Impact of venetoclax monotherapy on the quality of life of patients with relapsed or refractory chronic lymphocytic leukemia: results from the phase 3b VENICE II trial

Abstract

Venetoclax, a potent B-cell lymphoma-2 (BCL-2) inhibitor, has demonstrated clinical efficacy in chronic lymphocytic leukemia (CLL). VENICE II is an open-label, single-arm, phase 3b study (NCT02980731) evaluating the impact of venetoclax monotherapy (400 mg once daily) for ≤2 years on health-related quality of life (HRQoL) of patients with relapsed/refractory CLL. The primary endpoint was mean change in the global health status (GHS)/quality of life (QoL) subscale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) from baseline to Week 48. Overall, 210 patients received ≥1 dose of venetoclax; median treatment duration was 67.4 weeks. The primary endpoint was met with mean improvement of +9.3 points (n = 156, 95% confidence interval 6.1–12.5; p=.004) in GHS/QoL. At Week 48, clinically meaningful improvements were observed for role functioning, fatigue, and insomnia domains of EORTC QLQ-C30, suggesting venetoclax monotherapy has a positive impact on HRQoL. No new safety signals were reported.

Keywords:

• CLL
• health-related quality of life
• relapsed/refractory
• venetoclax

Introduction

Chronic lymphocytic leukemia (CLL) accounts for approximately 30% of all leukemias, with a median age at diagnosis of 67 years and a 5-year relative survival of >80% [1–3]. While a ‘watch and wait’ approach is recommended for asymptomatic disease, therapy is indicated for those with symptomatic CLL; however, it is not curative [4,5].

CLL and its associated symptomology can negatively impact several aspects of health-related quality of life (HRQoL) [4,6]. Patients with CLL report significantly impaired global health status (GHS), as recorded by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30, a self-report questionnaire validated for use in oncology studies) [7]. Patients with CLL score poorly in most domains of the EORTC QLQ-C30 compared with healthy controls, particularly that of fatigue [4,7,8]. Quality of life (QoL) may be further affected by the emotional burden of living with a chronic disease, as indicated by impairment of emotional functioning QoL domains and reports of greater health-related worries [4,9,10]. Chemoimmunotherapy (CIT) has been the traditional treatment for CLL [3] but this does not consistently improve HRQoL; on the contrary, negative impact on HRQoL has been reported, likely resulting from treatment-related toxicities [7,10,11].

The emergence of targeted oral therapies has changed the CLL treatment paradigm [4,12]. Venetoclax is a potent, selective, orally available, inhibitor of B-cell lymphoma-2 (BCL-2); BCL-2 overexpression is a major contributor to the pathogenesis of lymphoid malignancies, including CLL [13,14], and is thought to promote chemotherapy resistance [14,15]. Venetoclax is an approved therapy for treatment naïve and relapsed/refractory (R/R) CLL, and has proven efficacy in patients with high risk disease, such as those with deletions in chromosome 17p (del17p) [16–18].

There is a need to understand the impact of targeted therapies on HRQoL so that these considerations can be incorporated into treatment decision making. The currently available data regarding HRQoL with targeted therapies are limited, but suggestive of HRQoL improvement; however, the degree of benefit may not be clinically meaningful, or may only benefit specific patient subgroups [9,19–23].

Here, we report the primary analysis of VENICE II, a phase 3b study conducted to assess the impact of venetoclax monotherapy on the QoL of patients with R/R CLL.

Materials and methods

Study design and treatment

This open-label, single-arm, phase 3b, study (NCT02980731) enrolled patients across 32 research sites in Latin America, Eastern Europe, and Asia-Pacific.

Venetoclax monotherapy was administered orally once daily (QD) with food and water. The starting dose of venetoclax 20 mg QD was escalated to 50 mg QD after 1 week, followed by subsequent weekly increases to 100 mg QD, 200 mg QD, and the maximum dose of 400 mg QD. This 5-week ramp-up schedule was designed to gradually reduce tumor burden and mitigate the risk of tumor lysis syndrome (TLS). Before starting venetoclax, tumor burden assessments, including physical examination, blood chemistry, and radiographic evaluation, were performed for all patients; TLS prophylaxis and monitoring measures included hydration and uric acid-reducing agents [24,25]. Patients could receive venetoclax for up to 108 weeks unless disease progression, unacceptable toxicity, or other reasons warranted earlier discontinuation. In countries where venetoclax was not commercially available, patients who continued to derive benefit after 2 years of treatment were able to extend their treatment for up to 2 additional years. Patients were followed for disease progression and survival for 2 years after venetoclax discontinuation.

