Genomic Aberrations, VH Mutation Status and Outcome after Fludarabine and Cyclophosphamide (FC) or FC Plus Rituximab (FCR) in the CLL8 Trial
Authors: Stilgenbauer Stephan , Zenz Thorsten , Winkler Dirk , Bühler Andreas , Busch Raymonde , Fingerle-Rowson Günther , Fischer Kirsten , Fink Anna- Maria , Jäger Ulrich , Böttcher Sebastian , Kneba Michael , Wenger Michael , Mendila Myriam , Hallek Michael , Döhner Hartmut 
Published: October 2019

Abstract
The international multicenter randomized CLL8 trial evaluated 1st line treatment with FC or FCR in 817 CLL patients. Analyses of genomic aberrations by FISH and VH mutation status by DNA sequencing were scheduled for a subset of countries in a central reference laboratory. Samples were available for 648 (79%) patients and this cohort was representative of the full trial population regarding other baseline prognostic factors and demographics.
The incidences of the most common genomic aberrations were 13q- 56.7%, 13q- single 36.4%, 11q- 24.6%, +12 12.0%, and 17p- 8.2%. No aberration was found for these regions in 22.4%. VH was unmutated in 63.4% and V3-21 was rearranged in 4.9%. Distributions of genetic parameters were not significantly different between treatment arms. Outcome was analyzed for subgroups defined by genetic parameters in univariate analyses. Genomic aberrations according to the hierarchical model were correlated with differences in CR, CR+PR, PFS and OS in both treatment arms combined and individually (all p<.001). Particularly poor outcome was observed for 17p- in both arms (FC and FCR): CR (4.5% and 19.0%), CR+PR (45.5% and 71.4%), PFS (at 24 months: 0.0% and 29.6%), and OS (at 24 months: 41.0% and 53.3%). Unmutated VH status was correlated with shorter PFS in both arms combined and individually (all p<.001), shorter OS in the FC arm (p=.006), and a trend towards shorter OS in the FCR arm (p=.092).
Treatment results of FCR and FC were compared in subgroups defined by genetic parameters to identify prognostic and predictive markers. While FCR in general improved outcome, this effect was different in specific genetic subgroups (Table).
Table: Treatment effect of FCR (odds ratio (OR) and hazard ratio (HR) with respective significance level for improvement of outcome in genetic subgroups)
VH mut VH unmut 17p- 11q- +12 normal 13q-single CR OR 3.196 3.360 4941 10.000 9.000 154 2.386 p-value <.001 <.001 <.185 <.001 <.001 .274 .003 CR+PP OR 3.537 2.730 3.000 1.370 1.774 1.038 14,884 p-value .083 .008 .124 .723 1.000 1.000 .001 PFS HR .476 .599 .495 .405 .544 .962 .372 p-value .008 .001 .032 .001 251 .890 .001 OS HR .877 .625 .715 .328 .370 1.678 387 p-value .800 .073 .420 .047 .373 .339 .104
Multivariate analysis was performed by Cox regression with backward selection including age, sex, stage, treatment arms, VH status and genomic aberrations as parameters. Regarding PFS, independent prognostic factors were 17p- (HR 6.76, p<.001), unmutated VH (HR 1.97, p<.001), FCR (HR 0.51, p<.001) and +12 (HR 0.58, p=.020). Regarding OS, only 17p- (HR 7.47, p<.001) and unmutated VH (HR 2.09, p=.018) were identified as significant independent factors, while a trend was observed for FCR (HR 0.66, p=.085). In conclusion, genetic parameters remain powerful prognostic markers after 1st line FC and FCR treatment in CLL. The overall improvements by FCR result from specific treatment effects in distinct genetic subgroups and 11q- appears to benefit particularly. However, 17p- and unmutated VH status remain predictors for shorter PFS and OS independently of the overall improvement by FCR.