title: Independent prognostic value of BCR-ABL1-like signature and IKZF1 deletion, but not high CRLF2 expression, in children with B-cell precursor ALL.
abstract: Most relapses in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) are not predicted using current prognostic features. Here, we determined the co-occurrence and independent prognostic relevance of 3 recently identified prognostic features: BCR-ABL1-like gene signature, deletions in IKZF1, and high CRLF2 messenger RNA expression (CRLF2-high). These features were determined in 4 trials representing 1128 children with ALL: DCOG ALL-8, ALL9, ALL10, and Cooperative ALL (COALL)-97/03. BCR-ABL1-like, IKZF1-deleted, and CRLF2-high cases constitute 33.7% of BCR-ABL1-negative, MLL wild-type BCP-ALL cases, of which BCR-ABL1-like and IKZF1 deletion (co)occurred most frequently. Higher cumulative incidence of relapse was found for BCR-ABL1-like and IKZF1-deleted, but not CRLF2-high, cases relative to remaining BCP-ALL cases, reflecting the observations in each of the cohorts analyzed separately. No relapses occurred among cases with CRLF2-high as single feature, whereas 62.9% of all relapses in BCR-ABL1-negative, MLL wild-type BCP-ALL occurred in cases with BCR-ABL1-like signature and/or IKZF1 deletion. Both the BCR-ABL1-like signature and IKZF1 deletions were prognostic features independent of conventional prognostic markers in a multivariate model, and both remained prognostic among cases with intermediate minimal residual disease. The BCR-ABL1-like signature and an IKZF1 deletion, but not CRLF2-high, are prognostic factors and are clinically of importance to identify high-risk patients who require more intensive and/or alternative therapies.
authors: Department of Pediatric Oncology, Erasmus University Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands;
authors: Arian
authors: A
authors: van der Veer
authors: Esmé
authors: E
authors: Waanders
authors: Rob
authors: R
authors: Pieters
authors: Marieke E
authors: ME
authors: Willemse
authors: Simon V
authors: SV
authors: Van Reijmersdal
authors: Lisa J
authors: LJ
authors: Russell
authors: Christine J
authors: CJ
authors: Harrison
authors: William E
authors: WE
authors: Evans
authors: Vincent H J
authors: VH
authors: van der Velden
authors: Peter M
authors: PM
authors: Hoogerbrugge
authors: Frank
authors: F
authors: Van Leeuwen
authors: Gabriele
authors: G
authors: Escherich
authors: Martin A
authors: MA
authors: Horstmann
authors: Leila
authors: L
authors: Mohammadi Khankahdani
authors: Dimitris
authors: D
authors: Rizopoulos
authors: Hester A
authors: HA
authors: De Groot-Kruseman
authors: Edwin
authors: E
authors: Sonneveld
authors: Roland P
authors: RP
authors: Kuiper
authors: Monique L
authors: ML
authors: Den Boer
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics*; D015994:Incidence; D007223:Infant; D008297:Male; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000453:epidemiology / Q000235:genetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000453:epidemiology* / Q000235:genetics*; D011237:Predictive Value of Tests; D011379:Prognosis; D018121:Receptors, Cytokine / Q000235:genetics*; D012008:Recurrence; D012307:Risk Factors
chemical_list: C581634:BCR-ABL1 fusion protein, human; C498762:CRLF2 protein, human; C497239:IKZF1 protein, human; D018121:Receptors, Cytokine; D051740:Ikaros Transcription Factor; D016044:Fusion Proteins, bcr-abl
references: Leukemia. 2010 Feb;24(2):309-19
references: 20016528
references: Cancer Cell. 2012 Aug 14;22(2):153-66
references: 22897847
references: Blood. 2013 Jan 17;121(3):485-8
references: 23212523
references: Leukemia. 2011 Feb;25(2):254-8
references: 21102428
references: Br J Haematol. 2012 Sep;158(6):772-7
references: 22816614
references: Leukemia. 2010 Mar;24(3):642-5
references: 19907440
references: Leukemia. 2010 Feb;24(2):265-84
references: 20010625
references: Blood. 2010 Jul 1;115(26):5312-21
references: 20139093
references: J Exp Med. 2012 Feb 13;209(2):395-406
references: 22291095
references: FEBS Lett. 2010 Dec 15;584(24):4910-4
references: 20888815
references: Leukemia. 2010 Feb;24(2):298-308
references: 20016530
references: Blood. 2012 Oct 25;120(17):3510-8
references: 22955920
references: Blood. 2010 Jul 1;115(26):5393-7
references: 20378752
references: Lancet Oncol. 2009 Feb;10(2):125-34
references: 19138562
references: Leukemia. 2012 Oct;26(10):2204-11
references: 22441210
references: Blood. 2009 Sep 24;114(13):2688-98
references: 19641190
references: Leukemia. 2012 Apr;26(4):644-53
references: 21960247
references: J Clin Oncol. 2011 Feb 10;29(5):551-65
references: 21220611
references: Nat Genet. 2009 Nov;41(11):1243-6
references: 19838194
references: J Exp Med. 2009 Aug 3;206(8):1739-53
references: 19620627
references: PLoS One. 2012;7(7):e40934
references: 22848414
references: Methods Mol Biol. 2009;538:115-50
references: 19277574
references: Haematologica. 2013 Mar;98(3):428-32
references: 22875627
references: Genes Cancer. 2011 Aug;2(8):805-17
references: 22393465
references: Leukemia. 2010 Jul;24(7):1258-64
references: 20445578
references: Blood. 2012 Apr 12;119(15):3512-22
references: 22368272
references: Leukemia. 2010 Jun;24(6):1200-4
references: 20393504
references: J Immunol. 2007 Sep 15;179(6):3662-71
references: 17785802
references: Genes Chromosomes Cancer. 2012 Jun;51(6):525-35
references: 22334400
references: J Immunol. 2006 Oct 15;177(8):5420-9
references: 17015728
references: N Engl J Med. 2009 Jan 29;360(5):470-80
references: 19129520
references: Blood. 2011 Feb 17;117(7):2129-36
references: 21106984
references: Blood. 2010 Dec 2;116(23):4874-84
references: 20699438
references: Blood. 2011 Sep 15;118(11):3080-7
references: 21680795
references: J Exp Med. 2011 May 9;208(5):901-8
references: 21536738
references: Proc Natl Acad Sci U S A. 2010 Jan 5;107(1):252-7
references: 20018760