title: Prospective evaluation of clonal evolution during long-term follow-up of patients with untreated early-stage chronic lymphocytic leukemia.
abstract: OBJECTIVE
  Retrospective studies suggest cytogenetic abnormalities detected by interphase fluorescent in situ hybridization (FISH) can identify patients with chronic lymphocytic leukemia (CLL) who will experience a more aggressive disease course. Other studies suggest that patients may acquire chromosome abnormalities during the course of their disease. There are minimal prospective data on the clinical utility of the widely used hierarchical FISH prognostic categories in patients with newly diagnosed early-stage CLL or the frequency of clonal evolution as determined by interphase FISH.
  
  
  METHODS
  Between 1994 and 2002, we enrolled 159 patients with previously untreated CLL (83% Rai stage 0/I) on a prospective trial evaluating clonal evolution by FISH. Patients provided baseline and follow-up specimens for FISH testing during 2 to 12 years.
  
  
  RESULTS
  Chromosomal abnormalities detected by FISH at study entry predicted overall survival. Eighteen patients experienced clonal evolution during follow-up. The rate of clonal evolution increased with duration of follow-up with only one occurrence in the first 2 years (n = 71; 1.4%) but 17 occurrences (n = 63; 27%) among patients tested after 5+ years. Clonal evolution occurred among 10% of ZAP-70-negative and 42% of ZAP-70-positive patients at 5+ years (P = .008).
  
  
  CONCLUSIONS
  This clinical trial confirms prospectively that cytogenetic abnormalities detected by FISH can predict overall survival for CLL patients at the time of diagnosis, but also suggests that many patients acquire new abnormalities during the course of their disease. Patients with higher ZAP-70 expression may be more likely to experience such clonal evolution. These findings have important implications for both clinical management and trials of early treatment for patients with high-risk, early-stage CLL.
authors.affiliation: Mayo Clinic College of Medicine, Department of Internal Medicine, Division of Hematology, Rochester, MN 55905, USA.
authors.forename: Tait D
authors.initials: TD
authors.lastname: Shanafelt
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Witzig
authors.forename: Stephanie R
authors.initials: SR
authors.lastname: Fink
authors.forename: Robert B
authors.initials: RB
authors.lastname: Jenkins
authors.forename: Sarah F
authors.initials: SF
authors.lastname: Paternoster
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Smoley
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Stockero
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Nast
authors.forename: Heather C
authors.initials: HC
authors.lastname: Flynn
authors.forename: Renee C
authors.initials: RC
authors.lastname: Tschumper
authors.forename: Susan
authors.initials: S
authors.lastname: Geyer
authors.forename: Clive S
authors.initials: CS
authors.lastname: Zent
authors.forename: Tim G
authors.initials: TG
authors.lastname: Call
authors.forename: Diane F
authors.initials: DF
authors.lastname: Jelinek
authors.forename: Neil E
authors.initials: NE
authors.lastname: Kay
authors.forename: Gordon W
authors.initials: GW
authors.lastname: Dewald
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002869:Chromosome Aberrations; D015331:Cohort Studies; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011446:Prospective Studies; D012189:Retrospective Studies; D016896:Treatment Outcome; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000096:biosynthesis
chemical_list: D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human