@article{Stephan Stilgenbauer_Sandrine Sander_Lars Bullinger_Axel Benner_Elke Leupolt_Dirk Winkler_Alexander Kröber_Dirk Kienle_Peter Lichter_Hartmut Döhner_2007, place={Pavia, Italy}, title={Clonal evolution in chronic lymphocytic leukemia: acquisition of high-risk genomic aberrations associated with unmutated VH, resistance to therapy, and short survival}, volume={92}, url={https://haematologica.org/article/view/4566}, DOI={10.3324/haematol.10720}, abstractNote={In chronic lymphocytic leukemia (CLL), the acquisition of new genomic aberrations during the disease course (<em>clonal evolution</em>) is thought to be an infrequent phenomenon but comprehensive analyses are limited. Genomic aberrations were analyzed by fluorescence <em>in situ</em> 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 rosk of death (HR = 2.97, 95% CI 1.40–6.27, <em>p</em>=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 <em>in vivo</em> 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. <em>In vivo</em&gt; resistance to chemotherapy of CLL clones with del(17p13) emphasizes the need for alternative treatment approaches in these patients.}, number={9}, journal={Haematologica}, author={Stephan Stilgenbauer and Sandrine Sander and Lars Bullinger and Axel Benner and Elke Leupolt and Dirk Winkler and Alexander Kröber and Dirk Kienle and Peter Lichter and Hartmut Döhner}, year={2007}, month={Sep.}, pages={1242-1245} }