Patient-Reported Quality of Life Outcomes with Venetoclax-Based First-Line Combinations in CLL: An Analysis from the Phase 3 GAIA/CLL13 Trial

Background The phase 3 GAIA/CLL13 trial recently demonstrated superior progression-free survival for time-limited venetoclax-obinutuzumab (GV) and venetoclax-obinutuzumab-ibrutinib (GIV) compared to both, chemoimmunotherapy (CIT) and venetoclax-rituximab (RV) in the first-line treatment of CLL. Currently, no direct comparisons of health-related quality of life (QoL) measures of different venetoclax regimens are available. Here, we report a preplanned analysis of patient-reported QoL outcomes (PRO) from the GAIA/CLL13 trial. Methods PRO questionnaires were completed at baseline (BL), month 3 (MO3), MO6, MO9, MO12, MO15, MO18, MO21, MO24 and then annually until MO60. Changes in functioning scales, global health status (GHS)/QoL and symptoms were assessed using the EORTC QLQ-C30 and QLQ-CLL16 questionnaires. For functioning scales and GHS/QoL, higher scores indicate a better level of functioning/improvement of QoL, on symptom scales higher scores show a higher level of symptoms. The minimal important difference (MID) was defined as the minimal change from BL indicating a clinically meaningful improvement and was calculated using a distribution-based approach as previously described (e.g. van der Straten et al., Blood 2023). For patients who completed a questionnaire at baseline and at least at one further time point post-baseline, time until deterioration (TUD) and improvement (TUI) were calculated from start of treatment until deterioration or improvement of at least MID. Results In total, 863 of 926 patients (93.2%) returned at least one questionnaire. Completion rates were 76.0% at BL, 72.7% at MO3, 69.4% at MO6, 61.2% at MO9, 75.4% at MO12 and 49.2% at MO15. BL characteristics were balanced between patients evaluable and non-evaluable for QoL. Mean BL values for GHS were 68.4 (CIT), 67.9 (RV), 67.8 (GV) and 69.5 (GIV). In the RV and GV arm, GHS improved after initiation of treatment (mean change from BL, RV: +5.2 [MO3]; +6.1 [MO6]; +8.8 [MO9]; +9.4 [MO12]; +8.4 [MO15]; GV: +5.5; +5.1; +9.0; +9.3; +10.1) and mean changes from BL above the MID (5.9) were maintained throughout the study. In the GIV arm, no mean increase above the MID was observed during the first 12 months of treatment but at MO15 when most patients had finished treatment (+2.4; +0.2; +2.5; +4.4; +10.2). In the CIT arm (+1.3; -0.6; +4.9; +5.0; +5.4), the first mean improvement above MID was reported at MO24 (+6.1). The symptom burden (QLQ-CLL16 questionnaire, MID 7.3) improved promptly after treatment initiation in the RV arm (-5.4; -5.3; -5.5; -5.8; -7.3) and GV arm (-5.0; -4.3; -5.6; -5.5; -7.8), while with GIV (-0.2; +1.1; 0.0; -1.5; -5.1) and CIT (-1.3; -1.7; -3.8; -4.0; -3.7) similar mean changes from BL were reached later. Similar temporal dynamics, i.e. later improvements in the CIT and GIV arms compared to RV and GV were also reported for physical functioning, role functioning, social functioning (all QLQ-C30) and physical condition (QLQ-CLL16). Clinically meaningful improvements (≥MID of 8.9) in fatigue were reported in most patients across treatment arms with a median TUI of 7.5 months (CIT), 5.4 (RV), 5.7 (GV) and 5.8 (GIV). TUD in nausea/vomiting was worse with GIV compared to CIT (HR 1.46 [95%CI 1.08-1.98]) and to RV (HR 1.76 [1.31-2.37], while the comparison of GIV versus GV showed a HR of 1.34 [0.999-1.78]). In the GIV arm, patients also reported higher scores in diarrhea with mean changes from BL above the MID (10.4) at MO3 (+12.9), MO6 (+14.3) and MO9 (+12.9) and higher scores in bruising with a mean change from BL above the MID (10.7) at MO6 (+13.5), while the mean changes from BL did not reach the MID in the other arms at any time. The risk of a clinically meaningful deterioration of diarrhea was higher with GIV compared to CIT (TUD, HR 2.37 [1.74-3.23]), RV (HR 1.58 [1.21-2.07]) and GV (HR 1.53 [1.16-2.02]). Conclusions For patients treated with GV or RV, rapid improvements in QoL measures and key functioning scales were observed shortly after treatment initiation. Similar improvements were consistently reported later, after the end of treatment in patients receiving GIV, while later and smaller improvements were seen for patients receiving CIT. This difference in the timing of QoL improvements between the triple combination and the RV/GV doublets appeared to be driven by a higher symptom burden during treatment with GIV. This should be considered when comparing efficacy outcomes of different venetoclax combinations in CLL.