Treatment Effectiveness of Venetoclax-Based Therapy After Bruton Tyrosine Kinase Inhibitors in Chronic Lymphocytic Leukemia: An International Real-World Study

The treatment landscape of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) has evolved drastically with the introduction of targeted agents, including covalent Bruton tyrosine kinase inhibitors (cBTKis) and B-cell lymphoma 2 inhibitors (BCL2is) [1]. However, the development of cBTKi resistance (leading to disease progression) and intolerance due to adverse events limits durable cBTKi efficacy [1].

Venetoclax-based therapy, including fixed-treatment-duration combinations, has demonstrated improved and sustained efficacy and manageable toxicity versus chemotherapy/chemoimmunotherapy (CT/CIT) for patients with previously untreated or relapsed/refractory CLL in phase 3 clinical trials [1]. Because cBTKis were not yet or were just recently approved during patient recruitment for the initial venetoclax landmark clinical trials, there were few patients with previous exposure to cBTKis and, thus, limited evidence supporting venetoclax efficacy in these settings [2].

Although clinical trials like M14-032 have established the clinical benefit of venetoclax after cBTKis, real-world studies report on small subgroups of patients with CLL or patients who received venetoclax primarily in later lines of therapy, following CT/CIT [2-5]. Additionally, there is limited literature evaluating real-world venetoclax outcomes among patients stratified by reasons for cBTKi discontinuation [3], venetoclax-based regimen (particularly, VR combination) [4, 5], or prior CT/CIT exposure. This study assessed real-world clinical outcomes of patients with CLL/SLL, who received venetoclax-based therapy after cBTKi therapy, overall and stratified by line of therapy, prior CT/CIT exposure, discontinuation of cBTKi therapy due to intolerance or disease progression, and for treatment with venetoclax + rituximab (VR).

Data for the current analysis (06/01/2018–12/27/2023) were collected as part of the CLL Collaborative Study of Real-World Evidence (CORE; Supporting Information). Adult patients diagnosed with CLL/SLL were included if they initiated a first-line (1 L) or new line of therapy in a relapsed/refractory setting after 02/12/2014 (US approval date of ibrutinib for CLL/SLL) and if they received a venetoclax-based therapy (i.e., monotherapy or combination therapy with rituximab or obinutuzumab) following discontinuation of a cBTKi-based regimen.

Clinical outcomes assessed following initiation of venetoclax-based therapy included overall response rate (ORR), time to next treatment or death (TTNT-D), and progression-free survival (PFS). Outcomes were assessed for the overall population and stratified by line of therapy (1 L cBTKi➔second-line [2 L] venetoclax; 2 L cBTKi➔third-line [3 L] venetoclax), CT/CIT exposure before cBTKi treatment for 2 L cBTKi➔3 L venetoclax, primary reason for cBTKi discontinuation (either intolerance [D_I group] or progression [D_P group]), and VR treatment. Additional details are provided in Supporting Information.

Among the 2293 patients in CORE, 205 received venetoclax after cBTKi and were included in the analyses (Figure S1). The median (IQR) age at venetoclax initiation was 68.7 (62.2, 76.4) years and 68.8% were male (Table S1). Of patients with documented genetic characterization, 69.6% (48/69) had unmutated IGHV (D_I: 63.0% [17/27], D_P: 73.1% [19/26], VR: 69.6% [16/23]) and 24.2% (30/124) had 17p deletion or TP53 mutation (D_I: 14.3% [7/49], D_P: 34.6% [18/52], VR: 17.4% [8/46]) at venetoclax-based therapy initiation. The most common comorbidities were cardiovascular (46.8%) and endocrine/metabolic (23.4%) conditions. Additional patient characteristics are provided in Supporting Information.

Overall, 123 patients initiated venetoclax monotherapy (60.0%), 64 initiated VR (31.2%), and 18 initiated venetoclax + obinutuzumab (VO; 8.8%; Table S2). Seventy-one patients (34.6%) initiated venetoclax-based therapy in the 2 L (i.e., 1 L cBTKi➔2 L venetoclax group; VR: 31/71 [43.7%]), while 73 (35.6%) did so in the 3 L (i.e., 2 L cBTKi➔3 L venetoclax group; VR: 23/73 [31.5%]); the remaining 61 initiated venetoclax in the fourth line or later. A median (IQR) of 2 (1, 3) prior lines of therapy was received among all patients. The median (IQR) treatment duration with venetoclax was 14.4 (3.9, 28.0) months (monotherapy: 14.1 [3.7, 30.1]; VR: 16.4 [7.17, 28.2], VO: 6.3 [2.6, 16.5]), and 80.0% maintained the same dose through the treatment; only 18.0% of patients required a dose reduction. The median (IQR) follow-up after venetoclax-based therapy initiation was 16.5 (6.0, 30.5) months. Additional treatment characteristics are provided in Supporting Information.

