Despite attempts to improve the definitions of ambiguous lineage leukemia (ALAL) during the last 2 decades, general therapy recommendations are missing. Herein, we report a large cohort of children with ALAL and propose a treatment strategy. A retrospective multinational study (International Berlin-Frankfurt-Münster Study of Leukemias of Ambiguous Lineage [iBFM-AMBI2012]) of 233 cases of pediatric ALAL patients is presented. Survival statistics were used to compare the prognosis of subsets and types of treatment. Five-year event-free survival (EFS) of patients with acute lymphoblastic leukemia (ALL)-type primary therapy (80% ± 4%) was superior to that of children who received acute myeloid leukemia (AML)-type or combined-type treatment (36% ± 7.2% and 50% ± 12%, respectively). When ALL- or AML-specific gene fusions were excluded, 5-year EFS of CD19+ leukemia was 83% ± 5.3% on ALL-type primary treatment compared with 0% ± 0% and 28% ± 14% on AML-type and combined-type primary treatment, respectively. Superiority of ALL-type treatment was documented in single-population mixed phenotype ALAL (using World Health Organization and/or European Group for Immunophenotyping of Leukemia definitions) and bilineal ALAL. Treatment with ALL-type protocols is recommended for the majority of pediatric patients with ALAL, including cases with CD19+ ALAL. AML-type treatment is preferred in a minority of ALAL cases with CD19- and no other lymphoid features. No overall benefit of transplantation was documented, and it could be introduced in some patients with a poor response to treatment. As no clear indicator was found for a change in treatment type, this is to be considered only in cases with ≥5% blasts after remission induction. The results provide a basis for a prospective trial.

1st Department of Pediatrics University of Athens Athens Greece

Bioinformatics Centre 2nd Faculty of Medicine Charles University Prague Czech Republic

Center of Children's Oncohematology and BMT National Children's Specialized Hospital OHMATDYT Kiev Ukraine

Center of Oncocytogenetics Institute of Medical Biochemistry and Laboratory Diagnostics General University Hospital and 1st Faculty of Medicine Charles University Prague Czech Republic

Childhood Leukemia Investigation Prague Prague Czech Republic

Comenius University Children's Hospital Bratislava Slovakia

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

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

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

Department of Pediatric Hematology Oncology and Transplantology University of Medical Sciences Poznan Poland

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

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

Department of Pediatrics University Medical Center Schleswig Holstein Campus Kiel Kiel Germany

Dutch Childhood Oncology Group The Hague The Netherlands

Helios Klinikum Berlin Buch Berlin Germany

Hematology and Oncology Hospital Nacional de Pediatría Prof Dr J P Garrahan Buenos Aires Argentina

Hospital del Salvador Universidad de Chile Santiago Chile

Immunology and Rheumatology and

Institute of Medicine Faculty of Medicine University of Copenhagen Copenhagen Denmark

Laboratory of Pediatric Oncohematology Department of Woman's and Child's Health University of Padova Padova Italy

National Program for Antineoplastic Drugs for Children Chilean National Pediatric Oncology Group Hospital Roberto del Rio Universidad de Chile Santiago Chile

Nordic Society for Pediatric Hematology and Oncology Department of Pediatrics and Adolescent Medicine The Juliane Marie Centre Rigshospitalet Copenhagen University Hospital Copenhagen Denmark

Northern Institute for Cancer Research Newcastle University Newcastle upon Tyne United Kingdom

Nottingham University Hospitals NHS Trust Nottingham United Kingdom

Pediatric Hematology and Oncology University Children's Hospital Essen Essen Germany; and

Pediatric Hematology Oncology Baylor College of Medicine Houston TX

Pediatric Hematology Oncology Schneider Children's Medical Center Petah Tikva Israel

Pediatrics Department Faculty of Medicine Federal University of Rio de Janeiro Rio de Janeiro Brazil

Princess Máxima Center for Pediatric Oncology Utrecht The Netherlands

Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel

Sydney Children's Hospital Network Westmead NSW Australia

University Medical Center Christian Albrechts University Kiel Kiel Germany

Blood. 2018 Jul 19;132(3):239-240. doi: 10.1182/blood-2018-05-850248. PubMed

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