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. 2024 Jun 25;8(12):3200-3213.
doi: 10.1182/bloodadvances.2023011771.

Optimized cytogenetic risk-group stratification of KMT2A-rearranged pediatric acute myeloid leukemia

Romy E van Weelderen  1   2 , Christine J Harrison  3 , Kim Klein  1   2   4 , Yilin Jiang  1 , Jonas Abrahamsson  5 , Todd Alonzo  6 , Richard Aplenc  7 , Nira Arad-Cohen  8 , Emmanuelle Bart-Delabesse  9 , Barbara Buldini  10 , Barbara De Moerloose  11 , Michael N Dworzak  12 , Sarah Elitzur  13 , José M Fernández Navarro  14 , Alan Gamis  15 , Robert B Gerbing  16 , Bianca F Goemans  1 , Hester A de Groot-Kruseman  1   17 , Erin Guest  15 , Shau-Yin Ha  18 , Henrik Hasle  19 , Charikleia Kelaidi  20 , Hélène Lapillonne  21 , Guy Leverger  21 , Franco Locatelli  22 , Takako Miyamura  23 , Ulrika Norén-Nyström  24 , Sophia Polychronopoulou  20 , Mareike Rasche  25 , Jeffrey E Rubnitz  26 , Jan Stary  27 , Anne Tierens  28 , Daisuke Tomizawa  29 , C Michel Zwaan  1   30 , Gertjan J L Kaspers  1   2
Affiliations

Optimized cytogenetic risk-group stratification of KMT2A-rearranged pediatric acute myeloid leukemia

Romy E van Weelderen et al. Blood Adv. .

Abstract

A comprehensive international consensus on the cytogenetic risk-group stratification of KMT2A-rearranged (KMT2A-r) pediatric acute myeloid leukemia (AML) is lacking. This retrospective (2005-2016) International Berlin-Frankfurt-Münster Study Group study on 1256 children with KMT2A-r AML aims to validate the prognostic value of established recurring KMT2A fusions and additional cytogenetic aberrations (ACAs) and to define additional, recurring KMT2A fusions and ACAs, evaluating their prognostic relevance. Compared with our previous study, 3 additional, recurring KMT2A-r groups were defined: Xq24/KMT2A::SEPT6, 1p32/KMT2A::EPS15, and 17q12/t(11;17)(q23;q12). Across 13 KMT2A-r groups, 5-year event-free survival probabilities varied significantly (21.8%-76.2%; P < .01). ACAs occurred in 46.8% of 1200 patients with complete karyotypes, correlating with inferior overall survival (56.8% vs 67.9%; P < .01). Multivariable analyses confirmed independent associations of 4q21/KMT2A::AFF1, 6q27/KMT2A::AFDN, 10p12/KMT2A::MLLT10, 10p11.2/KMT2A::ABI1, and 19p13.3/KMT2A::MLLT1 with adverse outcomes, but not those of 1q21/KMT2A::MLLT11 and trisomy 19 with favorable and adverse outcomes, respectively. Newly identified ACAs with independent adverse prognoses were monosomy 10, trisomies 1, 6, 16, and X, add(12p), and del(9q). Among patients with 9p22/KMT2A::MLLT3, the independent association of French-American-British-type M5 with favorable outcomes was confirmed, and those of trisomy 6 and measurable residual disease at end of induction with adverse outcomes were identified. We provide evidence to incorporate 5 adverse-risk KMT2A fusions into the cytogenetic risk-group stratification of KMT2A-r pediatric AML, to revise the favorable-risk classification of 1q21/KMT2A::MLLT11 to intermediate risk, and to refine the risk-stratification of 9p22/KMT2A::MLLT3 AML. Future studies should validate the associations between the newly identified ACAs and outcomes and unravel the underlying biological pathogenesis of KMT2A fusions and ACAs.

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Conflict of interest statement