For all patients who initiated venetoclax-based therapy, the median (IQR) treatment duration for the prior cBTKi was 20.2 (8.4, 39.2) months, and the most common reasons for discontinuation included intolerance (42.9%) and disease progression (37.1%, Table S2). The prior cBTKi treatment regimens received included ibrutinib (85.4%), acalabrutinib (6.8%), and ibrutinib + rituximab (2.9%). Among the 73 patients who initiated venetoclax-based therapy as 2 L cBTKi➔3 L venetoclax, 1 L treatment regimens prior to cBTKi included CT/CIT (86.3%), targeted agents (11.0%; i.e., ibrutinib: 6.9%; other: 4.1%), and rituximab (2.7%).

Clinical outcomes are presented in Table 1, Figure S2 (ORR), Figure S3, (PFS), and Figure S4 (TTNT-D).

Overall: ORR was 79.4%, median PFS was 44.1 months (18-month rate: 76.2%), and median TTNT-D was 44.2 months (18-month rate: 73.7%).

1 L cBTKi➔2 L venetoclax group: ORR was 85.1%, median PFS was 43.2 months (18-month rate: 80.8%), and median TTNT-D was not reached (NR; 18-month rate: 73.6%).

2 L cBTKi➔3 L venetoclax group: ORR was 80.4%, median PFS was 44.3 months (18-month rate: 82.1%), and median TTNT-D was 44.2 months (18-month rate: 78.4%).

CT/CIT exposure: In the 2 L cBTKi➔3 L venetoclax group, 63/73 (86.3%) patients had exposure to CT/CIT before cBTKi. ORR was 78.6% (among 42/63 [66.7%] patients with response information), median PFS was 44.1 months (18-month rate: 80.7%), and median TTNT-D was 44.2 months (18-month rate: 78.8%). Among the 10 patients without CT/CIT exposure, the ORR was 88.9% (9 [90.0%] patients with response information). PFS and TTNT-D could not be calculated due to low event rates.

Overall: ORR was 85.0%, median PFS was NR (18-month rate: 84.1%), and median TTNT-D was NR (18-month rate: 79.3%).

1 L cBTKi➔2 L venetoclax group: ORR was 86.4%, median PFS was 39.5 months (18-month rate: 84.1%), and median TTNT-D was 39.5 months (18-month rate: 77.5%).

2 L cBTKi➔3 L venetoclax group: ORR was 88.5%, median PFS was NR (18-month rate: 89.0%), and Median TTNT-D was NR (18-month rate: 87.2%).

Overall: ORR was 76.5%, median PFS was 30.1 months (18-month rate: 71.0%), and median TTNT-D was 30.4 months (18-month rate: 75.3%). The median (IQR) duration on prior cBTKi was 32.0 (14.5, 46.7 months).

1 L cBTKi➔2 L venetoclax group: ORR was 90.0%, median PFS was 31.9 months (18-month rate: 62.2%), and median TTNT-D was 31.9 months (18-month rate: 53.3%).

2 L cBTKi➔3 L venetoclax group: ORR was 68.4%, median PFS was 31.8 months (18-month rate: 73.1%), and median TTNT-D was 37.4 months (18-month rate: 75.2%).

Overall: ORR was 71.4%, median PFS was 39.5 months (18-month rate: 77.0%), and median TTNT-D was 37.4 months (18-month rate: 75.7%).

1 L cBTKi➔2 L venetoclax group: ORR was 78.9%, median PFS was 43.2 months (18-month rate: 88.4%), and median TTNT-D was NR (18-month rate: 85.0%).

2 L cBTKi➔3 L venetoclax group: ORR was 73.3%, median PFS was 36.3 months (18-month rate: 85.9%), and median TTNT-D was 37.4 months (18-month rate: 79.8%).

This international analysis from the CORE study contributes important, real-world evidence, showing that patients with CLL initiating venetoclax-based therapy following cBTKis achieved an ORR of nearly 80%. Moreover, this study is among the first to demonstrate that venetoclax-based therapy is associated with a long PFS, regardless of its use in the 2 L (43.2 months) or 3 L (44.3 months), even with prior CT/CIT exposure (44.1 months). While this appears to be nearly double the median PFS of 24.7 months reported in the phase 2, open-label clinical trial of heavily pretreated patients with CLL who relapsed after or were refractory to ibrutinib (M14-032) [6], the present findings provide real-world evidence of venetoclax effectiveness following cBTKis, even with CT/CIT pretreatment.

