IGHV-Mutation Status, IGHV-Gene Usage and Chromosomal Aberrations In CLL: Pooled Analysis within First-Line Clinical Trials of the German CLL Study Group (GCLLSG)
Authors: Bühler Andreas , Zenz Thorsten , Winkler Dirk , Busch Raymonde , Fischer Kirsten , Fink Anna , Wendtner Clemens , Eichhorst Barbara , Edelmann Jennifer , Hallek Michael , Doehner Hartmut , Stilgenbauer Stephan 
Published: October 2019

Abstract
Abstract 3609

Introduction:
IGHV mutation status and genomic aberrations are of independent prognostic importance in CLL. Furthermore IGHV-gene usage showed prognostic value for distinct subgroups (e.g. VH3-21). While the introduction of chemoimmunotherapy (i.e. FCR) has led to remarkable improvement of outcome in CLL, it is unclear which of the known genetic markers retain their prognostic value. We therefore performed a pooled analysis of first-line CLL patients from 3 prospective clinical trials of the GCLLSG namely “CLL2M” (R-Bendamustine) “CLL4” (F vs. FC) and “CLL8” (FC vs. R-FC) to evaluate those genetic markers in a large, well characterized CLL cohort.
Material and Methods: Genetic characterization was performed in a central laboratory (Ulm). IGHV data was available for 1063 patients. Genomic aberrations (FISH) were generated for 1053 patients. After pooling genetic data from the outlined GCLLSG first-line trials we investigated the impact of IGHV mutation status and VH gene usage within the hierarchical model of genomic abnormalities (deletion 13q (del(13q)) single (n=353), trisomy 12 (n=115), deletion 11q (del(11q)) (n=229), deletion 17p (del(17p)) (n=73)) concerning, progression free survival (PFS events= PD/death) and overall survival (OS). Median follow-up was 39.1 months.

Results:
For the del(13q) patients, with 56 % carrying a mutated IGHV gene, we found a significant difference in PFS and OS between the del(13q)/IGHV mutated and the IGHV unmutated subgroup (PFS: p-value 0.002; HR: 1.596; OS: p-value 0.002; HR: 2.15; median PFS mut./70.5 months vs. unmut./41.5 months).
In the trisomy 12 subgroup 35 % of patients showed a mutated IGHV whereas 65 % showed an unmutated IGHV. For the trisomy12/IGHV unmutated subgroup we could detect a trend towards a shorter PFS and OS compared to the trisomy12/IGHV mutated group although this was not statistically significant (PFS: p-value 0.059; HR: 1.784; OS: p-value 0.079; HR: 3.05; median PFS not reached vs. 36.8 months).
In the del(11q) subgroup 17 % were IGHV mutated, whereas 83 % were unmutated. For none of the clinical endpoints (PFS, OS) a significant difference between the 11q-/IGHV mutated group and the 11q-/IGHV unmutated group could be detected (PFS: p-value 0.451; OS: p-value 0.64; median PFS 32.7 months for both subgroups).
Finally among the del(17p) pts. with 23 % IGHV-mutated cases we could not find any difference in PFS or OS among the IGHV-mutated or unmutated subgroup (PFS: p-value 0.995; HR: 0.998; OS: p-value 0.584; HR: 0.80, median PFS 8.8 vs. 9.6 months).
In contrast to previous findings we detected no significant difference in clinical behaviour of the mutated VH3-23 subgroup in comparison to all non-VH3-23 mutated cases with regard to PFS and OS within the CLL8 cohort. (median PFS not reached vs. 59.7 months).
For unmutated VH1-69 cases no significant differences concerning the clinical endpoints in comparison to all non-VH1-69 unmutated cases were detected. Finally the 66 VH3-21 patients in the pooled data set showed a PFS and OS which was surprisingly more comparable to that of IGHV-mutated cases (PFS: p-value 0.488; OS: p-value 0.467; median PFS 51.9 months for VH3-21 vs. 63.6 months for mutated non-VH3-21). However, stereotyped HCDR3 motifs have not been considered in this analysis.

Conclusions:
The current data were derived from pooled subgroup analyses based on genomic aberrations among patients enrolled in 1st line treatment trials (i.e. patients requiring treatment). It revealed a differential influence of IGHV-mutation status and gene usage in the different genomic subgroups. This might hint to different biological behaviour apart from postulated mechanisms like B cell receptor mediated antigen drive and could also be reflected by differences in clinical course. The impact of VH3-21 usage and potentially other VH genes appears to be less pronounced in this cohort. The prognostic role of distinct IGHV-genes must be further evaluated in different clinical situations also considering stereotyped B-cell receptors.

Disclosures:
Bühler: Roche Pharma: Consultancy, Research Funding. Zenz:Roche: Honoraria; Boehringer: Honoraria; GSK: Honoraria; Celgene: Honoraria. Winkler:Roche Pharma AG: Consultancy, Research Funding. Fischer:Roche Pharma AG: Consultancy. Fink:Roche Pharma AG: Consultancy. Wendtner: Celgene, BayerSchering, Roche, Mundipharma: Consultancy, Honoraria. Eichhorst:Roche Pharma AG: Consultancy. Edelmann:Roche Pharma AG: Consultancy, Research Funding. Hallek:Roche Pharma AG: Consultancy. Stilgenbauer:Roche, Bayer, Celgene, GSK, Amgen, Mundipharma: Consultancy, Honoraria, Research Funding.