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1856 Outcomes with Venetoclax-Based Treatment in Patients with Covalent Bruton Tyrosine Kinase Inhibitor (cBTKi)-Treated, Chemotherapy-Naïve Chronic Lymphocytic Leukemia (CLL): An International Retrospective Study

Program: Oral and Poster Abstracts
Session: 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Poster I
Hematology Disease Topics & Pathways:
Research, Lymphoid Leukemias, Adult, CLL, Clinical Research, Diseases, Therapy sequence, Real-world evidence, Treatment Considerations, Lymphoid Malignancies, Study Population, Human
Saturday, December 7, 2024, 5:30 PM-7:30 PM

Paul J. Hampel, MD1, Kari G. Rabe, MS2*, Romain Guieze, MD, PhD3*, Yucai Wang, MD, PhD1, Emmanuelle Ferrant4*, Saad S. Kenderian, MD1, Marie Sarah Dilhuydy, MD5*, Eli Muchtar, MD1, Anne-Sophie Michallet, MD, PhD6*, Jose F. Leis, MD, PhD7, Luca Inchiappa8*, Mazie Tsang, MD9, Aline Clavert, MD10*, Talal Hilal, MD11, Stephane Lepretre, MD12*, Ricardo D. Parrondo, MD13, Emmanuelle Tchernonog14*, Amber Koehler, PA-C15*, Lin Wang16*, Susan M. Schwager1*, Susan L. Slager, PhD1, Neil E. Kay, MD17, Luc-Matthieu Fornecker, MD, PhD18*, Sameer A. Parikh, MBBS1 and Loic Ysebaert, MD, PhD19*

1Division of Hematology, Mayo Clinic, Rochester, MN
2Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, MN
3CHU Estaing, Clermont Ferrand, FRA
4Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Service d’Hématologie Clinique, Pierre-Bénite, France
5CHU Bordeaux, PESSAC, FRA
6Centre Leon Berard, LYON, France
7Mayo Clinic, Phoenix, AZ
8Hematology Department, Institut Paoli-Calmettes, MARSEILLE CEDEX 09, France
9Division of Hematology and Oncology, Department of Medicine, Mayo Clinic, Phoenix, AZ
10CHU Angers, Angers, FRA
11Division of Hematology and Oncology, Mayo Clinic Arizona, Phoenix, AZ
12Centre Henri Becquerel, Rouen, FRA
13Division of Hematology-Oncology, Mayo Clinic-Florida, Jacksonville, FL
14Hematology Department, CHU Montpellier, Montpellier Cedex 5, France
15Mayo Clinic, Rochester, MN
16BMS, Lawrence Township, NJ
17Department of Immunology, Mayo Clinic, Rochester, MN
18Institut De Cancérologie Strasbourg Europe, Hematology Department, Strasbourg, France
19Hematology Department, Institut Universitaire du Cancer Toulouse Oncopole, Toulouse, France

Introduction

Venetoclax + rituximab resulted in a 2-year progression-free survival estimate of 85% in the mostly 2nd-line, post-chemotherapy setting of the MURANO clinical trial (Seymour NEJM 2018). Short remissions with venetoclax in patients (pts) with prior cBTKi treatment (tx) for CLL are reported. However, these cohorts have included heavily pre-treated pts. Here, we report outcomes with venetoclax-based regimens in a contemporary cohort with cBTKi-exposed CLL and no prior chemotherapy.

Methods

We conducted a retrospective study of pts who received venetoclax for relapsed CLL after prior cBTKi tx at Mayo Clinic and across 8 centers in France. Pts with any prior chemotherapy tx were excluded. Pts were grouped as cBTKi-resistant (CLL disease progression on cBTKi) and cBTKi-exposed (any prior cBTKi tx but without disease progression). Overall survival (OS) was analyzed as the time from initiation of venetoclax until date of death or last known to be alive. Time to next therapy or death (TTNTD) after venetoclax was defined as the time from venetoclax initiation until the earliest date of next tx or death. Cox proportional hazards regression models were used to estimate associations of factors with OS and TTNTD.

Results

A total of 85 pts received venetoclax, including: venetoclax monotherapy (n=13, 15%), venetoclax + rituximab (n=45, 53%), and venetoclax + obinutuzumab (n=27, 32%). Patient characteristics at the time of venetoclax start were as follows: median age 69 years (interquartile range [IQR] 62-77), 59 (69%) male, 45% (33/73 evaluated) with TP53 disruption (del(17p) or TP53 mutation), 82% (46/56 evaluated) with unmutated IGHV, and 41% (15/37 evaluated) with complex karyotype (CK; ≥3 clonal structural or numerical abnormalities on karyotype). The median prior lines of therapy was 1 (IQR 1, 2); 32 (38%) pts had received prior anti-CD20 monoclonal antibody and 8 (9%) pts had received 2 prior cBTKi. Prior cBTKi tx was stopped for a reason other than disease progression in 46 (54%) pts (cBTKi-exposed) and due to CLL progression in 39 (46%) pts (cBTKi-resistant). TP53 disruption, unmutated IGHV, and CK were more common in the cBTKi-resistant subgroup. Among pts with cBTKi-resistant CLL, 60% (12/20 evaluated) had a BTK and/or PLCG2 mutation. Median follow-up from start of venetoclax-based therapy was 20 months. The median TTNTD and OS for the entire cohort was 36 (95% CI 29-not evaluable [NE]) and 68 (95% CI 39-NE) months, respectively.

