title: Prognostic effect of chromosomal abnormalities in childhood B-cell precursor acute lymphoblastic leukaemia: results from the UK Medical Research Council ALL97/99 randomised trial.
abstract: BACKGROUND
  Chromosomal abnormalities in childhood acute lymphoblastic leukaemia are well established disease markers and indicators of outcomes. However, the long-term prognosis and independent prognostic effect of some abnormalities has been questioned. Also, little is known about the association between cytogenetics and the characteristics of relapse (eg, time and site of relapse) that are known to predict outcome after relapse.
  
  
  METHODS
  We analysed cytogenetic data from 1725 children with B-cell precursor acute lymphoblastic leukaemia who were included in the UK Medical Research Council ALL97/99 study and followed up for a median time of 8.2 years. Univariate and multivariate analysis were done to examine risk of relapse, event-free survival, and overall survival associated with 21 chromosomal abnormalities and three cytogenetic risk groups constructed from these data.
  
  
  RESULTS
  Two chromosomal abnormalities were associated with a significantly better outcome (ETV6-RUNX1, hazard ratio [HR] 0.51, 95% CI 0.38-0.70 and high hyperdiploidy, 0.60, 0.47-0.78), whereas five abnormalities were associated with an increased risk of relapse (intrachromosomal amplification of chromosome 21 [iAMP21], 6.04, 3.90-9.35; t(9;22), 3.55, 2.21-5.72; MLL translocations, 2.98, 1.71-5.20; abnormal 17p, 2.09, 1.30-3.37; and loss of 13q, 1.87, 1.09-3.20). Multivariate analysis incorporating age, white-cell count, and treatment parameters showed that six cytogenetic abnormalities (ETV6-RUNX1, high hyperdiploidy, iAMP21, t(9;22), loss of 13q, and abnormal 17p) retained their significance for effect on relapse risk. Based on these data, patients were classified into good, intermediate, and poor cytogenetic risk groups. Slow early treatment response correlated with cytogenetic risk group: 34 of 460 (7%) in the good-risk group, 22 of 211 (10%) in the intermediate-risk group, and 27 of 95 (28%) in the poor-risk group had a slow response (p<0.0001). Additionally, the proportion of patients with a very early (<18 months) relapse varied by cytogenetic risk group: eight of 129 (6%) patients in the good-risk group had a very early relapse, compared with 24 of 98 (24%) in the intermediate-risk group, and 37 of 82 (45%) in the poor-risk group (p<0.0001). However, there was no difference in the site of relapse by cytogenetic risk group.
  
  
  CONCLUSIONS
  Individual chromosomal abnormalities are strong independent indicators of outcome, especially risk of relapse. Diagnostic cytogenetics identifies patients with a higher rate of relapse and those who are likely to have a high-risk relapse.
  
  
  BACKGROUND
  Leukaemia and Lymphoma Research (LLR).
authors.affiliation: Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK. anthony.moorman@ncl.ac.uk
authors.forename: Anthony V
authors.initials: AV
authors.lastname: Moorman
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Ensor
authors.forename: Sue M
authors.initials: SM
authors.lastname: Richards
authors.forename: Lucy
authors.initials: L
authors.lastname: Chilton
authors.forename: Claire
authors.initials: C
authors.lastname: Schwab
authors.forename: Sally E
authors.initials: SE
authors.lastname: Kinsey
authors.forename: Ajay
authors.initials: A
authors.lastname: Vora
authors.forename: Chris D
authors.initials: CD
authors.lastname: Mitchell
authors.forename: Christine J
authors.initials: CJ
authors.lastname: Harrison
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D006801:Humans; D007223:Infant; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000628:therapy; D011379:Prognosis; D016019:Survival Analysis