Health-related quality of life with fixed-duration venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: Results from the randomized, phase 3 CLL14 trial

Chronic lymphocytic leukemia (CLL)-related symptoms impair the well-being of patients, making improvement of health-related quality of life (QoL) a goal of treatment. The CLL14 trial demonstrated higher efficacy of fixed-duration venetoclax-obinutuzumab (Ven-Obi) compared to chlorambucil-obinutuzumab (Clb-Obi) in patients with previously untreated CLL. To assess patients' QoL, the following patient-reported outcomes (PRO) measures were assessed: the M.D. Anderson Symptom Inventory (MDASI) core instrument and CLL module and the EORTC Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). At treatment start, physical functioning (mean 75.9 [standard deviation (SD) ± 20.1] in the Clb-Obi arm and 76.9 [±19.4] in the Ven-Obi arm), role functioning (73.6 [±27.86] and 72.6 [±26.9]) and GHS/QoL (63.6 [±21.0] and 60.3 [±20.5]) were comparable between treatment arms per EORTC QLQ-C30 scale scores. Baseline levels of physical and role functioning were maintained throughout treatment and follow-up, with no relevant improvement or deterioration. On average, patients treated with Ven-Obi showed a meaningful improvement of GHS/QoL during treatment and follow-up by at least eight points at cycle three, whereas improvement was delayed until cycle eight with Clb-Obi. According to MDASI scores, CLL symptoms (1.5 [±1.2] and 1.6 [±1.3]), core cancer symptoms (1.5 [±1.4] and 1.8 [±1.7]) and symptom interference (2.1 [±2.3] and 2.3 [±2.3]) were generally low and comparable between treatment arms at baseline and were maintained throughout treatment and follow-up. This analysis demonstrates that the higher efficacy of Ven-Obi is not associated with QoL impairment and that Ven-Obi achieves early relief of CLL-related symptoms in elderly unfit patients.


| INTRODUCTION
One of the main aims of treatment optimization for patients with chronic lymphocytic leukemia (CLL) is the improvement of remission Michael Hallek and Kirsten Fischer contributed equally to this study. rates as well as depth of remissions by novel targeted compounds.
This has led to numerous targeted agents being used for CLL therapy, particularly among elderly patients with coexisting conditions unable to tolerate intensive chemoimmunotherapy such as fludarabine, cyclophosphamide and rituximab (FCR).
Less toxic approaches, however, initially developed to be more tolerable, did not yield similar efficacy. 1,2 Recently, the CLL14 trial showed that a combination treatment with the targeted agents venetoclax plus obinutuzumab over a fixed period of time can achieve considerable rates of undetectable minimal residual disease (uMRD) in elderly patients with coexisting conditions. In this trial, patients with previously untreated CLL and co-existing conditions were randomized to receive six cycles of obinutuzumab together with either 12 cycles of venetoclax or 12 cycles of chlorambucil (hereafter Ven-Obi vs Clb-Obi). A significantly longer progression-free survival was shown with Ven-Obi compared to Clb-Obi and uMRD levels of 76% were observed at the end of treatment. 3,4 The rate and types of adverse events were comparable between both arms, with no excess toxicities observed among this vulnerable group of patients.
To ensure that higher treatment efficacy was not achieved at the expense of patients' health-related quality of life (HRQoL), and to further evaluate the effects of treatment on symptoms as well as functional/HRQoL burden associated with both disease and treatment within this patient population, 5,6 patient-reported outcomes (PROs) assessments were conducted during and after treatment in both arms.
Here, we report the analyses of PRO data from the CLL14 study.

| Patients and study design
The CLL14 study is an ongoing global, phase III, open-label, randomized study of Ven-Obi compared with Clb-Obi in patients with previously untreated CLL and coexisting conditions. Details on the study design and eligibility criteria were outlined previously. 3   Note, CLL symptoms, core cancer symptoms, and symptom interference were assessed using the MDASI-CLL. Lower MDASI-CLL scores (range 0-10) indicate lower symptom severity or interference.
Patients were asked to complete the questionnaires at enrolment and subsequently on Day 1 of each treatment cycle (cycle two to cycle 12), at Day 28 after treatment completion and then at follow-up month 3, 6, 12, 15, 18, 24 and 30.
Key PRO endpoints evaluating disease and treatment-related symptoms following treatment with Ven-Obi or Clb-Obi as measured by the MDASI-CLL scale, and changes in physical functioning, role functioning, and global health status as measured by the EORTC QLQ-C30 scales, were used to compare study arms.