All patients provided written informed consent and the study was conducted in accordance with the protocol, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines, applicable regulations and guidelines governing clinical study conduct, and ethical principles that have their origin in the Declaration of Helsinki. Independent ethics committee/institutional review board approval was obtained before study commencement at each site.

Patients

Patients with R/R CLL and an indication for treatment according to the International Workshop on CLL (iwCLL) 2008 guidelines [26] were eligible for enrollment. Eligible patients were ≥18 years old with an Eastern Cooperative Oncology Group (ECOG) performance status of ≤2 and clinically measurable disease (lymphocytosis >5 × 10⁹/L and/or palpable and measurable nodes by physical examination and/or organomegaly assessed by physical examination), with or without del17p or TP53 mutation. Prior B-cell receptor (BCR) inhibitor therapy was permitted. Patients were excluded if they had developed Richter's transformation or prolymphocytic leukemia, or had active and uncontrolled autoimmune cytopenias within 2 weeks of screening, including autoimmune hemolytic anemia, or immune thrombocytopenia, despite low-dose corticosteroids. Patients who had received prior allogeneic stem cell transplantation were excluded.

Efficacy endpoints

The primary endpoint was the mean change from baseline to Week 48 on the GHS/QoL subscale of the EORTC QLQ-C30 version 3. The EORTC QLQ-C30 is a self-report questionnaire that records 30 items arranged into five function scales (physical, role, cognitive, emotional, and social functions), three symptom scales (fatigue, pain, and nausea and vomiting), one GHS/QoL scale, and six single items (dyspnea, appetite loss, insomnia, constipation, diarrhea, and financial impact). Each item has four possible responses (‘not at all,’ ‘a little,’ ‘quite a bit,’ and ‘very much’) except the GHS/QoL scale, which has a range of responses from 1 ‘very poor’ to 7 ‘excellent’ [8].

Secondary endpoints included assessments of QoL subscales/items based on the EORTC QLQ Chronic Lymphocytic Leukemia Module 16 (EORTC QLQ-CLL16, a CLL-specific module supplementing EORTC QLQ-C30 that includes 16 questions covering five HRQoL domains of particular importance to CLL {fatigue, treatment side effects and disease symptoms, infections, social activities, and future health concerns]) [9,23], EuroQoL 5 Dimension 5 Level Questionnaire (EQ-5D-5L, a generic self-assessment of health utility using five items and a visual analog scale) [27], and remaining subscales from the EORTC QLQ-C30. Additional secondary endpoints included overall response rate (ORR), complete remission (CR) rate (CR + CR with incomplete marrow recovery [CRi]), CR among BCR inhibitor-experienced patients, duration of overall response (DOR), time to progression (TTP), duration of progression-free survival (PFS), and overall survival (OS).

Assessments

Efficacy

Patients completed QoL assessments at baseline (within 72 h of the first dose of venetoclax), Weeks 4, 8, 12, 24, 36, and 48, then every 12 weeks until the end of treatment (Week 108). The GHS/QoL subscale was calculated as per EORTC scoring manual and summarized at each visit. Improvement in EORTC QLQ-C30 GHS or functioning domains is indicated by a positive change, while improvement in symptoms or financial difficulties is indicated by a negative change. For EORTC QLQ-CLL16 symptom or problem scores, a negative change represents an improvement. For the primary endpoint, the clinical relevance of changes in the GHS/QoL subscale was based on a ≥5-point change indicating a clinically meaningful difference. For the remaining domains, the clinical relevance of changes in HRQoL was determined based on the minimum important difference (MID) of values from baseline to each assessment time point, whereby a 5-point change from baseline (the lower bound of the 5–10-point range considered a ‘little’ change for EORTC QLQ-C30) was used for MID, and ≥10-point change in mean scores was considered clinically meaningful [28,29].

