Quality of Life in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia Improves after Minimal Residual Disease-Guided Treatment with Ibrutinib Plus Venetoclax
Authors: Eurelings Laura Elisabeth Maria , Rotbain Emelie Curovic , Kersting Sabina , Van Der Straten Lina , Enggaard Lisbeth , Veldhuis Gerrit Jan , Mous Rogier , Poulsen Christian Bjørn , Frederiksen Henrik , Janssens Ann , Schjoedt Ida , Dompeling Ellen C , Ranti Juha , Brieghel Christian , Mattsson Mattias , Bellido Mar , Tran Hoa T , Stege Claudia A M , Nasserinejad Kazem , Kater Arnon P. , Niemann Carsten Utoft , Levin Mark-David 
Published: December 2024

Introduction: Improving health-related quality of life (HRQoL) is a critical treatment objective for patients with chronic lymphocytic leukemia (CLL) due to its incurable nature. The HOVON 141/Vision trial has demonstrated high efficacy for MRD-guided, time-limited treatment with ibrutinib plus venetoclax (IV) in patients with relapsed or refractory (RR) CLL. However, data on the impact of MRD-guided IV on HRQoL remain limited.

Methods: Assessment of HRQoL in patients with RR CLL was conducted within the framework of the HOVON 141/Vision study as a pre-planned analysis. RR CLL patients were treated with IV for 15 cycles. In patients with detectable MRD (≥10-4), I was continued, while patients with undetectable MRD (uMRD in blood and bone marrow, &lt; 10-4) were randomized 1:2 for I maintenance or treatment cessation. Upon MRD recurrence in the treatment cessation arm, IV was reinitiated followed by I maintenance (Niemann 2024).

Changes in functioning scales, global health status (GHS)/QoL, and symptoms were assessed using the EORTC QLQ-C30 and QLQ-CLL16 questionnaires, completed at baseline, the end of IV (cycle 15), and at 6 months, 1, 2, and 3 years after cycle 15. Minimal important differences (MID) were used to determine whether changes in scores are clinically meaningful. MIDs were calculated using a distribution-based approach (van der Straten, Blood 2023).

Results: 224 patients completed at least one questionnaire and were included in the analysis. At baseline, the mean GHS of the full cohort was 66. After 15 cycles of IV, the majority of patients reported clinically relevant improvement (positive change in score &gt;8, the MID) or stable GHS (change between +8 and -8) (44% and 41% respectively), while 15% showed a clinically relevant decrease in GHS (negative change in score &gt;8, the MID). A clinically relevant improvement in the mean GHS was observed after 15 cycles of IV (+10; 95% CI +7 to +13). Similarly, a clinically relevant decrease in future health concerns was observed (-12; 95% CI -8 to -16). After induction treatment, 72 patients with uMRD were randomly assigned to a treatment group, 24 to ibrutinib maintenance (uMRD I) and 48 to treatment cessation (uMRD cessation). The remaining patients continued with ibrutinib monotherapy (I continuation). One year after the end of induction (EOIT) treatment, the majority of patients reported a clinically relevant improvement or stable GHS: 24% and 57% for uMRD I, 22% and 65% for uMRD cessation, and 21% and 64% for I continuation.

In the full cohort, 6 months after induction treatment, a clinically relevant improvement was seen in the GHS (+11; 95% CI 8 to 14), fatigue (-12; 95% -9 to -15), disease-related symptoms (-12; 95% CI -10 to -14), and future health worries (-17; 95% CI -13 to -21) compared to baseline. These effects persisted up until 3 years after the EOIT. A transient increase in treatment-related symptoms and diarrhea was observed at the EOIT (+8; 95% CI 5 to 11 and +14; 95% CI 10 to 18 respectively). However, these symptom scores returned to the baseline scores 6 months after the EOIT in each treatment group.

Clinically relevant improvements were observed 1 year after the end of IV compared to baseline for GHS (+9), role functioning (+16), emotional functioning (+9), cognitive functioning (+7), and future health worries (-17) in the uMRD I arm. In the uMRD cessation arm, improvements were observed for GHS (+11), fatigue (-14), disease-related symptoms (-12), and future health worries (-15). In the I continuation arm improvements were observed for GHS (+12), physical functioning (+6), role functioning (+11), fatigue (-15), dyspnea (-15), disease-related symptoms (-14), and future health worries (-17).

Conclusion: MRD-guided treatment with IV significantly improves HRQoL for RR CLL and mitigates fatigue, disease-related symptoms, and health concerns. These effects are durable, lasting for at least three years after end of induction treatment with IV. The clinically relevant improvements in GHS and health concerns are seen in patients continuing ibrutinib, as well as after cessation. Overall, MRD-guided IV therapy confers substantial HRQoL benefits in RR CLL, in addition to the previously documented high efficacy of IV MRD-guided time-defined treatment.