Towards Response Prediction Using Integrated Genomics in Chronic Lymphocytic Leukaemia: Results on 250 First-Line FCR Treated Patients from UK Clinical Trials

摘要: Background : Major progress has been made in understanding disease biology and therapeutic options for patients with chronic lymphocytic leukaemia (CLL). Recurrent mutations have discovered using next generation sequencing, but the exception of TP53 disruption their potential impact on response to treatment is unknown. In order address this question, we characterised genomic landscape 250 first-line chemo-immunotherapy treated CLL within UK clinical trials targeted resequencing whole-genome SNP array. Methods We studied from two UK-based Phase II randomised controlled (AdMIRe ARCTIC) receiving FCR-based a setting. A TruSeq Custom Amplicon panel (TSCA, Illumina) was designed targeting 10 genes recurrently mutated based recent publications.Average sequencing depth 2260X. The cumulated length targets sequenced 7.87 kb 330 amplicons covering 160 exons. Alignment variant calling included combination three pipelines confidently detect SNVs, indels low level frequency mutations. array testing performed HumanOmni2.5-8 BeadChips, (Illumina) data analysed Nexus 6.1 Discovery Edition, Biodiscovery. genome-wide arrays selected samples’ germline material confirm somatic (n=40). Univariate multivariate analyses minimal residual (MRD) as outcome measure were 220 patients. Results Pathogenic identified 165 (66%) patients, totalling 268 genes. ATM most frequently gene affecting 67 (29%) followed by SF3B1 (n=56, 24%), NOTCH1 (n= 32, 14%), 21, 9%), BIRC3 17, 7%) XPO1 (n=14, 6%). Less recurrent seen SAMHD1 (n=8, 3%), MYD88 4, 2%), MED12 (n=7, 3%) ZFPM2 (n=5, 2%). Integrating results increased one or more driver mutation 66% 94%. As previously reported del17p are co-occurring associate MRD positivity all cases (n=15, p=0.0002). report minor subclones 11 (VAF 1-5%), 8 whom available also associated positivity. Deletions 11q present 44 patients. These lesions always not . Bialleleic 27 (significantly positivity) 4 Rather surprisingly, trisomy 12 (n=33) (n=28) negativity (p=0.006 0.097, respectively). Analysing clonal subclonal per revealed majority (65% 87% contrast almost clonally distributed. There an association between negativity, compared mutations, difference remaining From our copy number , presence (p=0.05). Combining important multiple logistic regression analysis predict positivity, bialleleic disruption, together strongest predictors, whereas monoalleleic medium predictor negativity. Conclusion This first integrated distribution associations drivers, deep whole genome shown profiles For CLL-associated begun unravel hierarchies. developed comprehensive model found strongly Using status robust proxy PFS only enables us previous studies, advantageous considerably reducing timeframe results. Indeed, suggest that should be assessed routinely future studies complement modern genomics approaches. Disclosures Hillmen: Pharmacyclics, Janssen, Gilead, Roche: Honoraria, Research Funding.