Disease assessments were carried out by the investigator based on laboratory results and physical examinations according to the 2008 modified iwCLL National Cancer Institute-sponsored Working Group (iwCLL NCI-WG) guidelines for tumor response [26] alongside computed tomography (CT) scan (or magnetic resonance imaging [MRI]). Disease assessments were performed at screening, and at Weeks 24, 36, and 48. To confirm response, a CT scan or MRI was performed at Week 48 on all patients, and bone marrow samples were collected from patients with CR.

Safety

Safety analyses were performed on all patients who received at least one dose of venetoclax. Safety was assessed through evaluations of drug exposure, adverse event (AE) monitoring, vital signs, physical examination, and laboratory assessments. AE analyses only included treatment emergent AEs (TEAEs) with an onset or worsening on or after the first dose of venetoclax and up to 30 days after discontinuation of venetoclax. TEAEs were summarized by preferred terms within a System and Organ Class according to the most current Medical Dictionary for Regulatory Activities (MedDRA). The severity of each AE was rated according to the National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTAE) v4.03.

Statistical analyses

An improvement of 5 units in the EORTC QLQ-C30 GHS/QoL subscale was considered clinically meaningful. Using a one-sided alpha of 0.025, 90% power, and a standard deviation of 20.5, 177 patients were required to reject the null hypothesis in favor of the alternative hypothesis that venetoclax improves GHS/QoL by at least 5 units. To account for potential dropouts by Week 48, a total of 200 patients were to be dosed.

The data cutoff for primary analysis was determined to be when the last patient completed the Week 48 QoL and disease assessments or after all patients had discontinued venetoclax, whichever occurred earlier. QoL scores were calculated based on their respective scoring manuals, and mean change from baseline was summarized along with interval estimates at each timepoint of interest. A paired t-test was used to assess whether the study provided statistically significant evidence that the typical improvement in GHS/QoL scores was at least 5 units. All time-to-event endpoints, including DOR, TTP, PFS, and OS, were analyzed using Kaplan–Meier methodology. ORR and CR/CRi rates were evaluated using point estimates and corresponding 95% confidence intervals (CIs).

Results

Patient demographics and clinical characteristics

A total of 235 patients were screened, and 210 patients were enrolled, all of whom received at least one dose of venetoclax. At the primary analysis cutoff date of 30 June 2019, 145 patients (69%) remained on active treatment. The median duration of venetoclax was 67.4 weeks (range 0.1–129.7), and 156 patients (74%) had completed their Week 48 GHS/QoL assessment. Of the 65 patients (31%) who discontinued venetoclax, 25 discontinued due to progressive disease (12%) and 20 discontinued due to AEs (10%) (Figure 1).

Figure 1. Patient disposition. ^aOne patient was excluded for >1 reason. AE: adverse event.

Patient demographics and clinical characteristics are summarized in Table 1. The median age was 65 years, and 33% of patients were female. All patients had received at least one prior CLL therapy, with a median of 2 prior lines (range 1–9), and 19% of patients had previously received a BCR inhibitor. Investigator-reported del17p and TP53 mutations were detected in 21% and 13% of patients at baseline, respectively (Table 1).

Table 1. Patient demographics and clinical characteristics.

Characteristic^a	All patients, N = 210
Age at enrollment
Median age (range) years	65 (24–86)
≥65 years	108 (51)
Male	141 (67)
Race
White	182 (87)
Black or African American	1 (<1)
Asian	18 (9)
American Indian or Alaska Native	8 (4)
Native Hawaiian or other Pacific Islander	1 (<1)
ECOG PS
0	75 (36)
1	105 (50)
2	30 (14)
Number of prior therapies
1	86 (41)
2	45 (21)
≥3	79 (38)
Prior CLL therapies (≥10% of patients)^b
Bendamustine	56 (27)
Chlorambucil	73 (35)
Cyclophosphamide	132 (63)
Fludarabine	118 (56)
Ibrutinib	30 (14)
Prednisolone	30 (14)
Rituximab	153 (73)
Vincristine	33 (16)
Prior BCRi therapy	39 (19)
17p deletion status^c
Deleted	45 (21)
Not deleted	108 (51)
Not reported^d	57 (27)
TP53 mutation status^c
Mutated	28 (13)
Not mutated	39 (19)
Not reported^d	143 (68)
Absolute lymphocyte count
<25 × 10^9/L	98 (47)
25 to <100 × 10^9/L	69 (33)
≥100 × 10^9/L	37 (18)
Missing^e	6 (3)
Largest lymph node diameter
<5 cm	113 (54)
5 to <10 cm	64 (30)
≥10 cm	21 (10)
Missing^d	12 (6)

