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. 2024 Sep;38(9):1929-1937.
doi: 10.1038/s41375-024-02333-4. Epub 2024 Jul 4.

Rearrangements involving 11q23.3/KMT2A in adult AML: mutational landscape and prognostic implications - a HARMONY study

Alberto Hernández-Sánchez  1   2   3 , Teresa González  2   3 , Marta Sobas  4 , Eric Sträng  5 , Gastone Castellani  6 , María Abáigar  2   3 , Peter J M Valk  7 , Ángela Villaverde Ramiro  2   3 , Axel Benner  8 , Klaus H Metzeler  9 , Raúl Azibeiro  1   2 , Jesse M Tettero  10 , Joaquín Martínez-López  11 , Marta Pratcorona  12 , Javier Martínez Elicegui  2   3 , Ken I Mills  13 , Christian Thiede  14 , Guillermo Sanz  15   16 , Konstanze Döhner  17 , Michael Heuser  18 , Torsten Haferlach  19 , Amin T Turki  20   21 , Dirk Reinhardt  22 , Renate Schulze-Rath  23 , Martje Barbus  24 , Jesús María Hernández-Rivas  1   2   3   25 , Brian Huntly  26 , Gert Ossenkoppele  10 , Hartmut Döhner  17 , Lars Bullinger  27
Affiliations

Rearrangements involving 11q23.3/KMT2A in adult AML: mutational landscape and prognostic implications - a HARMONY study

Alberto Hernández-Sánchez et al. Leukemia. 2024 Sep.

Abstract

Balanced rearrangements involving the KMT2A gene (KMT2Ar) are recurrent genetic abnormalities in acute myeloid leukemia (AML), but there is lack of consensus regarding the prognostic impact of different fusion partners. Moreover, prognostic implications of gene mutations co-occurring with KMT2Ar are not established. From the HARMONY AML database 205 KMT2Ar adult patients were selected, 185 of whom had mutational information by a panel-based next-generation sequencing analysis. Overall survival (OS) was similar across the different translocations, including t(9;11)(p21.3;q23.3)/KMT2A::MLLT3 (p = 0.756). However, independent prognostic factors for OS in intensively treated patients were age >60 years (HR 2.1, p = 0.001), secondary AML (HR 2.2, p = 0.043), DNMT3A-mut (HR 2.1, p = 0.047) and KRAS-mut (HR 2.0, p = 0.005). In the subset of patients with de novo AML < 60 years, KRAS and TP53 were the prognostically most relevant mutated genes, as patients with a mutation of any of those two genes had a lower complete remission rate (50% vs 86%, p < 0.001) and inferior OS (median 7 vs 30 months, p < 0.001). Allogeneic hematopoietic stem cell transplantation in first complete remission was able to improve OS (p = 0.003). Our study highlights the importance of the mutational patterns in adult KMT2Ar AML and provides new insights into more accurate prognostic stratification of these patients.

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Conflict of interest statement

