INTRODUCTION

We aim to identify factors that impact outcomes of venetoclax for patients with CLL treated in routine practice at a tertiary center. We report on the use of venetoclax in the most frequently encountered disease scenarios: first-line, relapsed/Bruton tyrosine kinase inhibitor (BTKi)-naïve, and relapsed/BTKi-exposed.

METHODS

We identified patients who received venetoclax therapy for CLL (between 4/2012-4/2023) from the Mayo Clinic CLL Database. Undetectable measurable residual disease (uMRD) was defined as <1 CLL cell per 10,000 leukocytes using 8-color flow cytometry on peripheral blood (PB) or bone marrow (BM). Overall survival (OS) was defined as the time from venetoclax start until date of death or last known to be alive. Treatment-free survival (TFS) after venetoclax was defined as the time from venetoclax start until the earliest of date of next treatment, or death. Kaplan-Meier was used to display OS and TFS. Multivariable Cox proportional hazards regression models were used to estimate associations of factors with time-to-event outcomes.

RESULTS

A total of 155 patients received venetoclax: firstline therapy (in combination with obinutuzumab, n=55) and relapsed CLL (n=100; 17 had relapsed/BTKi-naïve CLL, and 83 had previously received BTKi [55 with progression after BTKi], relapsed/BTKi-exposed). The median follow-up for the cohorts of first-line therapy, relapsed/BTKi-naïve, and relapsed/BTKi-exposed was 12.9 months, 37.0 months, and 27.6 months, respectively. Baseline characteristics at the time of venetoclax initiation for all patients are shown in Table 1. The median TFS for the overall cohort was 39.0 months. The median OS was 54.6 months.

Among patients treated with venetoclax as first-line therapy (n=55), the 2-year TFS ( Figure 1) and 2-year OS rates were both 91%. MRD testing was performed in 28 patients and was uMRD in 23 (82%) patients (only PB assessed, n=7; only BM assessed, n=2; PB and BM assessed, n=14). Detectable MRD was identified in 3 patients, and 2 patients had discordant results (PB uMRD and BM detectable disease).

Among patients treated with venetoclax in the relapsed/BTKi-naïve setting (n=17), the 2-year TFS rate was 73% ( Figure 1) and the 2-year OS rate was 100%. MRD testing was performed in 7 patients and was uMRD in all 7 (100%) (only PB assessed, n=3; only BM assessed, n=2; PB and BM assessed, n=2). The median time to first uMRD result was 14.1 months.

Among relapsed/BTKi-exposed venetoclax-treated patients (n=83), the median TFS was 26.9 months ( Figure 1), and the median OS was 39.4 months.In this subgroup, the median TFS for patients with (n=55) and without (n=28) prior disease progression on prior BTKi were 22.3 and 42.3 months, respectively. Median TFS with venetoclax monotherapy (n=30) was 24.0 months, venetoclax in combination with rituximab (n=37) was 26.9 months, and venetoclax in combination with obinutuzumab (n=16) was 39.0 months. BTKi-exposed patients that were chemotherapy-naïve (n=27) and chemotherapy-exposed (n=56) had median TFS of 29.1 and 24.0 months, respectively. MRD testing was performed in 28 patients and was uMRD in 16 (57%) patients (only PB assessed, n=9; only BM assessed, n=2; PB and BM assessed, n=5). Detectable MRD was identified in 11 patients, and 1 had discordant results (PB uMRD and BM detectable disease). The median time to first uMRD result was 11.5 months.

TP53 disruption, unmutated IGHV genes, older age, complex karyotype (CK; defined as more than 3 chromosomal aberrations on CpG stimulated karyotype), and disease progression on prior BTKi were associated with shorter TFS in the overall cohort on univariate analysis. TP53 disruption, older age, CK, and disease progression on prior BTKi were associated with shorter OS in the overall cohort on univariate analysis. Multivariable analysis was performed by including only those patients where all variables significant in univariable analysis were available (OS model n=65, TFS model n=53). In these models, only CK was significantly associated with shorter TFS (HR 8.5; 95%CI 2.5-29.1; P<0.001) and shorter OS (HR 4.1; 95%CI 1.2-14; P=0.03).

CONCLUSIONS

Patients with BTKi-exposed CLL, particularly those with prior disease progression on BTKi, had worse outcomes. Our study identified CK as one of the most important baseline predictors of adverse TFS and OS in the overall cohort of patients, supporting karyotype assessment for prognostication prior to venetoclax treatment.

Wang:Eli Lilly: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Morphosys: Research Funding; Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Genmab: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Innocare: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Novartis: Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy. Kenderian:Lentigen: Research Funding; MustangBio: Patents & Royalties; Mettaforge: Patents & Royalties; Torque: Consultancy; Tolero/Sumtomo: Research Funding; Morphosys: Research Funding; LEAHLabs: Consultancy, Current equity holder in private company, Research Funding; CapstanBio: Consultancy, Other: Scientific advisory board; Juno/BMS: Other: Membership on an entity's board of directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Patents & Royalties, Research Funding, Speakers Bureau; Humanigen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Sendero: Patents & Royalties; Kite/Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Luminary therapeutics: Other: scientific advisory board . Ding:DTRM: Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria; MEI pharama: Consultancy, Honoraria; AstraZeneca: Research Funding; Octapharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Research Funding. Muchtar:Protego: Consultancy. Koehler:AbbVie: Consultancy, Other: Advisory Board; Jannsen: Other: Advisory Board; Astra Zeneca: Other: Advisory Board. Tsang:Poseida Therapeutics: Current holder of stock options in a privately-held company. Kay:Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Research Funding; Bristol Meyer Squib / Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Pharmcyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sunesis: Research Funding; Vincerx: Research Funding; Agios Pharm: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Dren Bio: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; 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: Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees. Parikh:AbbVie Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Accerta Pharmaceuticals: Research Funding; Bristol Myers Squibb-Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sunesis: Research Funding; Genentech: Research Funding; Dren Bio: Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Vincerx: Research Funding; Beigene: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim Pharmaceuticals Incc: 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.

Figure 1
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2023
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