title: IKZF1 deletion is an independent prognostic marker in childhood B-cell precursor acute lymphoblastic leukemia, and distinguishes patients benefiting from pulses during maintenance therapy: results of the EORTC Children's Leukemia Group study 58951.
abstract: The added value of IKZF1 gene deletion (IKZF1(del)) as a stratifying criterion in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is still debated. We performed a comprehensive analysis of the impact of IKZF1(del) in a large cohort of children (n=1223) with BCR-ABL1-negative BCP-ALL treated in the EORTC-CLG trial 58951. Patients with IKZF1(del) had a lower 8-year event-free survival (EFS, 67.7% versus 86.5%; hazard ratio (HR)=2.41; 95% confidence interval (CI)=1.75-3.32; P<0.001). Importantly, despite association with high-risk features such as high minimal residual disease, IKZF1(del) remained significantly predictive in multivariate analyses. Analysis by genetic subtype showed that IKZF1(del) increased risk only in the high hyperdiploid ALLs (HR=2.57; 95% CI=1.19-5.55; P=0.013) and in 'B-other' ALLs, that is, lacking classifying genetic lesions (HR=2.22; 95% CI=1.45-3.39; P<0.001), the latter having then a dramatically low 8-year EFS (56.4; 95% CI=44.6-66.7). Among IKZF1(del)-positive patients randomized for vincristine-steroid pulses during maintenance, those receiving pulses had a significantly higher 8-year EFS (93.3; 95% CI=61.3-99.0 versus 42.1; 95% CI=20.4-62.5). Thus, IKZF1(del) retains independent prognostic significance in the context of current risk-adapted protocols, and is associated with a dismal outcome in 'B-other' ALL. Addition of vincristine-steroid pulses during maintenance may specifically benefit to IKZF1(del) patients in preventing relapses.
authors.affiliation: Department of Genetics, Robert Debré Hospital, APHP, Paris, France.|Hematology University Institute, Paris-Diderot University, Paris, France.
authors.forename: E
authors.initials: E
authors.lastname: Clappier
authors.affiliation: Centre de Biologie Pathologie PM Degand, INSERM U837, Lille, France.
authors.forename: N
authors.initials: N
authors.lastname: Grardel
authors.affiliation: Department of Hematology, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: Bakkus
authors.affiliation: EORTC Headquarters, Brussels, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Rapion
authors.affiliation: Department of Pediatric Hematology-Oncology, Ghent University Hospital, Ghent, Belgium.
authors.forename: B
authors.initials: B
authors.lastname: De Moerloose
authors.affiliation: Department of Cancer Biology, Institute of Genetics and Molecular and Cellular Biology (IGBMC), Illkirch, France.
authors.forename: P
authors.initials: P
authors.lastname: Kastner
authors.affiliation: Department of Genetics, Robert Debré Hospital, APHP, Paris, France.|Hematology University Institute, Paris-Diderot University, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Caye
authors.affiliation: Department of Genetics, Robert Debré Hospital, APHP, Paris, France.|Hematology University Institute, Paris-Diderot University, Paris, France.
authors.forename: J
authors.initials: J
authors.lastname: Vivent
authors.affiliation: Department of Pediatrics, Portuguese Oncology Institute, Porto, Portugal.
authors.forename: V
authors.initials: V
authors.lastname: Costa
authors.affiliation: Department of Pediatric Onco-Hematology, Hôpital Universitaire des Enfants Reine Fabiola (ULB), Brussels, Belgium.
authors.forename: A
authors.initials: A
authors.lastname: Ferster
authors.affiliation: Department of Hematology, Hautepierre University Hospital, Strasbourg, France.
authors.forename: P
authors.initials: P
authors.lastname: Lutz
authors.affiliation: Department of Pediatric Hematology-Oncology, Lille University Hospital, Lille, France.
authors.forename: F
authors.initials: F
authors.lastname: Mazingue
authors.affiliation: Department of Hematology, J Bernard University Hospital, Poitiers, France.
authors.forename: F
authors.initials: F
authors.lastname: Millot
authors.affiliation: Department of Pediatric Onco-Hematology, Grenoble University Hospital, La Tronche, France.
authors.forename: D
authors.initials: D
authors.lastname: Plantaz
authors.affiliation: Department of Pediatric Onco-Hematology, Purpan University Hospital, Toulouse, France.
authors.forename: G
authors.initials: G
authors.lastname: Plat
authors.affiliation: Department of Pediatric Onco-Hematology, Besançon University Hospital, Besançon, France.
authors.forename: E
authors.initials: E
authors.lastname: Plouvier
authors.affiliation: Department of Pediatric Onco-Hematology, Nice University Hospital, Nice, France.
authors.forename: M
authors.initials: M
authors.lastname: Poirée
authors.affiliation: Department of Pediatric Onco-Hematology, Montpellier University Hospital, Montpellier, France.
authors.forename: N
authors.initials: N
authors.lastname: Sirvent
authors.affiliation: Department of Pediatrics, University Hospital Gasthuisberg, Leuven, Belgium.
authors.forename: A
authors.initials: A
authors.lastname: Uyttebroeck
authors.affiliation: Department of Pediatric Hematology, Robert Debré Hospital, APHP, Paris, France.
authors.forename: K
authors.initials: K
authors.lastname: Yakouben
authors.affiliation: Hematology Laboratory, IHOP, Lyon, France.
authors.forename: S
authors.initials: S
authors.lastname: Girard
authors.affiliation: Hematology Laboratory, University Hospital Purpan, Toulouse, France.
authors.forename: N
authors.initials: N
authors.lastname: Dastugue
authors.affiliation: EORTC Headquarters, Brussels, Belgium.
authors.forename: S
authors.initials: S
authors.lastname: Suciu
authors.affiliation: Department of Pediatric Hematology-Oncology, Ghent University Hospital, Ghent, Belgium.
authors.forename: Y
authors.initials: Y
authors.lastname: Benoit
authors.affiliation: Department of Pediatric Hematology, IHOP and Claude Bernard University, Lyon, France.
authors.forename: Y
authors.initials: Y
authors.lastname: Bertrand
authors.affiliation: Department of Genetics, Robert Debré Hospital, APHP, Paris, France.|Hematology University Institute, Paris-Diderot University, Paris, France.
authors.forename: H
authors.initials: H
authors.lastname: Cavé
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005260:Female; D017353:Gene Deletion; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics*; D007223:Infant; D008297:Male; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D011379:Prognosis; D012008:Recurrence
chemical_list: C497239:IKZF1 protein, human; D051740:Ikaros Transcription Factor