BCRi: B-cell-antigen receptor signal inhibitor; CLL: chronic lymphocytic leukemia; ECOG PS: Eastern Cooperative Oncology Group performance status.

a Values are n (%) unless otherwise stated.

b Includes agents given as part of combination therapy.

c All chromosomal aberrations were assessed by the investigator's local laboratory.

d As reported by investigator.

e Values were not recorded at least 24 h prior to venetoclax start.

Quality of life assessment

Compliance (the number of patients who completed at least one questionnaire) was 99.0% at baseline and 95.1% at Week 48. Based on 156 patients who had completed 48 weeks of venetoclax, the primary endpoint was met, with a mean improvement in EORTC QLQ-C30 GHS/QoL scores from baseline to week 48 of +9.3 points (95% CI +6.1, +12.5, p=.004) (Table 2 and Figure 2A).

Figure 2. Mean change in EORTC QLQ-C30 GHS/QoL (A), functioning (B), and symptoms (C) subscales, and EORTC QLQ-CLL16 subscales (D) from baseline to Week 48 in all treated patients. Overall changes from baseline in a patient-reported EORTC QLQ-C30 (A–C) and EORTC QLQ-CLL16 (D) scores until Week 48 of venetoclax treatment. (A) ≥5-point change indicated a clinically meaningful difference for the GHS/QoL subscale; error bars are 95% CI. (B–D) Clinical relevance of changes in HRQoL was determined based on the MID of values from baseline to each assessment time point. 5–10-point considered a little change while a ≥10-point change indicated a clinically meaningful difference. Improvement in functional subscales is indicated by positive change; improvement in symptom subscales is indicated by negative change. *p=.004. BL: baseline; CI: confidence interval; EORTC: European Organization for Research and Treatment of Cancer; QLQ-C30: Quality of Life Core Questionnaire Core 30; QLQ-CLL16: Quality of Life Questionnaire Chronic Lymphocytic Leukemia Module 16; GHS: global health status; HRQoL: health-related quality of life; MID: minimum important difference; QoL: quality of life; Wk: week.

Table 2. Mean change from baseline to week 48 in key QoL measures for all treated patients.

	Baseline Mean (SD) n = 209	Mean change (SD) from baseline to Week 48 n = 157	Patients with ≥10-point change from baseline, n (%) n = 157
EORTC QLQ-C30 parameter
GHS/QoL^a^,^b	62.0 (22.74)	+9.3 (20.17)**	85 (54)
Physical functioning	77.5 (21.14)	+5.2 (16.90)	61 (39)
Role functioning	73.0 (30.77)	+10.5 (26.17)	73 (46)
Emotional functioning^a^,^b	79.8 (20.89)	+5.7 (17.69)	60 (38)
Cognitive functioning^a^,^b	82.7 (21.29)	+3.8 (17.13)	67 (43)
Social functioning^a^,^b	76.4 (28.05)	+9.9 (22.86)	72 (46)
Fatigue	37.7 (26.51)	−13.0 (21.44)	109 (69)
Nausea and vomiting	6.5 (15.49)	−0.6 (19.51)	48 (31)
Pain^b	20.1 (24.90)	−4.6 (20.35)	76 (49)
Dyspnea^b	21.7 (29.01)	−8.5 (27.27)	61 (39)
Insomnia	28.7 (28.59)	−11.7 (25.84)	68 (43)
Appetite loss	17.4 (26.16)	−7.9 (24.21)	51 (32)
Constipation^a^,^c	7.1 (26.16)	−0.2 (18.41)	30 (19)
Diarrhea^a^,^b	9.9 (19.87)	−4.1 (21.20)	50 (32)
Financial difficulties^a^,^b	20.2 (29.28)	−9.0 (26.60)	54 (35)
EORTC QLQ-CLL16 parameter
Fatigue scale	41.1 (39.22)	−16.2 (35.50)	92 (59)
Treatment side effects scale	19.6 (20.99)	−7.6 (19.21)	61 (39)
Disease effects scale	28.9 (24.93)	−13.6 (23.69)	76 (48)
Infection scale	23.3 (25.98)	−9.0 (25.63)	66 (42)
Social problems^c^,^d	33.2 (43.01)	−15.7 (40.97)	69 (45)
Future health concerns^c^,^d	61.7 (47.16)	−24.3 (41.84)	82 (53)
EQ-5D-5L
EQ-5D VAS^a^,^b	68.85 (19.09)	10.37	82 (53)
EQ-5D health index^e	0.83 (0.14)	0.04 (0.13)	–

