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

Abstract

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).

TABLE 1. Clinical outcomes for the overall sample and stratified by line of therapy, discontinuation of cBTKi therapy due to intolerance or disease progression, and treatment with VR.

		Response		PFSa				TTNT-Db
		N	ORRc	N	Median (CI), months	Rate, %		N	Median (CI), months	Rate, %
						12 months	18 months			12 months	18 months
Overall (N = 205)	Overall	141	79.4%	201	44.1 (36.3, NR)	84.0%	76.2%	205	44.2 (31.9, NR)	83.5%	73.7%
	1 L → 2 L	47	85.1%	70	43.2 (39.5, NR)	87.5%	80.8%	71	NR (31.9, NR)	86.1%	73.6%
	2 L → 3 L	51	80.4%	70	44.3 (36.3, NR)	86.5%	82.1%	73	44.2 (37.0, NR)	84.5%	78.4%
DId (N = 88)	Overall	60	85.0%	86	NR	87.8%	84.1%	88	NR	84.4%	79.3%
	1 L → 2 L	22	86.4%	35	39.5 (39.5, NR)	92.7%	84.1%	36	39.5 (39.5, NR)	89.7%	77.5%
	2 L → 3 L	26	88.5%	32	NR	89.0%	89.0%	33	NR	87.2%	87.2%
Dpd (N = 76)	Overall	51	76.5%	74	30.1 (22.1, NR)	82.2%	71.0%	76	30.4 (26.3, NR)	86.2%	75.3%
	1 L → 2 L	10	90.0%	15	31.9 (13.2, NR)	77.8%	62.2%	15	31.9 (12.5, NR)	77.8%	53.3%
	2 L → 3 L	19	68.4%	28	31.8 (22.1, NR)	82.6%	73.1%	30	37.4 (26.3, NR)	84.0%	75.2%
VR (N = 64)	Overall	42	71.4%	60	39.5 (31.8, NR)e	86.2%	77.0%	64	37.4 (31.6, NR)e	82.3%	75.7%
	1 L → 2 L	19	78.9%	30	43.2 (39.5, NR)	88.4%	88.4%	31	NR (39.5, NR)	85.0%	85.0%
	2 L → 3 L	15	73.3%	20	36.3 (23.7, NR)	93.8%	85.9%	23	37.4 (31.6, NR)	85.9%	79.8%

• Abbreviations: 1 L, first-line; 2 L, second-line; 3 L, third-line; cBTKi, covalent Bruton tyrosine kinase inhibitor; CI, confidence intervals; CR, complete response; CT, computed tomography; D_I, discontinuation of prior cBTKi due to intolerance; D_P, discontinuation of prior cBTKi due to disease progression; NR, not reached; ORR, overall response rate; PFS, progression-free survival; PR, partial response; TTNT-D, time to next treatment or death; VR, venetoclax + rituximab.
• a PFS was defined as the time from the start of venetoclax-based therapy to disease progression or death (i.e., event). Patients without events were censored at the last date of follow-up; medians and corresponding 95% CIs were estimated using the Kaplan–Meier method. Kaplan–Meier estimates at 12 and 18 months were also reported.
• b TTNT-D was defined as the time from the start of venetoclax-based therapy to alternative treatment or death (i.e., event). Patients without events were censored at the last date of follow-up; medians and corresponding 95% CIs were estimated using the Kaplan–Meier method. Kaplan–Meier estimates at 12 and 18 months were also reported.
• c ORR was measured as the proportion of patients with CR or PR among those with available information on responses in their medical charts based on physician assessment. CR and PR were based on physician-reported information as recorded in the patient charts. Although CT scans and bone marrow biopsies were not mandated to assess response, abstractors were provided with the 2018 International Workshop on Chronic Lymphocytic Leukemia response criteria for reference when completing data collection.
• d Seven patients for whom both intolerance and progression were selected were excluded from the cBTKi discontinuation stratified analyses.
• e The longer median PFS than TTNT-D observed in the VR subgroup may be due to progression events not being systematically reported in the charts for all patients or because progression may not have occurred (in the case of intolerance) prior to initiation of the subsequent treatment in the real-world data.