cancer Hospital Egypt (CCHE-57357), Cairo, Egypt; Department of Pediatric Oncology, National Cancer Institute, Cairo University, Cairo, Egypt https://orcid.org/0000-0002-8322-4194
  • Alaa Elhaddad Department of Pediatric Oncology, Children’s Cancer Hospital Egypt (CCHE-57357), Cairo, Egypt; Department of Pediatric Oncology, National Cancer Institute, Cairo University, Cairo, Egypt

DOI:

https://doi.org/10.2340/1651-226X.2025.43878

Keywords:

KMT2A-r, additional cytogenetics, AML, different partners

Abstract

Background and purpose: Chromosomal rearrangements involving KMT2A (KMT2A-r) occur in 20% of paediatric acute myeloid leukaemia (AML). Previous studies reported that the outcome depends on the specific fusion partner. The study aimed to report the outcomes of paediatric KMT2A-r AML patients and to assess the impact of different fusion partners.

Patient/material and methods: We retrospectively analysed 610 paediatric patients with intermediate-risk (IR) AML diagnosed at Children’s Cancer Hospital Egypt, from January 2008 to December 2021. Patients were assigned to four groups based on fusion partner.

Results: Of 610 patients diagnosed with IR-AML, 150 (24.6%) had KMT2A rearrangements. KMT2A-r was significantly associated with hyperleukocytosis (P = 0.029), central nervous system (CNS) disease (P = 0.003), monocytic differentiation (P = 0.001), additional cytogenetic abnormalities (ACA) (P = 0.04), and complex karyotype (P = 0.001). Fusion partner, t(9;11) (p22;q23) (9p22/KMT2A::MLLT3 fusion) was most prevalent (40.8%). KMT2A-r was an independent predictor of relapse with a cumulative incidence of relapse (CIR) of 46% versus 30% in KMT2A negative group (P = 0.006). Within the KMT2A-r group, ACA and complex karyotype adversely affected the outcome with 5-year overall survival (OS) of 34% versus 53% (P = 0.027) and 26% versus 51% (P = 0.004), respectively. Outcome varied depending on fusion partner. Event-free survival (EFS) ranged from 50% to 17%, OS from 54% to 27%, and CIR from 75% to 38%.

Interpretation: KMT2A-r is an independent prognostic factor for relapse, and presence of ACA and a complex karyotype in KMT2A-r patients is associated with poorer outcomes, emphasising the need for aggressive and innovative therapeutic strategies.

Downloads

Download data is not yet available.

References

Shimony S, Stahl M, Stone RM. Acute myeloid leukemia: 2023 update on diagnosis, risk-stratification, and management. Am J Hematol. 2023;98:502–526.

https://doi.org/10.1002/ajh.26822 DOI: https://doi.org/10.1002/ajh.26822

Tomizawa D, Tsujimoto, SI. Risk-stratified therapy for pediatric acute myeloid leukemia. Cancers. 2023,15:4171.

https://doi.org/10.3390/cancers15164171 DOI: https://doi.org/10.3390/cancers15164171

van Weelderen R, Klein K, Harrisonvan CJ, Jiang Y, Abrahamsson J,Arad-Cohen N, et al. Measurable residual disease and fusion partner independently predict survival and relapse risk in childhood KMT2A- rearranged acute myeloid leukemia: a study by the international Berlin-Frankfurt-Munster Study Group. J Clin Oncol.41, 2963-2974. 2023.

https://doi.org/10.1200/JCO.22.02120 DOI: https://doi.org/10.1200/JCO.22.02120

Döhner H, Wei AH, Appelbaum FR, Craddock C, DiNardo CD, Dombret H, et al. Diagnosis and management of AML in adults:2022.recommendations from an international expert panel on behalf of the ELN. Blood. 140 (12): 1345–1377. 2022.

https://doi.org/10.1182/blood.2022016867 DOI: https://doi.org/10.1182/blood.2022016867

