The development of a second malignancy after the diagnosis of childhood acute lymphoblastic leukemia (ALL) is a rare event. Certain second malignancies have been linked with specific elements of leukemia therapy, yet the etiology of most second neoplasms remains obscure and their optimal management strategies are unclear. This is a first comprehensive report of non-Hodgkin lymphomas (NHLs) following pediatric ALL therapy, excluding stem-cell transplantation. We analyzed data of patients who developed NHL following ALL diagnosis and were enrolled in 12 collaborative pediatric ALL trials between 1980-2018. Eighty-five patients developed NHL, with mature B-cell lymphoproliferations as the dominant subtype (56 of 85 cases). Forty-six of these 56 cases (82%) occurred during or within 6 months of maintenance therapy. The majority exhibited histopathological characteristics associated with immunodeficiency (65%), predominantly evidence of Epstein-Barr virus-driven lymphoproliferation. We investigated 66 cases of post-ALL immunodeficiency-associated lymphoid neoplasms, 52 from our study and 14 additional cases from a literature search. With a median follow-up of 4.9 years, the 5-year overall survival for the 66 patients with immunodeficiency-associated lymphoid neoplasms was 67.4% (95% confidence interval [CI], 56-81). Five-year cumulative risks of lymphoid neoplasm- and leukemia-related mortality were 20% (95% CI, 10.2-30) and 12.4% (95% CI, 2.7-22), respectively. Concurrent hemophagocytic lymphohistiocytosis was associated with increased mortality (hazard ratio, 7.32; 95% CI, 1.62-32.98; P = .01). A large proportion of post-ALL lymphoid neoplasms are associated with an immunodeficient state, likely precipitated by ALL maintenance therapy. Awareness of this underrecognized entity and pertinent diagnostic tests are crucial for early diagnosis and optimal therapy.

Amsterdam Academic Medical Center Emma Children's Hospital Amsterdam The Netherlands

Beatson West of Scotland Cancer Centre Glasgow United Kingdom

Cancer and Blood Disorders Institute Johns Hopkins All Children's Hospital St Petersburg FL

Children's Hospital Western University London ON Canada

Department of Haematology Royal Hospital for Children and Young People Edinburgh United Kingdom

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

Department of Paediatric Haematology and Oncology University Hospital Leuven Leuven Leuven Belgium

Department of Paediatric Haematology Great Ormond Street Hospital London United Kingdom

Department of Paediatric Haematology Royal Hospital for Children Glasgow United Kingdom

Department of Paediatric Oncology Haematology and Clinical Immunology Medical Faculty Heinrich Heine University Duesseldorf Germany

Department of Pathology School of Medicine La Plata National University La Plata Argentina

Department of Pediatric Hemato Oncology Soroka Medical Center Ben Gurion University of the Negev Beer Sheva Israel

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

Department of Pediatric Hematology and Oncology St Anna Children's Hospital Medical University of Vienna Vienna Austria

Department of Pediatric Hematology and Oncology Zabrze and Medical University of Silesia Katowice Poland

Department of Pediatric Hematology and Oncoogy University Medical Centre Hamburg Eppendorf Hamburg Germany

Department of Pediatric Hematology Hôpital Robert Debré Assistance Publique Hôpitaux de Paris Paris France

Department of Pediatric Hematology Oncology Massachusetts General Hospital for Children Harvard Medical School Boston MA

Department of Pediatric Oncology and Department of Pediatrics University Hospital Brno and Faculty of Medicine Masaryk University Brno Czech Republic

Department of Pediatric Oncology and Hematology Hospital Luis Calvo Mackenna Santiago Chile

Department of Pediatric Oncology Centre Hospitalier Universitaire de Montpellier Montpellier France

Department of Pediatric Oncology University Children's Hospital Zurich Switzerland

Department of Pediatrics and Adolescent Medicine Kepler University Clinic Linz Austria

Department of Pediatrics and Adolescent Medicine The University Hospital Rigshospitalet and Institute of Clinical Medicine Faculty of Medicine University of Copenhagen Copenhagen Denmark

Department of Pediatrics Christian Albrechts University Kiel and University Medical Center Schleswig Holstein Kiel Germany

Department of Pediatrics Hokkaido University Graduate School of Medicine Sapporo Japan

Department of Statistics and Data Science Hebrew University Jerusalem Israel

Division of Pediatric Hematology Oncology Bone Marrow Transplant and Cellular Therapy Seattle Children's Hospital and the Ben Towne Center for Childhood Cancer Research University of Washington Seattle WA

Division of Pediatric Hematology Oncology Mackay Children's Hospital and Mackay Medical College Taipei Taiwan

Faculty of Medical and Human Sciences University of Manchester and Royal Manchester Children's Hospital Central Manchester University Hospitals NHS Foundation Trust Manchester Academic Health Science Centre Manchester United Kingdom

Institut d'Hematologie et d'Oncologie Pediatrique Hospices Civils de Lyon Lyon France

Leukaemia Research Cytogenetics Group Wolfson Childhood Cancer Centre Clinical and Translational Research Institute Newcastle University Newcastle upon Tyne United Kingdom

Paediatric Oncology Leeds Children's Hospital Leeds United Kingdom

Pediatric Hematology and Oncology Hospital for Children and Adolescents Johann Wolfgang Goethe University Frankfurt Germany

Pediatric Hematology and Oncology University Hospital Münster Münster Germany

Pediatric Hematology Oncology Ochsner Children's Hospital New Orleans LA

Pediatric Hematology Oncology Riley Hospital for Children Indiana University School of Medicine Indianapolis IN

Pediatric Oncology Hematology and Stem Cell Transplantation Program University Children's Hospital Würzburg Würzburg Germany

Pediatric Oncology Nice University Hospital Nice France

Pediatrics and Adolescent Medicine University of Augsburg Augsburg Germany

Phoenix Children's Hospital Center for Cancer and Blood Disorders Phoenix AZ

Princess Máxima Center for Pediatric Oncology Utrecht The Netherlands

Shaare Zedek Medical Centre and The Faculty of Medicine Hebrew University Jerusalem Israel

Blood. 2023 Feb 16;141(7):689-691. doi: 10.1182/blood.2022018748. PubMed

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