title: EBF1-PDGFRB fusion in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL): genetic profile and clinical implications.
abstract: The EBF1-PDGFRB gene fusion accounts for <1% of B-cell precursor acute lymphoblastic leukemia (ALL) cases and occurs within the Philadelphia-like ALL subtype. We report 15 EBF1-PDGFRB-positive patients from childhood ALL treatment trials (ALL 97/99, UKALL 2003, UKALL 2011) in the United Kingdom. The fusion arose from interstitial deletion of 5q33 (n = 11), balanced rearrangement (n = 2), or complex rearrangement (n = 2). There was a predominance of females (n = 11), median age of 12 years, and median white blood cell count of 48.8 × 10(9)/L. Among 12 patients who achieved complete remission on earlier trials (ALL 97/99 and UKALL 2003), 10 were positive for minimal residual disease (MRD) at the end of induction, and 7 relapsed 18 to 59 months after diagnosis. The majority (9 of 12) remained alive 6 to 9 years after diagnosis. There are reports of EBF1-PDGFRB-positive patients who are refractory to conventional chemotherapy who achieve complete response when treated with the tyrosine kinase inhibitor imatinib. These findings have prompted screening for EBF1-PDGFRB in patients entered onto the current UKALL 2011 trial for whom induction therapy failed, who did not achieve remission by day 29, or who remained MRD positive (>0.5%) at week 14. Two UKALL 2011 patients, positive for EBF1-PDGFRB, received imatinib; 1 died 6 months after a matched unrelated bone marrow transplant as a result of undefined encephalopathy, and the other remained in remission 10 months after diagnosis.
authors.affiliation: Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, United Kingdom;
authors.forename: Claire
authors.initials: C
authors.lastname: Schwab
authors.affiliation: Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, United Kingdom;
authors.forename: Sarra L
authors.initials: SL
authors.lastname: Ryan
authors.affiliation: Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, United Kingdom;
authors.forename: Lucy
authors.identifier: 0000-0002-3559-5644
authors.initials: L
authors.lastname: Chilton
authors.affiliation: Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, United Kingdom;
authors.forename: Alannah
authors.initials: A
authors.lastname: Elliott
authors.affiliation: Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, United Kingdom;
authors.forename: James
authors.initials: J
authors.lastname: Murray
authors.affiliation: Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, United Kingdom;
authors.forename: Stacey
authors.initials: S
authors.lastname: Richardson
authors.affiliation: Bristol Genetics Laboratory, Southmead Hospital, North Bristol National Health Service Trust, Bristol, United Kingdom;
authors.forename: Christopher
authors.initials: C
authors.lastname: Wragg
authors.affiliation: Department of Paediatric Haematology and Oncology, Bristol Royal Hospital for Children, Bristol, United Kingdom;
authors.forename: John
authors.initials: J
authors.lastname: Moppett
authors.affiliation: Department of Paediatric Haematology and Oncology, Bristol Royal Hospital for Children, Bristol, United Kingdom;
authors.forename: Michelle
authors.initials: M
authors.lastname: Cummins
authors.affiliation: Department of Paediatric Haematology and Oncology, Bristol Royal Hospital for Children, Bristol, United Kingdom;
authors.forename: Oliver
authors.initials: O
authors.lastname: Tunstall
authors.affiliation: Children's Cancer Group, Manchester Academic Health Sciences Centre, Institute of Cancer, University of Manchester, Manchester, United Kingdom;
authors.forename: Catriona A
authors.initials: CA
authors.lastname: Parker
authors.affiliation: Children's Cancer Group, Manchester Academic Health Sciences Centre, Institute of Cancer, University of Manchester, Manchester, United Kingdom; Department of Paediatric Oncology, Tata Translational Cancer Research Centre, Kolkata, India;
authors.forename: Vaskar
authors.initials: V
authors.lastname: Saha
authors.affiliation: Department of Haematology, Great Ormond Street Hospital, London, United Kingdom; and.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Goulden
authors.affiliation: Department of Haematology, Sheffield Children's Hospital, Sheffield, United Kingdom.
authors.forename: Ajay
authors.initials: A
authors.lastname: Vora
authors.affiliation: Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, United Kingdom;
authors.forename: Anthony V
authors.initials: AV
authors.lastname: Moorman
authors.affiliation: Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, United Kingdom;
authors.forename: Christine J
authors.initials: CJ
authors.lastname: Harrison
mesh_terms: D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D016026:Bone Marrow Transplantation; D002648:Child; D002675:Child, Preschool; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate / Q000627:therapeutic use; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D008297:Male; D018365:Neoplasm, Residual; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors / Q000235:genetics*; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors / Q000235:genetics*; D012074:Remission Induction; D017384:Sequence Deletion; D015534:Trans-Activators / Q000235:genetics*; D014178:Translocation, Genetic; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C081976:EBF1 protein, human; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D015534:Trans-Activators; D000068877:Imatinib Mesylate; C000605860:PDGFRB protein, human; D020797:Receptor, Platelet-Derived Growth Factor beta