Pollard JA, Guest E, Alonzo TA, Gerbing RB, Loken MR, Brodersen LE, et al. Gemtuzumab ozogamicin improves event-free survival and reduces relapse in pediatric KMT2A-rearranged AML: results from the phase III Children’s Oncology Group Trial AAML0531. J Clin Oncol. 2021;39(28):3149–60.

https://doi.org/10.1200/JCO.20.03048 DOI: https://doi.org/10.1200/JCO.20.03048

Quessada J, Cuccuini W, Saultier P, Loosveld M, Harrison CJ, Lafage-Pochitaloff M. Cytogenetics of pediatric acute myeloid leukemia: a review of the current knowledge. Genes 2021;12:924.

https://doi.org/10.3390/genes12060924 DOI: https://doi.org/10.3390/genes12060924

van Weelderen E, Harrison CJ, Klein K, Jiang Y, Abrahamsson J, Alonzo T, et al. Optimized cytogenetic risk-group stratification of KMT2A-rearranged pediatric acute myeloid leukemia. Blood Adv. 2024;8(12):3200–13.

https://doi.org/10.1182/bloodadvances.2023011771 DOI: https://doi.org/10.1182/bloodadvances.2023011771

Ahmed S, Elsherif M, Yassin D, El Sharkawy N, Mohamed AS, Yasser N, et al. Integration of measurable residual disease by WT1 gene expression and flow cytometry identifies pediatric patients with high risk of relapse in acute myeloid leukemia. Front. Oncol. 2024;14:1340909.

https://doi.org/10.3389/fonc.2024.1340909 DOI: https://doi.org/10.3389/fonc.2024.1340909

Balgobind BV, Raimondi SC, Harbott J, Zimmermann M, Alonzo TA, Auvrignon A, et al. Novel progostic subgroups in childhood 11q23/MLL-rearranged acute myeloid leukemia: results of an international retrospective study. Blood. 2009;114(12):2489–96.

https://doi.org/10.1182/blood-2009-04-215152 DOI: https://doi.org/10.1182/blood-2009-04-215152

Conneely SE, Rau RE. Fusion and flow: refining risk prediction in KMT2A-rearranged pediatric acute myeloid leukemia. Transl Pediatr 2023;12(12):2099–102.

https://doi.org/10.21037/tp-23-436 DOI: https://doi.org/10.21037/tp-23-436

Yuen K-Y, Liu Y, Zhou Y-Z, Wang Y, Zhou D-H, Fang J-P. Mutational landscape and clinical outcome of pediatric acute myeloid leukemia with 11q23/KMT2A rearrangements. Cancer Medicine. 2023;12:1418–1430.

https://doi.org/10.1002/cam4.5026 DOI: https://doi.org/10.1002/cam4.5026

Candoni A, Coppola G. A 2024 update on menin inhibitors. a new class of target agents against KMT2A-rearranged and NPM1-mutated acute myeloid leukemia. Hematol. Rep. 2024;16:244–54.

https://doi.org/10.3390/hematolrep16020024 DOI: https://doi.org/10.3390/hematolrep16020024

Downloads

Additional Files

Published

2025-09-18

How to Cite

Fayez , H., Elsherif, M., Salem, S., Elsharkawy, N., Elnashar, A., Kamal, M., … Elhaddad, A. (2025). Balancing benefit and burden: treatment intensification in paediatric KMT2A rearrangements acute myeloid leukaemia: KMT2A Rearrangements in Pediatric Intermediate-Risk Acute Myeloid Leukemia. Acta Oncologica, 64, 1227–1236. https://doi.org/10.2340/1651-226X.2025.43878

Issue

Vol. 64 (2025): Acta Oncologica

Section

Original article

License

Copyright (c) 2025 Hend Fayez , Mariam Elsherif, Sherine Salem, Nahla Elsharkawy, Amr Elnashar, Mohamed Kamal, Reham Khedr, Leslie Lehmann, Sonia Ahmed, Alaa Elhaddad

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.