GENETIC MARKERS AND OUTCOME IN THE CLL14 TRIAL OF THE GCLLSG COMPARING FRONT LINE OBINUTUZUMAB PLUS CHLORABMUCIL OR VENETOCLAX IN PATIENTS WITH COMORBIDITY Best abstract submitted by a young investigator / travel grant recipient (2019)

Introduction: 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). Methods: We assessed the incidence and impact of genomic aberrations via FISH, mutations in 13 genes via NGS and IGHV status in the phase 3 CLL14 trial comparing G-Clb vs. Ven-G in patients with CIRS>6 or creatinine clearance < 70 ml/min. Of the intention to treat population (n=432) FISH/IGHV/NGS was assessable in 418/408/421 cases. 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%, SF3B1 16%, ATM 13%, TP53 10%, XPO1 6%, RPS15 5%, POT1 5%, BRAF 4%, BIRC3 4%, NFKBIE 4%, EGR2 4%, MYD88 2% and FBXW7 1%. High coincidence was found for del(17p) and TP53mut. Overall response rate (ORR) to G-Clb was lower with del(17p), del(11q) TP53mut, ATMmut and BIRC3mut. None of the parameters impaired ORR to Ven-G. 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<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). 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 IGHVunmut (HR 3.4, p<0.001) were adverse factors. Ven-G was superior to G-Clb regarding PFS in most genetic subgroups including del(17p), del(11q), TP53mut, NOTCH1mut, SF3B1mut and ATMmut. Regarding IGHV, only patients with unmutated status had a significant PFS benefit from Ven-G in comparison to G-Clb (IGHVunmut HR 0.2, p<0.001; IGHVmut HR 0.6, p=0.29; Fig 1b). Multivariable testing for interaction between treatment and IGHV status was significant (p=0.03) indicating IGHVunmut 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<0.001; Ven-G: HR 3.4, p=0.03) and with TP53mut, BRAFmut and IGHVunmut in the G-Clb arm (HR 5.5, p=0.002; HR 6.6, p<0.01; HR 5.4, p=0.03), while none of the other factors were significantly associated with OS. Keywords: chronic lymphocytic leukemia (CLL); prognostic indices; venetoclax. Disclosures: Tausch, E: Consultant Advisory Role: Roche, Abbvie; Other Remuneration: Roche, Abbvie. Bahlo, J: Honoraria: Roche. Eichhorst, B: Consultant Advisory Role: Roche, Abbvie, Janssen, Gilead, Novartis, Celgene; Research Funding: Roche, Abbvie, Janssen, Gilead; Other Remuneration: Speakers' Bureau: Roche, Abbvie, Janssen, Gilead, Novartis, Celgene. Kreuzer, K: Consultant Advisory Role: Abbvie, Alexion, Amgen, Ariad, Baxalta, Bayer, Biotest, Bristol-Myers Squibb, Celgene, Daiichi, Chugai, Gilead, Grifols, Hexal, Janssen-Cilag, Jazz, Novartis, Otsuka, Pfizer, Roche; Honoraria: Abbvie, Alexion, Amgen, Ariad, Baxalta, Bayer, Biotest, Bristol-Myers Squibb, Celgene, Daiichi, Chugai, Gilead, Grifols, Hexal, Janssen-Cilag, Jazz, Novartis, Otsuka, Pfizer, Roche; Research Funding: Abbvie, Alexion, Amgen, Ariad, Baxalta, Bayer, Biotest, Bristol-Myers Squibb, Celgene, Daiichi, Chugai, Gilead, Grifols, Hexal, Janssen-Cilag, Jazz, Novartis, Otsuka, Pfizer, Roche; Other Remuneration: Abbvie, Alexion, Amgen, Ariad, Baxalta, Bayer, Biotest, Bristol-Myers Squibb, Celgene, Daiichi, Chugai, Gilead, Grifols, Hexal, Janssen-Cilag, Jazz, Novartis, Otsuka, Pfizer, Roche. Tandon, M: Employment Leadership Position: Roche. Humphrey, K: Employment Leadership Position: Roche; Stock Ownership: Roche. Jiang, Y: Employment Leadership Position: Genentech; Stock Ownership: Genentech. Schary, W: Employment Leadership Position: Abbvie; Stock Ownership: Abbvie. Porro Lurà, M: Employment Leadership Position: F. Hoffmann - La Roche Ltd; Stock Ownership: Yes. Fischer, K: Other Remuneration: Roche (Travel, Accommodations). Hallek, M: Consultant Advisory Role: Roche, Abbvie; Honoraria: Roche, Abbvie, Gilead, Janssen, Celgene, Boehringer Ingelheim; Research Funding: Roche, Abbvie; Other Remuneration: Speakers' Bureau: Roche, Abbvie. Stilgenbauer, S: Research Funding: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann La-Roche, Janssen, Novartis, Pharmacyclics, Sunesis; Other Remuneration: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann La-Roche, Janssen, Novartis, Pharmacyclics, Sunesis (Personal Fees).