EORTC: European Organization for Research and Treatment of Cancer; QLQ-C30: Quality of Life Core Questionnaire Core 30; QLQ-CLL16: Quality of Life Questionnaire Chronic Lymphocytic Leukemia Module 16; EQ-5D-5L: European Quality of Life 5 Dimension 5 Level Questionnaire; GHS: global health status; MID: minimum important difference; QoL: quality of life; SD: standard deviation; VAS: visual analog scale.

Within the Week 48 column, dark green shaded cells indicate a clinically meaningful improvement from baseline (≥5-point change for GHS/QoL; >10-point change for all other scales), light green shaded cells indicate an improvement from baseline that is greater than the MID (>5- to ≤10-point change), unshaded cells indicate no MID. No parameters demonstrated a deterioration meeting MID or clinically meaningful difference levels.

a N = 208 at baseline.

b N = 156 at Week 48.

c N = 155 at Week 48.

d N = 207 at baseline.

e 210 at baseline, 158 at Week 48.

**p=.004.

Overall, baseline EORTC QLQ-C30 scores for 208 patients with available data were suggestive of good HRQoL. Clinically meaningful improvement in GHS/QoL (≥5-point change) from baseline to Week 48 was experienced by 54% of patients. Within the remaining EORTC QLQ-C30 subscales, clinically relevant improvements (≥10-point change [28,29]) from baseline to Week 48 were observed for fatigue (−13.0), insomnia (−11.7), and role functioning (+10.5) domains, and no subscales demonstrated a clinically relevant deterioration.

For EORTC QLQ-CLL16, no subscales demonstrated clinically meaningful deterioration; clinically meaningful improvements (≥10-point change) to Week 48 were reported for fatigue (−16.2), social problems (−15.7), disease effects (−13.6), and future health concerns (−24.3) (Table 2 and Figure 2D). Within the EQ-5D-5L, mean EQ-5D visual analog scales scores improved by a mean of 10.37 points from baseline to Week 48 while the EQ-5L health index score remained unchanged (mean change of 0.04).

Changes occurred early, with clinically meaningful cutoff of 5 points noted as early as Week 8 and sustained until the end of treatment (Week 108) for GHS/QoL, and by Week 4 for insomnia, Week 8 for fatigue, and Week 12 for role functioning within the EORTC QLQ-C30 and as early as Week 4 in the EORTC QLQ-CLL16 scales.

Clinical efficacy

The ORR at data cutoff was 77% (161/210 patients), with CR/CRi in 19% (39 patients), and a further 1% (3 patients) reached nodular partial remission. Partial remission was reached in 57% (119 patients) and 10% (21 patients) had stable disease. The median time to first response was 5.3 months (range 2.5–10.9).

Within subgroup analyses, ORR was 67% (30/45 patients) for those with del17p versus 82% (89/108) for those without 17p deletion; and 61% (17/28) for patients with mutated TP53 versus 79% (31/39) for those without mutated TP53. Of 39 BCR inhibitor-experienced patients, ORR was 59% (23/39) versus 81% (138/171) for BCR inhibitor-naïve patients. CR/CRi was achieved by 13% (5 patients) who had received prior BCR inhibitor therapy and 20% (34 patients) who were BCR inhibitor-naïve (Appendix Figure S1).