Among the 46 pts with cBTKi-exposed CLL, the median duration of prior cBTKi tx was 6.7 months (IQR 1.8, 23.7). The median TTNTD and OS from venetoclax start were both 78 months in pts with cBTKi-exposed CLL. The 24-month TTNTD and OS estimates were 73% and 81%, respectively.

Among the 39 pts with cBTKi-resistant CLL, the median duration of prior cBTKi tx was 42.3 months (IQR 23.4, 60.1). The median TTNTD from venetoclax start in pts with cBTKi-resistant CLL was 30 months. The 24-month TTNTD estimate was 65% in the cBTKi-resistant subgroup, 53% with venetoclax monotherapy (n=5), 62% with venetoclax + rituximab (n=30), and 100% venetoclax + obinutuzumab (n=4). The median OS from venetoclax initiation was 39 months overall in pts with cBTKi-resistant CLL. The 24-month OS estimate was 84% in the cBTKi-resistant subgroup overall, 53% with venetoclax monotherapy, 87% with venetoclax + rituximab, and 100% with venetoclax + obinutuzumab.

On a univariate analysis in the whole cohort, only TP53 disruption was associated with shorter TTNTD (HR 2.23; 95% CI 1.02-4.87; P=0.04) and only older age was associated with shorter OS (HR 1.05; 95% CI 1.007-1.095, P=0.02).

On a univariate analysis in the cBTKi-resistant subgroup, only TP53 disruption was associated with shorter TTNTD (HR 6.68; 95% CI 1.51-29.46; P=0.01) and OS (HR 7.95; 95% CI 1.02-61.97; P=0.04). Duration of prior cBTKi exposure (as a continuous variable) was not associated with survival outcomes in the cBTKi-resistant subgroup.

Conclusions

Pts with chemotherapy-naïve, cBTKi-treated CLL had worse than expected outcomes with venetoclax-based tx in a mostly 2nd-line tx cohort, particularly pts with cBTKi-resistant CLL. The frequency of high-risk disease features, shorter duration of disease control with their initial cBTKi tx, and small cohort size warrant caution in generalizing these results to all pts with cBTKi-resistant disease. Novel tx trial strategies in 1st- and 2nd-line settings remain a high priority for high-risk pts.

Disclosures: Wang: InnoCare, AbbVie: Consultancy; Kite: Honoraria; Incyte, InnoCare, LOXO Oncology, Eli Lilly, MorphoSys, Novartis, Genentech, Genmab, AbbVie, BeiGene, Merck: Research Funding; Eli Lilly, LOXO Oncology, TG Therapeutics, Incyte, InnoCare, Kite, Jansen, BeiGene, AstraZeneca, Genmab, AbbVie: Other: Advisory Board. Ferrant: Astra Zeneca, BeiGene, Janssen, Cilag, AbbVie, Gilead: Honoraria; Astra Zeneca, BeiGene, Janssen: Consultancy. Kenderian: Novartis, Kite/Gilead, Juno/BMS, Capstan, Humanigen, Carisma: Membership on an entity's Board of Directors or advisory committees; Novartis, Kite/Gilead, Juno/BMS, Lentigen, Humanigen, Morphosys, Tolero, LeahLabs, InCyte, Viracta: Research Funding; Kite/Gilead, Novartis, Carisma, Juno/BMS, Humanigen, Luminary: Consultancy; Novartis, Humanigen, MustangBio,: Patents & Royalties. Muchtar: Protego: Consultancy. Tsang: AstraZeneca: Other: Advisory Board; Poseida Therapeutics: Current holder of stock options in a privately-held company; Novartis: Other: Advisory Board; AVEO: Other: Prior holder of stock options in a privately-held company; Genentech: Other: Advisory Board. Hilal: BeiGene: Consultancy, Research Funding. Parrondo: Sanofi Aventis: Honoraria; AstraZeneca: Honoraria; Bristol Myers Squibb, GSK: Research Funding. Wang: BMS: Current Employment. Kay: AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Other: data safety monitoring committee and advisory board; Behring: Membership on an entity's Board of Directors or advisory committees; BeiGene: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: data safety monitoring committee and advisory board; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios Pharma: Other: data safety monitoring committee; BMS –Celgene: Other: data safety monitoring committee; Vincerx: Research Funding; Sunesis: Research Funding; Genentech: Research Funding; Celgene: Research Funding; Bristol Meyer Squibb: Research Funding; Acerta Pharma: Research Funding; Dren Bio: Other: data safety monitoring committee; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding. Parikh: Kite: Consultancy; AstraZeneca: Consultancy, Research Funding; Amgen: Consultancy; AbbVie: Consultancy; MingSight: Consultancy; Novalgen Limited: Consultancy; Pharmacyclics: Consultancy; BeiGene: Consultancy; Merck: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Ysebaert: AbbVie, AstraZeneca, Janssen, Roche, Beigene, BMS/Celgene, Gilead/Kite: Membership on an entity's Board of Directors or advisory committees, Research Funding.

*signifies non-member of ASH