Acquired Genomic Copy Number Aberrations and Survival In CLL
Authors: Malek Sami , Parkin Brian , Peres Edward M. , Talpaz Moshe , Kaminski Mark S. , Kujawski Lisa , Collins Roxanne , Shedden Kerby , Ouillette Peter 
Published: October 2019

Abstract
Abstract 1713
Genomic aberrations like 17p and 11q deletions and mutations in p53 affect survival outcome in CLL. To further our understanding of the anatomy and clinical importance of various acquired genomic copy number aberrations (aCNA) in CLL, we have generated SNP 6.0 array-based genomic profiling data of DNA from sorted CD19+/CD3+ cells from 256 CLL patients, of which 201 were untreated and 55 relapsed (median number of prior therapies 1) at study enrollment. Acquired CNAs were detected using visual inspection of paired (CD19+: tumor/CD3+: normal reference DNA) genomic copy number heatmap displays using the validated software tool dChipSNP. This analytical approach is conservative and has been previously externally validated using FISH for other tumor types and lesions > 0.2 Mb.
The range of aCNA for all cases was 0–22 lesions, most of which were sub-chromosomal deletions. We did not detect a sub-chromosomal aCNA in 72/256=28% of the cases even at this ultra-high resolution, suggesting that sub- chromosomal aCNA are not involved in the pathogenesis of this CLL subset. Three or more sub-chromosomal lesions were found in 50/256=20% of all cases analyzed; this is likely a low estimate of the true frequency of this genomic CLL type given the aggressive clinical behavior. Of the 50 cases with ≥3 sub-chromosomal lesions, 26 harbored somatically acquired p53 exon 2–10 mutations (26/50=52%).
Next we determined the prognostic importance of various established and novel biomarkers on the clinical endpoint overall survival (OS; alternatively computed using either the CLL diagnosis date or the trial enrollment date as the reference date). For previously untreated patients (N=201) and for the OS analysis based on the diagnosis date and the date of death, OS was 84 months for p53 mutated cases (N=24), 94 months for 17p cases (N=16), 116 months for 11q cases (N=14), 237 months for ZAP70+ cases (N=85), 174 months for IgVH unmutated cases (N=82) and 167, 90 and 52 months for ≥2 (N=68), ≥3 (N=31) or ≥4 (N=19) aCNA based on SNP 6.0 array profiling, respectively.
For all patients (N=256) and for the OS analysis based on the diagnosis date and date of death, OS was 96 months for p53 mutated cases (N=36), 91 months for 17p cases (N=25), 123 months for 11q cases (N=25), 139 months for ZAP70+ cases (N=123), 123 months for IgVH unmutated cases (N=116) and 144, 108 and 77 months for ≥2 (N=100), ≥3 (N=50) or ≥4 (N=33) aCNA based on SNP 6.0 array profiling, respectively. Furthermore, CLL patients with wild type p53 exons 2–10 and SNP 6.0 array-based genomic lesion loads of 2 lesions or more had significantly (all p<0.05) shorter OS than the corresponding lower genomic complexity cases. Finally, similar data were obtained if the CLL trial enrollment date as opposed to the CLL diagnosis date was used to compute OS.
We proceeded with multivariate analyses including various base variables (del17p, del11q, p53 exon 2–10 mutations, ZAP70 status, IgVH status) in the models as well as SNP 6.0 array-based genomic complexity at various thresholds. Furthermore, models were based on previously untreated patients only or alternatively on all patients. Finally, models were based on the CLL diagnosis date or alternatively the CLL trial enrollment date as the reference date for OS computations.
Importantly, for all models, genomic complexity emerged as an independent and dominant predictor of short OS. For instance, for previously untreated patients (N=192) and OS based on the diagnosis date in CLL, the hazard ratio (HR) for short OS for genomic complexity ≥3 lesions was 3.95 (CI=1.12-13.95; p=0.03) when controlling for ZAP70 status HR=0.68 (CI=0.25-1.89; p=0.46), IgVH unmutated HR=2.64 (CI=0.91-7.68; p=0.07) and p53 exon 2–10 mutations HR=1.95 (CI=0.51-7.43; p=0.32). For all patients (N=247) the corresponding results were: genomic complexity ≥3 lesions HR=3.57 (CI=1.72-7.44; p<0.01) when controlling for ZAP70 status HR=1.55 (CI=0.74-3.23; p=0.23), IgVH unmutated HR=2.93 (CI=1.39-6.21; p<0.01) and p53 exon 2–10 mutations HR=0.9 (CI=0.4-2.03; p=0.79) with OS based on the diagnosis date. Similar results were obtained when controlling for 17p or 11q status.
In summary, this data demonstrates that a subgroup of CLL patients with elevated genomic complexity has poor overall survival (akin to patients with p53 mutations) and thus should be specifically targeted for novel therapeutic approaches.

Disclosures:
No relevant conflicts of interest to declare.