Impact of Ibrutinib on Quality of Life in Patients with Early-Stage, Asymptomatic Chronic Lymphocytic Leukemia: Results from the Phase III CLL12 Trial
Authors: Goergen Ellinor , Robrecht Sandra , Giza Adam , Zhang Can , Nieper Pascal , Simon Florian , Cramer Paula , Fürstenau Moritz , Al-Sawaf Othman , Kutsch Nadine , Fink Anna Maria , Vehling-Kaiser Ursula , Müller Lothar , Eckart Michael J. , Schlag Rudolf , Freier Werner , Gaska Tobias , Balser Christina , Reiser Marcel , Stauch Martina Beate , Wendtner Clemens-Martin , Tausch Eugen , Schneider Christof , Fischer Kirsten , Stilgenbauer Stephan , Eichhorst Barbara F. , Hallek Michael , Langerbeins Petra 
Published: December 2024

Background
The impact of treatment on quality of life (QoL), as compared to the effect of CLL alone, is not well studied. We analysed patient (pt)-reported QoL outcomes (PRO) of treatment-naïve, asymptomatic, early-stage pts treated with ibrutinib (n=182) or placebo (n=181) in the double-blind, randomized, phase III CLL12 trial (ClinicalTrials.gov/NCT02863718). The final analysis of the trial has shown (Langerbeins et al., Hemasphere 2023) that ibrutinib did not prolong the overall survival compared to placebo despite increasing event-free survival.
Methods
PRO questionnaires were regularly completed at baseline (BL), during treatment (TP) and follow-up phase (FUP) (i.e. 3-monthly in the first year of treatment, 6-monthly in the following years of treatment and yearly in the follow-up phase). 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, higher scores indicated a better level of functioning/improvement of QoL, on symptom scales higher scores showed 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 (van der Straten, Blood 2023). For pts who completed a questionnaire at BL and at least at one further time point post-BL, time to deterioration (TUD) and improvement (TUI) were calculated from start of treatment until deterioration or improvement by at least a MID.
Results
With a median observation time of 66.4 months (range, 0 - 93.4), 328 of 363 pts (90.4%) returned at least one questionnaire. Completion rates were 67.5% at BL, 74.0% at TP MO0-6, 75.4% at TP MO6-12, 72.3% at TP MO12-18 and 79.1% at TP MO18-24.
Mean BL values for GHS were 75.5 (ibrutinib, I) and 71.8 (placebo, PBO). The BL values for GHS did not differ significantly in either group, nor did they show any notable changes throughout treatment for the I and PBO group: 72.3 and 72.2 for MO0-6, 73.8 and 72.0 for MO6-12, 74.5 and 71.7 for MO12-18, 74.3 and 70.5 for MO18-24, 74.6 and 70.1 for MO24-30, 75.4 and 69.4 for MO30-36, 76.1 and 69.3 for MO36-48, 71.9 and 70.0 for MO48-60, 74.9 and 72.0 for MO60+. The mean values for physical functioning did not differ between I versus PBO treated pts. Similar results were found for fatigue/physical condition and symptom burden using QLQ-CLL16.
TUD did not significantly differ for GHS (HR 1.009, 95%-CI 0.738-1.378; P =0.957) in treated versus untreated pts. Using EORTC QLQ-C30, TUI did not differ significantly for fatigue (HR 1.095; 95%-CI 0.793-1.512; P=0.581). However, TUI of physical functioning was shorter in the I group (HR 1.427; 95%-CI 1.023-1.992; P=0.036) with a median of 9.6 versus 18.1 months.
When evaluating the impact of I-associated toxicity on QoL, the TUD for diarrhea (HR 1.143; 95%-CI 0.798-1.636; P=0.466) or skin problems (HR 1.284; 95%-CI 0.924-1.786; P=0.137) did not differ in both groups. In contrast, the TUD of bruising was shorter in the I group with 19.3 versus 51.6 months (HR 1.822; 95%-CI 1.288-2.577; P &lt;0.001).
Conclusions
In conclusion, ibrutinib therapy failed to show a major impact on global health status and on various QoL parameters in early-stage, asymptomatic CLL patients. Exceptions were a faster improvement in physical functioning and a shorter time to deterioration of bruising for patients treated with ibrutinib compared to placebo.