As of an estimated median follow-up of 16.4 months (range 0.1–28.4), the median OS and PFS were not yet estimable via Kaplan–Meier’ methodology. The Kaplan–Meier estimate for OS at 12 months was 87.9% (95% CI 82.6–91.6%) and for PFS was 83.4% (95% CI 77.5–87.8%) (Figure 3).

Figure 3. Kaplan–Meier estimates of OS (A) and PFS (B) in all treated patients. Patients at risk at each time point is shown below the graph. Tick marks indicate censored data. Values are % estimate (95% CI) at the given time point. CI: confidence interval; PFS: progression-free survival, OS: overall survival.

Median DOR and TTP were also not estimable, with an estimated 90.8% (95% CI 83.8–94.9%) of patients responding at 12 months and 90.1% (95% CI 85.0–93.6%) estimated progression-free at 12 months.

Safety

In total, 194 patients (92%) had experienced at least 1 AE at the time of the data cutoff. The most frequently reported AEs (>20% of patients) were neutropenia (40%), diarrhea (30%), upper respiratory tract infection (23%), and thrombocytopenia (21%) (Table 3). Grade ≥3 AEs were reported in 61% of patients, most commonly neutropenia (32%) and thrombocytopenia (17%). Serious AEs (SAEs) were reported in 38%, most commonly pneumonia (7%) and febrile neutropenia (3%) (Table 3). There were 4 (2%) AEs of laboratory TLS and no reports of clinical TLS. Death due to AEs occurred in 10 patients (5%), none of which were considered to be treatment related.

Table 3. Summary of any grade and Grade ≥3 treatment emergent AEs occurring in ≥10% of patients and serious AEs occurring in ≥3% of patients treated with venetoclax.

AE, n (%)	Any grade N = 210	Grade ≥3 N = 210	Serious AE N = 210
Any AE	194 (92)	129 (61)	80 (38)
Neutropenia	84 (40)	68 (32)	2 (1)
Diarrhea	62 (30)	3 (1)	2 (1)
Upper respiratory tract infection	49 (23)	1 (<1)	2 (1)
Thrombocytopenia	44 (21)	35 (17)	6 (3)
Nausea	32 (15)	0	0
Anemia	30 (14)	24 (11)	4 (2)
Pyrexia	27 (13)	3 (1)	8 (4)
Pneumonia	23 (11)	16 (8)	15 (7)
Febrile neutropenia	7 (3)	7 (3)	7 (3)

AE: adverse event.

AEs leading to dose interruption and reduction of venetoclax were experienced by 94 patients (45%) and 36 patients (17%), respectively, the most common being neutropenia (15% and 8%), thrombocytopenia (4% and 3%), and pneumonia (7% and 0%). Neutropenia was generally manageable with venetoclax interruption or dose reduction and granulocyte-colony stimulating factor. AEs that led to discontinuation of venetoclax were experienced by 25 patients (12%), the most common being neutropenia and thrombocytopenia (n = 3, 1% for both). No patient discontinued venetoclax due to an AE of TLS.

Discussion

As the CLL treatment paradigm evolves and OS and PFS improve, HRQoL is becoming an increasingly important consideration for treatment selection [4]. This phase 3b, single-arm study met its primary endpoint, finding that venetoclax monotherapy for R/R CLL is associated with a mean improvement of at least 5 points in the GHS/QoL subscale of the EORTC QLQ-C30 between baseline and Week 48, with a mean change of +9.3 (n = 156, 95% CI +6.1, +12.5; p=.004). Furthermore, a majority of patients (54%) experienced a clinically meaningful improvement at Week 48, mirrored by clinically important differences between baseline and Week 48 for several domains of EORTC QLQ-C30 and EORTC QLQ-CLL16. Improvements generally occurred early and were sustained through Week 48, consistent with phase 2 data [30,31].

Venetoclax monotherapy is associated with clinically relevant improvement in several key aspects of functioning and HRQoL [30,32], including for patients with poor prognostic features. In a phase 2 trial of venetoclax monotherapy for patients who had previously received a BCR inhibitor for CLL, clinically meaningful HRQoL improvements from baseline were observed early, and were sustained through Week 48 for GHS; fatigue; and role, social, and emotional functioning scales [31]. Similarly, venetoclax monotherapy for patients with R/R CLL and del17p was associated with clinically significant improvement from baseline through Week 96 for GHS; fatigue; and role, social, and emotional functioning scales of the EORTC-QLQ-C30 [30]. Improvements in HRQoL were accompanied by an ORR of 77% (95% CI 70.4–82.2%) with first response observed at a median of 5.3 months, consistent with previous venetoclax monotherapy studies, including the ongoing VENICE I trial in R/R CLL [16,18,33]. Notably, CR/CRi were reported in 19% of patients.

