Prospective evaluation of clonal evolution during long-term follow-up of patients with untreated early-stage chronic lymphocytic leukemia.
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.
Shanafelt
Tait D
TD
Mayo Clinic College of Medicine, Department of Internal Medicine, Division of Hematology, Rochester, MN 55905, USA.
Witzig
Thomas E
TE
Fink
Stephanie R
SR
Jenkins
Robert B
RB
Paternoster
Sarah F
SF
Smoley
Stephanie A
SA
Stockero
Kimberly J
KJ
Nast
Danielle M
DM
Flynn
Heather C
HC
Tschumper
Renee C
RC
Geyer
Susan
S
Zent
Clive S
CS
Call
Tim G
TG
Jelinek
Diane F
DF
Kay
Neil E
NE
Dewald
Gordon W
GW
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
D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human