To study the prognostic relevance of rare genetic aberrations in acute myeloid leukemia (AML), such as t(16;21), international collaboration is required. Two different types of t(16;21) translocations can be distinguished: t(16;21)(p11;q22), resulting in the FUS-ERG fusion gene; and t(16;21)(q24;q22), resulting in RUNX1-core binding factor (CBFA2T3). We collected data on clinical and biological characteristics of 54 pediatric AML cases with t(16;21) rearrangements from 14 international collaborative study groups participating in the international Berlin-Frankfurt-Münster (I-BFM) AML study group. The AML-BFM cohort diagnosed between 1997 and 2013 was used as a reference cohort. RUNX1-CBFA2T3 (n = 23) had significantly lower median white blood cell count (12.5 × 109/L, P = .03) compared with the reference cohort. FUS-ERG rearranged AML (n = 31) had no predominant French-American-British (FAB) type, whereas 76% of RUNX1-CBFA2T3 had an M1/M2 FAB type (M1, M2), significantly different from the reference cohort (P = .004). Four-year event-free survival (EFS) of patients with FUS-ERG was 7% (standard error [SE] = 5%), significantly lower compared with the reference cohort (51%, SE = 1%, P < .001). Four-year EFS of RUNX1-CBFA2T3 was 77% (SE = 8%, P = .06), significantly higher compared with the reference cohort. Cumulative incidence of relapse was 74% (SE = 8%) in FUS-ERG, 0% (SE = 0%) in RUNX1-CBFA2T3, compared with 32% (SE = 1%) in the reference cohort (P < .001). Multivariate analysis identified both FUS-ERG and RUNX1-CBFA2T3 as independent risk factors with hazard ratios of 1.9 (P < .0001) and 0.3 (P = .025), respectively. These results describe 2 clinically relevant distinct subtypes of pediatric AML. Similarly to other core-binding factor AMLs, patients with RUNX1-CBFA2T3 rearranged AML may benefit from stratification in the standard risk treatment, whereas patients with FUS-ERG rearranged AML should be considered high-risk.

Acute Myeloid Leukemia Berlin Frankfurt Münster Study Group Pediatric Hematology and Oncology Essen Germany

Children's Oncology Group Monrovia CA

Czech Pediatric Hematology Oncology University Hospital Motol and Charles University Prague Czech Republic

Department of Cytogenetics Saint Louis Hospital Paris France

Department of Oncology and

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

Department of Pediatric Hematology and Oncology Istituto di Ricovero e Cura a Carattere Scientifico Ospedale Pediatrico Bambino Gesù Rome Italy

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

Department of Pediatric Hematology Oncology Medical School Hannover Hannover Germany

Department of Pediatric Oncology and Hematology Institute of Pediatrics Jagiellonian University Medical College Krakow Poland

Department of Pediatric Sciences University of Pavia Pavia Italy

Department of Pediatrics and Adolescent Medicine Queen Mary Hospital University of Hong Kong Hong Kong

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

Department of Pediatrics Seattle Children's Hospital University of Washington Seattle WA; and

Division of Leukemia and Lymphoma Children's Cancer Center National Center for Child Health and Development Tokyo Japan

Dutch Childhood Oncology Group The Hague The Netherlands

Fred Hutchinson Cancer Research Center Seattle WA

Nordic Society for Pediatric Hematology and Oncology Department of Pediatrics Institution for Clinical Sciences Sahlgrenska Academy University of Gothenburg Gothenburg Sweden

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

Pediatric Oncology Hematology Erasmus MC Sophia Children's Hospital Rotterdam Rotterdam The Netherlands

Pediatrics and Adolescent Medicine Aarhus University Hospital Aarhus Denmark

Princess Máxima Center for Pediatric Oncology Utrecht The Netherlands

Women and Children's Health Hematology Oncology Laboratory University of Padova Padova Italy

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Analysis of rare driving events in pediatric acute myeloid leukemia

Integrative Genomic Analysis of Pediatric Myeloid-Related Acute Leukemias Identifies Novel Subtypes and Prognostic Indicators