Prophylactic and monitoring measures for TLS were effective, with no clinical TLS in this study. Venetoclax was well tolerated and safety data were consistent with the known profile of venetoclax monotherapy in R/R CLL, with no new safety signals [16,31,34]. Neutropenia was the most notable AE, and was generally manageable with granulocyte-colony stimulating factor and dose modifications.

HRQoL is difficult to measure in life-threatening illnesses, such as CLL, for a variety of reasons, including failing health and/or cognitive challenges associated with progressive disease, difficulty in data collection, and measurement variability between trials. The intertrial variability of QoL assessment tools limits cross-trial comparisons, but the few studies to have examined the impact of targeted therapy on HRQoL report inconsistent outcomes. In the phase 3 DUO study, the PI3K-δ,γ-inhibitor duvelisib was associated with consistently greater improvements in HRQoL versus ofatumumab in patients with R/R CLL who had received ≥2 prior therapies [19]. The positive impact of idelalisib in combination with rituximab on HRQoL was also demonstrated in a phase 3 trial where patients with relapsed CLL who received idelalisib experienced greater improvements in physical and functional well-being, as well as leukemia-related symptoms versus placebo [20]. Furthermore, in a smaller trial of acalabrutinib plus obinutuzumab, 45 patients with treatment-naïve or R/R CLL experienced significant improvements in global health, physical functioning, and three symptom items of the EORTC QLQ over 24 cycles of treatment [21]. In contrast, a recently published trial of ibrutinib in combination with bendamustine/rituximab versus bendamustine/rituximab alone in patients with R/R CLL reported that neither regimen impacted HRQoL, but post hoc analyses suggested that the addition of ibrutinib was associated with greater improvements to fatigue, physical functioning, and well-being among those patients who reported poorer scores in these domains at baseline [9]. These results were consistent with other studies that have reported small but nonsignificant improvements observed in HRQoL domains for those patients who received idelalisib [22] or ofatumumab [23] versus chemotherapy/CIT alone. This may be due, in part, to the associated toxicity profiles of chemotherapy/CIT regimens [4,9,21–23,30].

As newer treatments lead to improvements in long-term OS and PFS, there is a growing need to consider HRQoL as a complementary factor to efficacy and safety when selecting therapies for R/R CLL, especially due to the impact of treatment-related toxicity on HRQoL [4]. Despite the potentially profound effects of CLL on all aspects of a patient’s life, HRQoL is not always considered; yet this becomes a particularly relevant performance indicator when selecting between therapies of comparable clinical efficacy [6,35]. In such instances, it will be critical to integrate HRQoL parameters into quality-adjusted survival analyses to better inform treatment selection.

Incorporation of QoL assessments into trial designs and protocols is particularly important for chronic incurable diseases, such as CLL. Moreover, standardization of QoL assessments would enable greater cross-trial comparison. Currently, the Functional Assessment of Cancer Therapy (FACT) tool is more commonly used in the United States while European studies tend to utilize the EORTC QLQ tools; due to these disparate methodologies, it is difficult to compare results across measurement tools. This is particularly notable here, as all enrollment sites for this study were located in the EU.

The need for specific and standardized HRQoL tool utilization was highlighted by an assessment of HRQoL among patients with CLL predominantly treated with CIT from the Connect^® CLL registry. In their analysis, Sharman et al. noted that more patients experienced clinically meaningful improvement in leukemia FACT (FACT-Leu) scores than clinically meaningful reduction, while clinically meaningful improvement and reduction in EQ-5D-3L score were similar. The authors concluded that this may result from the leukemia-specific design of the FACT-Leu tool, which may be more sensitive at detecting improvement in these patients than the more generic EQ-5D-3L [36]. While this is a consideration for the results presented here, our study also utilized the leukemia-specific module of the EORTC (EORTC QLQ-CLL-16) as a key secondary endpoint, and it is noteworthy that these data were consistent with those of the EORTC QLQ-C30 primary endpoint.