The current study is among the first and the largest to demonstrate high response rates and durable disease control associated with VR among patients previously treated with cBTKis, a finding of particular clinical relevance given the limited prior literature evaluating this real-world setting and VR's preferable fixed-duration dosing schedule. Notably, Sobon et al. and Lew et al. assessed the real-world use of VR in small subgroups of patients with relapsed/refractory CLL and prior cBTKis and observed consistently robust median PFS (25.9–37.0 months) and ORR (81%) [4, 5].

When stratified by reason for cBTKi discontinuation, clinical effectiveness of venetoclax-based therapy was observed among both those who experienced intolerance (median PFS and TTNT-D were NR) and those with disease progression following cBTKis (median PFS and TTNT-D were ~30 months), though outcomes tended to be better in the former group likely because cBTKi progression may indicate more biologically aggressive CLL. A similar trend was observed by Eyre et al. for patients receiving venetoclax monotherapy (after a median of 3 prior lines of therapy), where ORR was slightly higher in the subgroup of patients discontinuing B-cell receptor inhibitors due to toxicity (92%) rather than CLL progression (84%) [3].

In conclusion, this multicenter, international, real-world study demonstrates that venetoclax-based therapy is an effective treatment option with high response rates, both overall in a cohort of older adults and as 2 or 3 L therapy (even with prior CT/CIT exposure) following cBTKi discontinuation due to intolerance or disease progression. Patients receiving fixed-duration VR as their venetoclax-based therapy also experienced consistently promising clinical outcomes. Notably, some study limitations should be considered (Supporting Information). As the CLL treatment paradigm continues to evolve, clinicians can use these timely results to inform their clinical practice.

Approval was received from institutional review boards from each of the centers included in the CORE database.

Patient consent was not required since the data collected were deidentified and retrospective.

