PMID- 17666364
OWN - NLM
STAT- MEDLINE
DCOM- 20080131
LR  - 20190608
IS  - 1592-8721 (Electronic)
IS  - 0390-6078 (Linking)
VI  - 92
IP  - 9
DP  - 2007 Sep
TI  - Clonal evolution in chronic lymphocytic leukemia: acquisition of high-risk 
      genomic aberrations associated with unmutated VH, resistance to therapy, and 
      short survival.
PG  - 1242-5
AB  - In chronic lymphocytic leukemia (CLL), the acquisition of new genomic aberrations 
      during the disease course (clonal evolution) is thought to be an infrequent 
      phenomenon but comprehensive analyses are limited. Genomic aberrations were 
      analyzed by fluorescence in situ hybridization (FISH) at various time points 
      during the disease course of 64 CLL patients. Results were correlated with the 
      mutation status of the immunoglobulin heavy-chain variableregion genes (VH) and 
      clinical characteristics. Following a median observation time of 42.3 months 
      (range 23.2-73) after first genetic study, 11 out of the 64 (17%) patients showed 
      clonal evolution with the following newly acquired aberrations: del(17p13) (n=4), 
      del(6q21) (n=3), del(11q23) (n=2), +(8q24) (n=1), and evolution from monoallelic 
      to biallelic del(13q14) (n=3). Interestingly, clonal evolution only occurred 
      among cases with unmutated VH status. The group with clonal evolution showed a 
      higher rate of progression in Binet stage (82% vs. 28%), a possibly greater need 
      for treatment (91% vs. 62% previously untreated patients received their first 
      therapy), and a higher hazard risk of death (HR = 2.97, 95% CI 1.40-6.27, 
      p=0.004) in multivariable analysis. The estimated median survival time after the 
      occurrence of clonal evolution was 21.7 months. Expansion of the clone with 
      del(17p13) was observed in all patients during treatment, indicating in vivo 
      resistance to therapy. In multivariable Andersen-Gill regression analysis, clonal 
      evolution was identified as an independent prognostic factor for overall 
      survival. Clonal evolution only occurred in CLL with unmutated VH indicating to 
      karyotypic instability as a pathomechanism. Acquisition of genomic aberrations 
      was associated with poor outcome based on multivariable analysis. In vivo 
      resistance to chemotherapy of CLL clones with del(17p13) emphasizes the need for 
      alternative treatment approaches in these patients.
FAU - Stilgenbauer, Stephan
AU  - Stilgenbauer S
AD  - Internal Medicine III, University of Ulm, Ulm, Germany. 
      stephan.stilgenbauer@uniklinik-ulm.de
FAU - Sander, Sandrine
AU  - Sander S
FAU - Bullinger, Lars
AU  - Bullinger L
FAU - Benner, Axel
AU  - Benner A
FAU - Leupolt, Elke
AU  - Leupolt E
FAU - Winkler, Dirk
AU  - Winkler D
FAU - Krober, Alexander
AU  - Krober A
FAU - Kienle, Dirk
AU  - Kienle D
FAU - Lichter, Peter
AU  - Lichter P
FAU - Dohner, Hartmut
AU  - Dohner H
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20070801
PL  - Italy
TA  - Haematologica
JT  - Haematologica
JID - 0417435
RN  - 0 (Immunoglobulin Heavy Chains)
SB  - IM
MH  - *Chromosome Aberrations
MH  - Cytogenetic Analysis
MH  - Disease Progression
MH  - Disease-Free Survival
MH  - Drug Resistance, Neoplasm/*genetics
MH  - Genome, Human
MH  - Humans
MH  - Immunoglobulin Heavy Chains/*genetics
MH  - In Situ Hybridization, Fluorescence
MH  - Leukemia, Lymphocytic, Chronic, B-Cell/*genetics/*pathology
MH  - *Mutation
MH  - Neoplasm Staging
MH  - Survival Rate
MH  - Treatment Outcome
EDAT- 2007/08/02 09:00
MHDA- 2008/02/01 09:00
CRDT- 2007/08/02 09:00
PHST- 2006/08/31 00:00 [received]
PHST- 2007/06/27 00:00 [accepted]
PHST- 2007/08/02 09:00 [pubmed]
PHST- 2008/02/01 09:00 [medline]
PHST- 2007/08/02 09:00 [entrez]
AID - 10.3324/921242 [pii]
AID - 10.3324/haematol.10720 [doi]
PST - ppublish
SO  - Haematologica. 2007 Sep;92(9):1242-5. doi: 10.3324/haematol.10720. Epub 2007 Aug 
      1.