The results presented here indicate that venetoclax monotherapy is associated with improvement in several key symptom and QoL domains while demonstrating potent antitumor activity in the majority of the patients, including those with poor prognostic features (e.g. genetic aberrations and/or failure of prior therapies), or who have previously received BCR inhibitor therapy. In particular, fatigue may be considered a key parameter for assessing HRQoL in patients with CLL because this is a significant burden observed in this population [4,7]. It is therefore noteworthy that in this study, the greatest mean improvement noted in any of the EORTC QLQ-C30 domains following 48 weeks of venetoclax was seen for fatigue, with a MID observed from Week 8 and a clinically meaningful difference from Week 12, which was sustained through end of treatment (Week 108). As the treatment landscape continues to develop, these promising data highlight the importance of examining HRQoL within clinical trials of novel therapies to better inform patient management. However, it should be noted that the study is limited by the single-arm design which confounds data interpretation.

This phase 3b study of 210 patients with R/R CLL, which included patients with poor prognostic features and prior BCR inhibitor use, found that venetoclax monotherapy was associated with clinically important and sustained improvements in overall QoL and in several domains and symptoms, including fatigue. Safety and efficacy profiles were consistent with prior reports. These data will contribute to treatment decision-making in patients with R/R CLL.

Acknowledgements

AbbVie and authors thank the patients and their families, investigators, study coordinators, and support staff. Medical writing support was provided by Fatemeh Atashi, PhD, an employee of AbbVie, and Hayley Ellis, PhD, of Fishawack Communications Ltd, funded by AbbVie. Authors would also like to acknowledge the following AbbVie team members; Susan Weszt, Ben Murphy, Marja Hare, and Tim Babin for their contributions to this study, and Wendy Sinai for her critical contributions during manuscript development.

Disclosure statement

Tara Cochrane: Honorarium: Celgene. Research funding: Beigene; Alicia Enrico: Speaker fees: Bristol, Novartis, and AbbVie; David Gomez-Almaguer: Advisory and speaker boards: AbbVie, Takeda, Celgene, Janssen, Roche, and Amgen; Evgueniy Hadjiev: Advisory and speaker boards: AbbVie, Janssen, Roche, Novartis, Genzyme, Pfizer, and Takeda; Ewa Lech-Maranda: Advisory board: AbbVie, Amgen, Janssen, Roche, Novartis, and Celgene; Tamas Masszi: Advisory board: AbbVie, Janssen-Cilag; Eugene Nikitin: Honoraria and speaker fees: AbbVie; Tadeusz Robak: Research grants: AbbVie, BeiGene, Janssen, Roche, AstraZeneca, UCB, Octapharma, Pfizer, Novartis, and Celgene; honoraria: Roche, AbbVie, BeiGene, Janssen, AstraZeneca, and Novartis; conference travel support: Roche, Janssen, and AbbVie; Robert Weinkove: Speaker fees: AbbVie, Janssen, and BeiGene; honoraria and advisory boards: AbbVie and Janssen; Shang-Ju Wu: Speaker fees: AbbVie; Kavita R Sail, John Pesko, Madhavi Pai, and Viktor Komlosi: Employees of AbbVie and may hold stock or options; Mary Ann Anderson: Honoraria: AbbVie, CSL, Novartis, AstraZeneca, BeiGene and Janssen; support for attending meetings and/or travel: support from AstraZeneca to attend EHA; employee of the Walter and Eliza Hall Institute, which receives payments in relation to venetoclax.

Data availability statement

AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual and trial-level data (analysis data sets), as well as other information (e.g. protocols and clinical study reports), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications. These clinical trial data can be requested by any qualified researchers who engage in rigorous, independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA). Data requests can be submitted at any time and the data will be accessible for 12 months, with possible extensions considered. For more information on the process, or to submit a request, visit the following link: https://www.abbvie.com/our-science/clinical-trials/clinical-trials-data-and-information-sharing/data-and-information-sharing-with-qualified-researchers.html.