UNFAVORABLE GENETICS IMPACT MRD RESPONSE TO VENETOCLAX+RITUXIMAB RETREATMENT IN RELAPSED OR REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA (R/R CLL): PHASE 3 MURANO SUBSTUDY

At the MURANO trial (NCT02005471) 5-yr update, median (95% CI) progression-free survival (PFS) was 54 (48–57) mo with venetoclax-rituximab (VenR) and 17 (15–22) mo with bendamustine-R (BR); 36% of pts on VenR and 63% on BR had received new anti-CLL therapy. A substudy from 2018 onward enrolled 34 R/R CLL pts with progressive disease (PD) after initial treatment (tx) to receive VenR as re-tx (n=25) or crossover from BR (n=9). We report on pts who had PD (median [range] PFS 46 [36–58] mo), required anti-CLL therapy, and were retreated with VenR. Molecular changes from the main study baseline (BL-1) to re-tx baseline (BL-2) were assessed, as were BL-2 genetic features and their association with minimal residual disease (MRD) response to VenR. Pts received Ven 400mg/d for 2 yrs and monthly R for the first 6 mo. Genomic complexity (GC; defined by copy number alterations [CNA]: 0–2 non-complex, 3–4 low, ≥5 high) was assessed by aCGH, chromosomal abnormalities by aCGH + FISH (high clone ≥20%, low clone 7–19%) and peripheral blood MRD by PCR and/or flow cytometry (undetectable [u]MRD threshold of <10-4). At data cutoff (Oct 13 2020), 25 pts were retreated with VenR; median (range) follow-up of 12 (3–21) mo and tx-free interval of 28 (12–38) mo. Unfavorable genetic characteristics were enriched from BL-1 to BL-2. At BL-2, 14/24 pts had del(17p) including 11 high clones: 3 newly acquired and 4 shifted from low to high. Median (range) CNA increased from 3 (1–6) at BL-1 to 4 (1–15) at BL-2 (P<0.05). 11/20 pts had GC (8 high GC) at BL-2 with either new chromosomal abnormalities or increased clone size in poor prognostic lesions (2p and 8q gain; 7q, 8p, 11q and 18p loss). Investigator-assessed objective response rate was 70% (14/20 evaluable pts; 50% [14/25] among ITT pts; 5 complete response, 9 partial response). Of 17 pts with MRD data at the re-tx end of combination tx (R-EOCT), 5 achieved uMRD and 12 were MRD+ (Figure). 16 pts had evaluable del(17p) results. Of 6 pts without del(17p) at BL-2, 4 attained uMRD at R-EOCT while all 10 with del(17p) at BL-2 were MRD+ at R-EOCT. Of these, 4/10 had new del(17p) from BL-1 or had evolved from low to high clone. GC status was available for 14 pts. Of 4 pts without GC at BL-2, 2 attained uMRD at R-EOCT. Of 10 pts with GC at BL-2, 8 were MRD+ and 2 had uMRD at R-EOCT; 5/10 had new or increased GC from BL-1. Of 10 pts with uMRD at main study EOCT, 4 re-attained uMRD at R-EOCT. Among the 6 unable to re-attain uMRD, 83% (5/6) had del(17p) at BL-2 (3 newly evolved from BL-1) vs 40% (2/5) at BL-1. EA – previously submitted to EHA 2021. The research was funded by: Venetoclax is being developed in collaboration between Genentech Inc. and AbbVie. Genentech Inc. and AbbVie provided financial support for the MURANO trial and participated in the design, study conduct, analysis and interpretation of data, as well as the writing, review, and approval of the abstract. Third-party editorial assistance, under the direction of Jenny Wu, was provided by Sinéad Holland of Ashfield MedComms, an Ashfield Health company, and was funded by F. Hoffmann-La Roche Ltd. Conflicts of interests pertinent to the abstract Employment or leadership position: Genentech Inc. / F. Hoffmann-La Roche Ltd Stock ownership: Genentech Inc. / F. Hoffmann-La Roche Ltd Consultant or advisory role Roche Honoraria: AbbVie, Astra Zeneca, Gilead, Jannsen, Mei Pharma, Nurix, Roche Research funding: AbbVie, Celgene, Jannsen, Roche Other remuneration: Speaker's bureau: AbbVie, Roche; Membership on an entity's Board of Directors or advisory committees: AbbVie, AstraZeneca, Roche Employment or leadership position: University Hospital of Cologne Consultant or advisory role Janssen, Roche, Novartis, AbbVie, Gilead, Celgene, ArQule, AstraZeneca, Oxford Biomedica (UK), BeiGene Employment or leadership position: Professor of Experimental Haematology, University of Leeds, Worsley Building, Leeds Consultant or advisory role Janssen, Pharmacyclics, Abbvie, Roche, Gilead, Apellis Honoraria: Janssen, Abbvie, AstraZeneca, Verastem, Apellis and Alexion, Pharmacyclics, BeiGene, Juno, Roche Research funding: Janssen, Pharmacyclics, Abbvie, Roche, Gilead, Apellis Other remuneration: Speaker's bureau: Abbvie, Janssen, Pharmacyclics, Gilead, Roche, AstraZeneca, Alexion, Juno/BMS, Apellis, BeiGene Employment or leadership position: University of California, San Diego Honoraria: Travel/ Honoraria 2019-2021: Pharmacyclics/Abbvie, Genentech, Janssen, Dava Oncology, iwNHL, TG Therapeutics, Celgene, Velosbio•Astra Zeneca, Loxo Oncology Research funding: National Cancer Institute/NIH, Breast Cancer Research Foundation, Oncternal Therapeutics, Inc., California Institute for Regenerative Medicine, Specialized Center of Research, Leukemia and Lymphoma Society Other remuneration: Cirmtuzumab was developed by T.J.K. in the T.J.K. laboratory and licensed by the University of California to Oncternal Therapeutics, Inc., which provided stock options and research funding to the T.J.K. laboratory. T.J.K. has received research funding and/or has served as an advisor to Oncternal, Pharmacyclics/Abbvie, Genentech, Janssen, Astra Zeneca, Pharmacyclics, and Velos Bio. Cirmtuzumab was developed by T.J.K.and licensed by the University of California to Oncternal Therapeutics, Inc., which has provided stock/options to the university and T.J.K Research funding: Roche-Genentech, Gilead Other remuneration: Speaker's bureau: Janssen Consultant or advisory role AbbVie, AstraZeneca, Janssen, Merck, Roche, Incyte, Novartis, Gilead Honoraria: AbbVie, Roche, Janssen, Astrazeneca, Merck, Servier, Novartis, Teva Research funding: Genentech, Roche Employment or leadership position: Amsterdam University Medical Centre Research funding: Genentech funding for microarray analysis Employment or leadership position: Amsterdam University Medical Centre Research funding: Genentech funding for microarray analysis Employment or leadership position: Abbvie Stock ownership: Abbvie Employment or leadership position: Genentech Stock ownership: Roche Employment or leadership position: Roche Stock ownership: Roche Employment or leadership position: Roche Products Limited Stock ownership: Roche Products Limited Employment or leadership position: Roche Stock ownership: Roche Employment or leadership position: Amsterdam University Medical Centers Consultant or advisory role Biogeneration, LAVA Honoraria: Celgene, Roche/Genentech, AstraZeneca, Janssen Research funding: Celgene, Roche/Genentech, AstraZeneca, Janssen

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