NG has received consulting fees from AbbVie, AstraZeneca, Janssen, Bristol Myers Squibb, Gilead Sciences/Kite Pharma, Beigene, Incyte, Roche/Genentech, Novartis, Loxo Oncology, Genmab, ADC Therapeutics and Ascentage Pharma; he has received research funding from Genentech/Roche, Bristol Myers Squibb, Gilead Sciences/Kite Pharma, Incyte, AstraZenca, AbbVie. NL: Advisory board member/consulting for Abbvie, BeiGene, EliLilly/Loxo, Genmab, Janssen, Pharmacyclics, Gilead, AstraZeneca; Institutional Research Funding: AbbVie, AstraZeneca, Eli Lilly/Loxo, Genentech, Genmab, Bei-Gene, MingSight, Oncternal, Octapharma. TAE: Roche: Education Honorarium, Advisory Board Honorarium, Travel support; Gilead: Honorarium; Research support; travel to scientific conferences; KITE: Advisory Board Honorarium; Janssen: Honorarium; Abbvie: Honorarium; travel to scientific conferences; AstraZeneca: Honorarium, Research funding; Loxo Oncology: Advisory Board Honorarium, Trial steering committee; Beigene: Advisory Board Honorarium, Research funding; Incyte: Advisory Board Honorarium; Secura Bio: Advisory Board Honorarium. CCC: Received honoraria/consulted for AbbVie, Allogene, AstraZeneca, Beigene, Genentech, Janssen, LOXO/Lilly, MEI Pharma, Mingsight, Octapharma, TG Therapeutics; Speaker's Bureau: AbbVie, AstraZeneca, Beigene, Genentech; Received research funding (paid to the institution) from AbbVie, AstraZeneca, Beigene, CarnaBio, LOXO/Lilly. BSM, NE, DJ, WS: employees of AbbVie and may hold stock or stock options. SEM: retired from AbbVie. JRB: Consultancy: Abbvie, Acerta/Astra-Zeneca, Alloplex Biotherapeutics, BeiGene, Galapagos NV, Genentech/Roche, Grifols Worldwide Operations, InnoCare Pharma Inc. iOnctura, Kite, Loxo/Lilly, Merck, Numab Therapeutics, Pfizer, Pharmacyclics; Research funding: BeiGene, Gilead, iOnctura, Loxo/Lilly, MEI Pharma, TG Therapeutics. HHT: Consultancy: Abbvie; Advisory Board: EliLilly/LOXO and Astrazeneca CU: Honorarium—Abbvie, Astrazeneca, Beigene, Genentech, Jansen, Lilly, Pharmacyclics; Research funding—AbbVie, Astrazeneca, Lilly, PCYC. LAL: Kite/Gilead, Beigene, Pharmacyclics, Abbvie, Genmab, SeaGen, Janssen, AstraZeneca, Eli Lily, Epizyme. Consultant/ad board: ADC Therapeutics, Kite/Gilead, Beigene, Pharmacyclics, Abbvie, Genmab, SeaGen, Janssen, AstraZeneca, Eli Lily, Epizyme, Merck. LER: Consultant for AbbVie, Ascentage, AstraZeneca, Beigene, Janssen, Loxo Oncology, Pharmacyclics, Pfizer, TG Therapeutics, is a member of a data safety monitoring committee (DSMC) for Ascentage, served as a CME speaker for DAVA, Curio, Medscape, and PeerView, holds minority ownership interest in Abbott Laboratories, received travel support from LOXO oncology, and has received research funding (paid to the institution) from Adaptive Biotechnologies, AstraZeneca, Genentech, AbbVie, Pfizer, Loxo Oncology, Aptose Biosciences, Dren Bio, and Qilu Puget Sound Biotherapeutics. LER is also supported in part by National Institutes of Health/National Cancer Institute Cancer Center support grant P30 CA008748. MSD: received research funding from AbbVie, AstraZeneca, Ascentage Pharma, Genentech, Novartis, Surface Oncology; and consulting fees from AbbVie, Adaptive Biosciences, Ascentage Pharma, AstraZeneca, BeiGene, BMS, Eli Lilly, Genentech, Genmab, Janssen, Merck, Mingsight Pharmaceuticals, Nuvalent, ONO Pharmaceuticals, Secura Bio, TG Therapeutics, Takeda. JMR: Consultancy: Abbvie, AstraZeneca, ADC Therapeutics, Beigene, Epizyme, Genentech, GenMab, Loxo Oncology, Janssen, Morphosys, Pharmacyclics, Pfizer Membership on a Board or Advisory Committee: Abbvie, Beigene, Janssen, Research Funding: Acerta, Beigene, Epizyme, Janssen, Loxo Oncology, Oncternal, Pharmacyclics, Velosbios. APS: Research support: AbbVie, Pharmacyclics, Verastem, Acerta Pharma, AstraZeneca, Celgene, Kite Pharma, and Bristol-Myers Squibb; Honoraria: AbbVie, Pharmacyclics, Genentech, Seattle Genetics, Novartis, Verastem, Jazz Pharmaceuticals, AstraZeneca, Celgene, Kite Pharma, BeiGene, Gilead Sciences; Consultancy: AbbVie, Pharmacyclics, AstraZeneca, Kite Pharma, Celgene, Genentech, Jazz Pharmaceuticals, Alexion; Speaker and consulting fees: Lilly, ADC Therapeutics. IF: Consultant and/or Advisory board: Abbvie, Astrazeneca, Beigene, Bristol Myers Squibb, Gilead, Incyte Janssen, Merck, Novartis, Roche, Seattle Genetics. BTH: Advisory boards for Genentech, AbbVie, Pharmacyclics, Gilead. Research funding: Genentech, AbbVie, Pharmacyclics. NM: Speaker and travel support: AbbVie, AstraZeneca, Janssen; Advisory Boards: AbbVie, AstraZeneca, BeiGene, Takeda. PMB: Consultancy for AbbVie; Research funding: Astrazeneca, TG therapeutics; consulting for AstraZeneca, TG, Pharmacyclics, Celgene, Genentech, Morphosys, Seattle Genetics, MEI, Gilead, Janssen. LP: Nothing to disclose. FL: Nothing to disclose. YC: Nothing to disclose. CEJ: Consultancy: AbbVie. SJS: Consultant and Institutional Research Funding: Novartis, Pharmacyclics, Celgene; Institutional Research Funding: Gilead, Janssen Research & Development, Merck; Scientific Advisory Committees: Nordic Nanovector; Consultant: Genentech, Acerta. IP, TW, and AG are employees of Analysis Group Inc. which has received consultancy fees from AbbVie. BF: Consultancy and Advisory Board: AbbVie, ADC therapeutics, AstraZeneca, BeiGene, BMS, Eli Lilly, Genentech, Genmab, Pharmacyclics; Research funding: AbbVie/Genmab, Loxo-Lilly, BMS, Angiocrine. Speaker Bureau: Loxo/Lilly. MS: Consulting, advisory boards, steering committees or data safety monitoring committees: Abbvie, Genentech, AstraZeneca, Genmab, Janssen, Beigene, Bristol Myers Squibb, Morphosys/Incyte, Kite Pharma, Eli Lilly, Mustang Bio, Fate therapeutics, Nurix and Merck; institutional research funding from Mustang Bio, Genentech, AbbVie, Beigene, AstraZeneca, Genmab, Morphosys/Incyte, and Vincerx; Stock options: Koi Biotherapeutics; Employment: Bristol Myers Squibb (spouse). DMS: has received consulting fees from Abbvie, AstraZeneca, Beigene, BMS, Celegene, Eli Lilly, Genentech, Janssen, Pharmacyclics. My institution has received clinical research grants from AstraZeneca, Novartis, BMS. MC: Nothing to disclose.