MS: honoraria from Novartis, Celgene, AOP Orphan, AbbVie. KHM: honoraria from AbbVie, Bristol Myers Squibb, Celgene, Janssen, Novartis, Pfizer, Otsuka; research funding from AbbVie. RA: honoraria from Astellas, Bristol Myers Squibb, Incyte, and Novartis. MP: honoraria from Novartis. CT: co-owner and CEO of AgenDix GmbH and has received lecture fees and/or participated in Ad-Boards from Novartis, Jazz Pharmaceuticals, Astellas, Janssen, Illumina; research funding from Novartis, Bayer. GS: honoraria from Takeda and has participated in Ad-Boards from Novartis, Celgene, Abbvie, Helsinn and Takeda. KD: honoraria from Novartis, Jazz Pharmaceuticals, Abbvie; has participated in Ad-Boards from Novartis, Bristol Myers Squibb, Jazz Pharmaceuticals, Abbvie; research funding from Novartis, Astellas, Agios, Bristol Myers Squibb, Kronos. MH: honoraria from Takeda, Novartis, Janssen, Jazz Pharmaceuticals, Eurocept, Abbvie and has participated in Ad-Boards from Kura Oncology, Glycostem, Daiichi Sankyo, Bristol Myers Squibb, Novartis, Jazz Pharmaceuticals, Abbvie, Pfizer, PinotBio, Roche, Tolremo; research funding from Glycostem, Daiichi Sankyo, Bristol Myers Squibb, Novartis, Jazz Pharmaceuticals, Abbvie, Pfizer, PinotBio, Roche, Astellas, Bayer, BergenBio, Loxo Oncology. TH: current employment at Munich Leukemia Laboratory, with part ownership. ATT: Consultancy for CSL Behring, Maat Pharma, Biomarin and Onkowissen; travel reimbursements from Neovii Biotech. DR: has participated in Ad-Boards from Bristol Myers Squibb, Novartis, Cerus, Medac, EUSA Pharma, Bluebird Bio; research funding from Novartis, BlueBird Bio. RSR: current employment at Bayer Pharma AG. MB: current employment at Abbvie. JMHR: honoraria from Bristol Myers Squibb, Pfizer, Amgen, Celgene, GSK, Novartis; advisory role for Bristol Myers Squibb, Pfizer, Amgen, Celgene, Novartis, Janssen, Roche, Abbvie, AstraZeneca, Beigene, Lilly, Gilead, Takeda, Jazz Pharmaceuticals, Rovi, Incyte; research funding from Bristol Myers Squibb, Celgene, Novartis. BH: honoraria from Pfizer, Bristol Myers Squibb, Novartis; research funding from AstraZeneca. GO: honoraria from Abbvie, Jazz Pharmaceuticals, Astellas, Gilead, Bristol Myers Squibb, Servier, Roche. HD: advisory role for AbbVie, Agios, Amgen, Astellas, AstraZeneca, Berlin-Chemie, Bristol Myers Squibb, Celgene, GEMoaB, Gilead Sciences, Janssen, Jazz Pharmaceuticals, Novartis, Syndax; research funding from AbbVie, Agios, Amgen, Astellas, Bristol Myers Squibb, Jazz Pharmaceuticals, Kronos-Bio, Novartis. LB: honoraria from AbbVie, Amgen, Astellas, Bristol Myers Squibb, Celgene, Daiichi Sankyo, Gilead, Hexal, Janssen, Jazz Pharmaceuticals, Menarini, Novartis, Pfizer, Roche and Sanofi; research funding from Bayer, Jazz Pharmaceuticals.

Figures

Fig. 1
Fig. 1. Mutational landscape and additional cytogenetic aberrations in KMT2Ar adult AML by fusion partner.
Only mutations present in at least five patients and most frequent cytogenetic aberrations are shown. Allo-HSCT allogeneic hematopoietic stem cell transplantation; CA complex cytogenetic aberrations (≥2 apart from KMT2Ar); MDS myelodysplastic syndrome; t-AML therapy-related acute myeloid leukemia.
Fig. 2
Fig. 2. Comparison of survival outcomes between t(9;11) and the rest of the KMT2Ar cohort.
A Overall survival. B Relapse-free survival.
Fig. 3
Fig. 3. Impact of different gene mutations on overall survival in KMT2Ar AML.
A KRAS, B DNMT3A, C TP53, D comparison of patients with either KRAS-mut, DNMT3A-mut or TP53-mut and the rest of the KMT2Ar AML cohort; OS overall survival; mut mutated; wt wildtype.
Fig. 4
Fig. 4. Multivariate Cox regression model for prediction of overall survival in intensively treated patients.
HR hazard ratio; CI confidence interval; AML acute myeloid leukemia; MDS myelodysplastic syndrome; mut mutated.
Fig. 5
Fig. 5. Impact of different gene mutations on overall survival in patients with de novo KMT2Ar AML and aged ≤60 years.
A KRAS, B TP53, C comparison of overall survival of patients with any high-risk genes mutated (either KRAS-mut, or TP53-mut) and the rest of patients aged ≤60 years with de novo AML, D comparison of relapse-free survival of patients with any high-risk mutated genes (either KRAS-mut or TP53-mut) and the rest of patients aged ≤60 years with de novo AML. OS overall survival; RFS relapse-free survival; mut mutated; wt wildtype; HR high-risk genes (KRAS, TP53).
See this image and copyright information in PMC

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