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.

Children's Cancer Center National Center for Child Health and Development Tokyo Japan

DCOG Dutch Childhood Oncology Group Utrecht The Netherlands

Department of Clinical Sciences Pediatrics Umeå University Umeå Sweden

Department of Hematology and Oncology Children's Mercy Hospital Kansas City MO

Department of Oncology St Jude Children's Research Hospital Memphis TN

Department of Pathobiology and Laboratory Medicine University Health Network Toronto General Hospital Toronto ON Canada

Department of Pediatric Hematology and Oncology Aghia Sophia Children's Hospital Athens Greece

Department of Pediatric Hematology and Oncology and Cell and Gene Therapy IRCCS Ospedale Pediatrico Bambino Gesù Catholic University of the Sacred Heart Rome Italy

Department of Pediatric Hematology and Oncology Hôpital Armand Trousseau Paris France

Department of Pediatric Hematology and Oncology Schneider Children's Medical Center and Tel Aviv University Tel Aviv Israel

Department of Pediatric Hematology and Oncology University Hospital Essen Essen Germany

Department of Pediatric Hematology and Oncology University Hospital Motol and 2nd Faculty of Medicine Charles University Prague Czech Republic

Department of Pediatric Hematology Oncology and Stem Cell Transplantation Ghent University Hospital Ghent Belgium

Department of Pediatric Hematology Oncology Ruth Rappaport Children's Hospital Rambam Health Care Campus Haifa Israel

Department of Pediatric Oncohematology Hospital Universitari i Politècnic la Fe Valencia Spain

Department of Pediatric Oncology Erasmus Medical Center Sophia Children's Hospital Rotterdam The Netherlands

Department of Pediatrics and Adolescent Medicine Aarhus University Hospital Aarhus Denmark

Department of Pediatrics and Adolescent Medicine Hong Kong Children's Hospital Kowloon Bay Hong Kong

Department of Pediatrics Institute of Clinical Sciences Salgrenska University Hospital Gothenburg Sweden

Department of Pediatrics Osaka University Graduate School of Medicine Suita Japan

Department of Pediatrics St Anna Children's Hospital Medical University of Vienna and St Anna Children's Cancer Research Institute Vienna Austria

Department of Pediatrics Wilhelmina Children's Hospital University Medical Center Utrecht Utrecht The Netherlands

Department of Statistics Children's Oncology Group Monrovia CA

Division of Biostatistics University of Southern California Los Angeles CA

Division of Oncology Children's Hospital of Philadelphia Philadelphia PA

Division of Pediatric Hematology Oncology and Stem Cell Transplant Department of Maternal and Child Health Padua University Padua Italy

Emma Children's Hospital Amsterdam University Medical Center Vrije Universiteit Amsterdam Amsterdam The Netherlands

Institut Universitaire du Cancer Toulouse Oncopole Laboratoire d'Hématologie secteur Génétique des Hémopathies Toulouse France

Leukemia Research Cytogenetics Group Translational and Clinical Research Institute Newcastle University Centre for Cancer Newcastle upon Tyne United Kingdom

Princess Máxima Center for Pediatric Oncology Utrecht The Netherlands

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