Frequent Evolution of Copy Number Alterations Following First‑line Treatment with FC(R) is Enriched with TP53 Alterations which Impact Long Term Survival – Results from the CLL8 Trial. Homo sapiens

To define clonal evolution of somatic copy number alterations (CNAs) in chronic lymphocytic leukemia (CLL), sequential samples of 103 individuals were investigated by SNP-array analysis for appearance of novel CNAs. Patients were enrolled on the CLL8 trial and uniformly received fludarabine, cyclophosphamide +/- rituximab (FC/FCR). Comparing two sequential samples prior to therapy (N=27, a median of 2.9 years apart), CNA evolution occurred in 19% of cases. In contrast, when comparing treatment‑initiation and relapse genomic profiles (a median of 3.6 years apart), CNA evolution was seen in 40% of cases. This suggested association of FC(R) treatment with higher rate of CNA evolution. The only clinical feature significantly associated with CNA evolution was FCR therapy compared with FC (OR=2.806, p=0.024). As this might be related to narrower evolutionary bottlenecks imposed by the more effective FCR therapy, which could execute more selection pressure, we examined matched minimal residual disease data. We found CNA evolution more frequently in cases with CLL cell numbers rapidly receding in early phases of treatment. Finally, we observed frequent rises of TP53 mutant/deficient clones with therapy (N=19, 22%) that were associated with decreased overall survival (p=0.016). These results demonstrated that re-examination of TP53 status upon relapse provides important information. Overall design: Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from cryopreserved diagnostic peripheral blood samples. Copy number analysis of Affymetrix® 6.0 arrays was performed for 216 CLL samples. There are also 52 samples from mononuclear cells negative for CD19 which were taken at treatment-initiation and used as references for copy number inference.