title: The clinical impact of IKZF1 deletions in paediatric B-cell precursor acute lymphoblastic leukaemia is independent of minimal residual disease stratification in Nordic Society for Paediatric Haematology and Oncology treatment protocols used between 1992 and 2013.
abstract: Paediatric B-cell precursor acute lymphoblastic leukaemias (BCP ALL) with IKZF1 deletions (∆IKZF1) are associated with a poor outcome. However, there are conflicting data as to whether ∆IKZF1 is an independent risk factor if minimal residual disease (MRD) and other copy number alterations also are taken into account. We investigated 334 paediatric BCP ALL, diagnosed 1992-2013 and treated according to Nordic Society for Paediatric Haematology and Oncology ALL protocols, with known IKZF1 status based on either single nucleotide polymorphism array (N = 218) or multiplex ligation-dependent probe amplification (N = 116) analyses. ∆IKZF1, found in 15%, was associated with inferior 10-year probabilities of event-free (60% vs. 83%; P < 0·001) and overall survival (pOS; 73% vs. 89%; P = 0·001). Adjusting for known risk factors, including white blood cell (WBC) count and MRD, ∆IKZF1 was the strongest independent factor for relapse and death. ∆IKZF1 was present in 27% of cases with non-informative cytogenetics ('BCP-other') and a poor 10-year pOS was particularly pronounced in this group (58% vs. 90%; P < 0·001). Importantly, neither MRD nor WBC count predicted events in the ∆IKZF1-positive cases. Co-occurrence of pseudoautosomal region 1 (PAR1) deletions in Xp22.33/Yp11.32 (P2RY8-CRLF2) and ∆IKZF1 increased the risk of relapse (75% vs. 30% for cases with only ∆IKZF1; P = 0·045), indicating that BCP-other ALL with both P2RY8-CRLF2 and ∆IKZF1 constitutes a particularly high-risk group.
authors.affiliation: Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden.
authors.forename: Linda
authors.initials: L
authors.lastname: Olsson
authors.affiliation: Department of Molecular Medicine and Surgery and Centre for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ingegerd
authors.initials: I
authors.lastname: Ivanov Öfverholm
authors.affiliation: Department of Clinical Sciences, Paediatrics, Umeå University, Umeå, Sweden.
authors.forename: Ulrika
authors.initials: U
authors.lastname: Norén-Nyström
authors.affiliation: Department of Molecular Medicine and Surgery and Centre for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Vasilios
authors.initials: V
authors.lastname: Zachariadis
authors.affiliation: Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Jessica
authors.initials: J
authors.lastname: Nordlund
authors.affiliation: Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Helene
authors.initials: H
authors.lastname: Sjögren
authors.affiliation: Department of Medical Biosciences, Medical and Clinical Genetics, Umeå University, Umeå, Sweden.
authors.forename: Irina
authors.initials: I
authors.lastname: Golovleva
authors.affiliation: Department of Molecular Medicine and Surgery and Centre for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ann
authors.initials: A
authors.lastname: Nordgren
authors.affiliation: Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden.
authors.forename: Kajsa
authors.initials: K
authors.lastname: Paulsson
authors.affiliation: Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Mats
authors.initials: M
authors.lastname: Heyman
authors.affiliation: Department of Molecular Medicine and Surgery and Centre for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Gisela
authors.initials: G
authors.lastname: Barbany
authors.affiliation: Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden.|Department of Clinical Genetics, University and Regional Laboratories Region Skåne, Lund, Sweden.
authors.forename: Bertil
authors.initials: B
authors.lastname: Johansson
mesh_terms: D000293:Adolescent; D000367:Age Factors; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D002881:Chromosomes, Human, Pair 12; D002891:Chromosomes, Human, Pair 21; D015331:Cohort Studies; D017353:Gene Deletion; D015870:Gene Expression; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics*; D007223:Infant; D018365:Neoplasm, Residual / Q000235:genetics*; D063868:Patient Outcome Assessment; D020641:Polymorphism, Single Nucleotide; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D011379:Prognosis; D020569:Proto-Oncogene Proteins c-rel / Q000235:genetics; D044463:Receptor, PAR-1 / Q000235:genetics; D013548:Sweden; D015534:Trans-Activators / Q000235:genetics; D000071230:Transcriptional Regulator ERG; D014178:Translocation, Genetic
chemical_list: C072312:ERG protein, human; C497239:IKZF1 protein, human; D020569:Proto-Oncogene Proteins c-rel; D044463:Receptor, PAR-1; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D051740:Ikaros Transcription Factor
keywords: IKZF1 deletion; P2RY8-CRLF2, minimal residual disease; paediatric B-cell precursor acute lymphoblastic leukaemia; risk-stratifying factors