S105 GENETIC MARKERS AND OUTCOME IN THE CLL14 TRIAL OF THE GCLLSG COMPARING FRONT LINE OBINUTUZUMAB PLUS CHLORAMBUCIL OR VENETOCLAX IN PATIENTS WITH COMORBIDITY
Authors: E. Tausch, J. Bahlo, S. Robrecht, C. Schneider, J. Bloehdorn, S. Schrell, C. Galler, O. Al‐Sawaf, A.‐M. Fink, B. Eichhorst, K.‐A. Kreuzer, M. Tandon, K. Humphrey, Y. Jiang, W. Schary, M. Porro Lurà, H. Döhner, K. Fischer, M. Hallek, S. Stilgenbauer
Journal: HemaSphere (2019)

Background: Genomic aberrations, IGHV mutation status and mutations in genes such as TP53 are established prognostic factors in CLL in the context of chemoimmunotherapy. Their role is less‐well established when using chemo‐free regimens such as obinutuzumab (GA‐101) plus venetoclax (Ven‐G). Aims: This study evaluates the prognostic impact of genetic risk factors on obinutuzumab+chlorambucil (G‐Clb) vs. obinutuzumab+Venetoclax (Ven‐G). Methods: We assessed the incidence and impact of genetic factors in the phase 3 CLL14 trial comparing G‐Clb vs.Ven‐G in patients with CIRS&gt;6 or creatinine clearance &lt; 70 ml/min. Genomic aberrations were assessed by FISH, IGHV by sequencing with a threshold of 98% homology and mutations via amplicon‐based targeted NGS for TP53 , NOTCH1 , SF3B1 , ATM , MYD88 , FBXW7 , POT1 , BIRC3 , XPO1 , NFKBIE , EGR2 and RPS15 for variants with allele fraction ≥10%. Of the intention to treat population (n = 432) FISH/IGHV/NGS was assessable in 418/408/421 cases. PFS and OS were estimated via Kaplan‐Meier method and compared by non‐stratified log‐rank test. Hazard ratios (HRs) were calculated via Cox proportional hazards regression modeling. Results: The incidence of genomic aberrations considering the hierarchical model were del(17p) 7%, del(11q) 18%, +(12q) 18% and del(13q) 35%. IGHV was unmutated in 61% of patients. The incidence of gene mutations was NOTCH1 23% (exon 34 and/or 3’UTR), SF3B1 16%, ATM 13%, TP53 10%, XPO1 6%, RPS15 5%, POT1 5%, BRAF 4%, BIRC3 4%, NFKBIE 4%, EGR2 4%, MYD88 2%, FBXW7 1%. High coincidence was found for del(17p) and TP53 mut in 77% of all del(17p) cases and 57% of all TP53 mut cases. None of the parameters impaired overall response rate (ORR) to Ven‐G at treatment completion. For G‐Clb, the ORR rate was lower in patients with del(17p) (36% vs. 73%), del(11q) (58% vs. 74%), TP53 mut (58% vs. 74%), ATM mut (56% vs. 75%) and BIRC3 mut (33% vs. 74%). At a median follow‐up of 29 months, there were 107 events for PFS and 37 for OS in the intention to treat population. Del(17p) was the only genomic abnormality with impact on PFS in G‐Clb (HR 4.6, p &lt; 0.001) and Ven‐G (HR 4.4, p = 0.001; Fig 1a). Similarly, TP53 mutations affected PFS in both treatment arms (G‐Clb HR 2.7, p = 0.001; Ven‐G HR 3.1, p = 0.01). However, TP53 mut without del(17p) was not associated with shorter PFS. None of the other evaluated factors affected Ven‐G efficacy, while for G‐Clb del(11q) (HR 2.3, p = 0.002), BIRC3 (HR 4.0, p = 0.001), NOTCH1 (HR 1.8, p = 0.03) and unmutated IGHV (HR 3.4, p &lt; 0.001) were adverse factors. In several genetic subgroups including del(17p), del(11q), TP53 mut , NOTCH1 mut , SF3B1 mut , ATM mut Ven‐G was superior to G‐Clb in PFS. Regarding IGHV, only patients with unmutated status had a significant PFS benefit from Ven‐G in comparison to G‐Clb (IGHV unm HR 0.2, p &lt; 0.001; IGHV mut HR 0.6, p = 0.29; Fig.1b). Multivariable testing for interaction between treatment and IGHV mutational status was significant (p = 0.03) indicating unmutated IGHV as a predictive factor for increased benefit from Ven‐G. OS was lower with del(17p) in both treatment arms (G‐Clb: HR 11.0, p &lt; 0.001; Ven‐G: HR 3.4, p = 0.03) and with TP53 mut , BRAF mut and IGHV unmut in the G‐Clb arm (HR 5.5, p = 0.002; HR 6.6, p &lt; 0.01; HR 5.4, p = 0.03), while none of the other factors were significantly associated with OS. Summary/Conclusion: Prognostic value of genomic aberrations, IGHV and gene mutations were confirmed for G‐Clb, while with Ven‐G only del(17p) and TP53 mut were associated with short PFS and only del(17p) with short OS. Unmutated IGHV was identified as a predictive factor characterizing a group of patients with particular benefit from Ven‐G. image