Conflict-of-interest disclosure: B.B. reports being on the speakers' bureau of Beckman Coulter, Becton Dickinson, and Amgen, and received travel and accommodation expenses from Beckman Coulter, Becton Dickinson, and Amgen. B.D.M. received honoraria from Novartis, Gilead Sciences, Pfizer, and Daiichi Sankyo, and travel expenses from Jazz Pharmaceuticals. S.E. received honoraria from Novartis and Medison, and reports a consulting or advisory role with Amgen. E.G. holds stock and other ownership interests in Pfizer and Moderna Therapeutics; reports a consulting or advisory role with Syndax and Jazz Pharmaceuticals; and is on the speakers' bureau of Jazz Pharmaceuticals. H.H. reports a consulting or advisory role with Novartis. F.L. received honoraria from Bellicum Pharmaceuticals, Miltenyi Biotec, bluebird bio, medac, Sobi, and Amgen, and reports a consulting or advisory role with Amgen, Novartis, and Pfizer. T.M. received honoraria from Amgen, Novartis, Sumitomo Dainippon Pharma Oncology, and Chugai Pharma. J.E.R. reports a consulting or advisory role in Kura Oncology, Biomea Fusion, and Pinotbio, and received research funding from AbbVie. A.T. received honoraria from and is on the speakers' bureau of BD Biosciences. C.M.Z. reports a consulting or advisory role in Takeda, Pfizer, AbbVie, Jazz Pharmaceuticals, Incyte, Novartis, and Kura Oncology, and received research funding from Takeda, AbbVie/Genentech, Pfizer, Jazz Pharmaceuticals, Kura Oncology, and Daiichi Sankyo. D.T. received honoraria from Amgen, Novartis, Chugai Pharma, Nippon Shinyaku, Ohara Pharmaceutical, Takeda, and Taiho Pharmaceutical, and reports a consulting or advisory role in Novartis and Meiji Seika Kaisha. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Distribution of the fusion-based groups and the presence and type of ACAs in our cohort of childhood KMT2A-r AML. 9p22/KMT2A::MLLT3 refers to t(9;11)(p22;q23) (n = 544), 10p12/KMT2A::MLLT10 to t(10;11)(p12;q23) (n = 218), 6q27/KMT2A::AFDN to t(6;11)(q27;q23) (n = 92), 19p13.1/KMT2A::ELL to t(11;19)(q23;p13.1) (n = 75), 19p13.3/KMT2A::MLLT1 to t(11;19)(q23;p13.3) (n = 56), 1q21/KMT2A::MLLT11 to t(1;11)(q21;q23) (n = 28), 10p11.2/KMT2A::ABI1 to t(10;11)(p11.2;q23) (n = 24), 19p13 to t(11;19)(q23;p13) without ascertained subband (n = 23), Xq24/KMT2A::SEPT6 to t(X;11)(q24;q23) (n = 22), 17q21 to t(11;17)(q23;q21) (n = 13), 1p32/KMT2A::EPS15 to t(1;11)(p32;q23) (n = 13), 4q21/KMT2A::AFF1 to t(4;11)(q21;q23) (n = 12), and 17q12 to t(11;17)(q23;q12) (n = 10). Of the 1200 patients with complete karyotypes, 638 had no ACAs and 562 had ACAs, of whom 211 had solely numerical ACAs, 159 solely structural aberrations, and 192 both numerical and structural ACAs. Figure created with BioRender.com.
Figure 2.
Figure 2.
Survival curves for pediatric patients with KMT2A-rearranged AML, stratified by fusion-based group. Kaplan-Meier estimates of (A) EFS, (B) CIR, and (C) OS of KMT2A fusion-based groups. KMT2A::MLLT3 refers to t(9;11)(p22;q23) (n = 544), KMT2A::MLLT10 to t(10;11)(p12;q23) (n = 218), KMT2A::AFDN to t(6;11)(q27;q23) (n = 92), KMT2A::ELL to t(11;19)(q23;p13.1) (n = 75), KMT2A::MLLT1 to t(11;19)(q23;p13.3) (n = 56), KMT2A::MLLT11 to t(1;11)(q21;q23) (n = 28), KMT2A::ABI1 to t(10;11)(p11.2;q23) (n = 24), 19p13 to t(11;19)(q23;p13) without ascertained subband (n = 23), KMT2A::SEPT6 to t(X;11)(q24;q23) (n = 22), 17q21 to t(11;17)(q23;q21) (n = 13), KMT2A::EPS15 to t(1;11)(p32;q23) (n = 13), KMT2A::AFF1 to t(4;11)(q21;q23) (n = 12), and 17q12 to t(11;17)(q23;q12) (n = 10).
Figure 3.
Figure 3.
Survival curves for pediatric patients with KMT2A-rearranged AML with and without specific, recurring ACAs. Kaplan-Meier estimates of EFS of patients with and without (A) add (12p), (B) del(9q), (C) monosomy 10, (D) trisomy 1, (E) trisomy 4, (F) trisomy 6, (G) trisomy 8, (H) trisomy 12, (I) trisomy 16, (J) trisomy 17, and (K) trisomy X. Patients with specific ACAs are compared with patients with other ACAs.
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