| Patient characteristics
We have previously described the patient characteristics along with efficacy and safety results. 3 In summary, 216 patients were randomized to receive Ven-Obi and 216 patients were randomized to receive Clb-Obi. Median age was 72 years, median CIRS was eight points and 57% of patients had an impaired renal function with a creatinine clearance below 70 ml/min (Table S1). Median treatment duration was 11.1 months in the Ven-Obi arm and 10.8 months in the Clb-Obi arm.

| EORTC QLQ-C30 results
For both questionnaires, the proportion of patients completing PRO assessments at baseline was 100% and at least 90% in both arms during treatment. During follow-up, completion rate remained above 85% past the 18-month mark as reported here.
At baseline, patient-reported physical functioning (mean score 76.9 with Ven-Obi vs. 75.9 with Clb-Obi), role functioning (72.6 vs. 73.6) and GHS/QoL (60.3 vs. 63.6) were comparable between both arms (Table 1), reflecting moderate-to-high functioning and moderate global health status. Baseline scores on the additional functioning and symptom scales were similarly comparable between arms (Table 1), showing moderate-to-high functioning and low symptom severity.  numerically higher for the Ven-Obi group at each timepoint. Improvement in PRO scores continued beyond timepoints of maximal clinical responses (cycle nine to follow-up month 3) and beyond end of treatment. Percentages of patients experiencing worsening were also comparable between arms, with fewer patients receiving Ven-Obi experiencing an increase in symptoms at most timepoints (Tables S4-S8 and Figures S3-S7).
The remaining functioning scales (social, cognitive, and emotional) demonstrated moderate-to-high scores at baseline that were stable during treatment and follow-up ( Figures S9-S11). Further symptom scales (nausea/vomiting, pain, constipation, diarrhea, appetite loss, financial difficulties) were low at baseline and remained stable during treatment (Figures S12-S17). In line with the previous report of diarrhea as an initial frequent adverse event with Ven-Obi, the PRO questionnaires indicated a transient increase on the diarrhea scale that returned to baseline by the end of treatment ( Figure S15).  (Table 1). Scores for both arms remained stable, but showed a tendency toward improvement (i.e., decreased symptom severity and interference) during treatment and follow-up ( Figure 3). The MMRM analyses showed no difference between treatment arms and no interaction between treatment and time.

| Exploratory MRD analyses
In order to explore whether depth of remission, as measured by MRD

| Exploratory clinical response analyses
Similar linear mixed effects models were used to evaluate clinical response in relation to these PROs. Both age and CIRS were initially included as covariates, but did not improve models and were ultimately excluded. Results showed no differences in PRO scores, with the exception of GHS/QOL in the Clb-Obi arm (Table S11). Plots of mean PRO score changes showed overlapping 95% confidence intervals and no consistent trends in most cases ( Figure S18).

| Exploratory subgroup analyses
Further subgroup analyses examined the same set of PROs across groups defined by disease burden (as captured by high/medium/low TLS risk status) and B symptoms (positive or negative). For the former, overall findings suggest that greater PRO improvement observed with Ven-Obi was driven by patients with higher disease burden; for the Clb-Obi arm, this trend was less pronounced (dyspnea, fatigue) or reversed (GHS/QOL, insomnia) ( Figures S19-S22). The latter B symptoms showed a similar trend toward PRO improvement for the B symptom positive group which was again more pronounced in the Ven-Obi arm, particularly for fatigue ( Figures S23-S26).

| DISCUSSION
The importance of patient quality of life has been emphasized by many cancer societies and organizations as well as funding and reimbursement agencies. 8-10 PRO data from randomized trials are of high value as they allow for a direct comparison of multiple treatment regimens and provide insight into patients' experience of treatment.
Moreover, they can be a sensitive tool to detect common toxicities of a treatment in addition to adverse event reporting by physicians, even within clinical trials. 11 It has been shown that chemoimmunotherapy as well as targeted treatment with BTK inhibitors and PI3K inhibitors can improve HRQoL, although agent-specific toxicities need to be considered. [12][13][14][15][16] Previous reports on venetoclax in patients with relapsed/refractory CLL indicated improvement based on some PRO measures. 17,18 However, these reports were based on single-agent, continuous treatment with venetoclax in relapsed/refractory CLL and did not include a comparative treatment arm.
The aim of this report was to analyze the impact of a novel fixedduration frontline treatment for CLL on the overall quality of life, as and unfit patients, suffering from co-existing conditions or comorbidities. 19 Post-hoc, exploratory analyses reported here indeed suggest that such improvements can be of particular benefit for these groups.
As with other types of indolent lymphoma, relapses or disease progressions after CLL treatment do not necessarily mandate initiation of a next line of therapy. 20  Open access funding enabled and organized by Projekt DEAL.

CONFLICT OF INTEREST
Othman Al-Sawaf reports personal fees and non-financial support from AbbVie, Roche, Gilead, and Janssen, during the conduct of study; Brit-

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.