Ibrutinib/Rituximab Preserves QOL vs FCR in Previously Untreated CLL
Continuous ibrutinib (Imbruvica) plus rituximab (Rituxan) did not compromise health-related quality of life (HR-QOL) compared with fludarabine, cyclophosphamide, and rituximab (FCR) in previously untreated patients with chronic lymphocytic leukemia (CLL), according to secondary end point data from the phase 3 FLAIR trial (NCT01844152) published in British Journal of Haematology.1
Findings showed that overall HR-QOL trajectories were similar between the two treatment arms. No statistically significant differences were reported between the arms regarding EQ-5D Utility Index (estimated mean difference, −0.00; 95% CI, −0.02 to 0.01) or EQ-VAS (0.60; 95% CI, −0.64 to 1.85) over 48 months.
On the EORTC QLQ-C30 functioning scales, physical functioning (estimate, 1.83; 95% CI, 0.52-3.15), role functioning (2.20; 95% CI, 0.10-4.30), and social functioning (2.97; 95% CI, 0.97-4.98) were statistically significantly in favor of ibrutinib/rituximab. Emotional functioning (–0.57; 95% CI, –2.06 to 0.92) and cognitive functioning (0.50; 95% CI, –1.00 to 2.00) did not differ significantly between arms.
On symptom scales using EORTC QLQ-C30, diarrhea significantly favored FCR (estimate, 3.31; 95% CI, 1.70-4.92), while fatigue (−3.16; 95% CI, −4.90 to −1.42) and dyspnea (−2.09; 95% CI, −3.84 to −0.34) favored ibrutinib/rituximab. On the EORTC QLQ-CLL16 model, disease effects significantly favored FCR (1.18; 95% CI, 0.07-2.28), while CLL fatigue (–2.43; 95% CI, –4.46 to –0.41), infection (–2.06; 95% CI, –3.55 to –0.57), and social problems (–3.29; 95% CI, –5.54 to –1.05) favored ibrutinib/rituximab. None of the observed differences exceeded the between-group minimally important difference threshold for any scale.
In a descriptive comparison of baseline vs 48-month time points, a higher proportion of FCR-treated patients experienced meaningful improvements—defined a change of at least 10 points from baseline—in EQ-5D Utility Index (FCR, 31.4%; ibrutinib/rituximab, 15.7%), EQ-VAS (39.9%; 24.7%), and fatigue on QLQ-C30 (55.7%; 47.4%). Conversely, fewer FCR-treated patients experienced meaningful deterioration in EQ-5D Utility Index (20.0%; 30.1%) and diarrhea (9.0%; 18.9%).
"Ibrutinib/rituximab is associated with minimal HR-QOL differences at 4 years compared [with] FCR. Such findings may seem counterintuitive given that other QOL studies of novel agents deployed for CLL treatment have demonstrated a favorable impact on QOL when compared [with] chemoimmunotherapy,” lead study author David J. Allsup, BSc, MBChB, FHEA, PhD, and colleagues wrote in a publication of the data. “However, this study was undertaken in a relatively young-fit patient group who are known to have excellent responses to FCR. This FCR-treated group may be less likely to have chemotherapy-related complications than [patients who are older or have co-morbidities].”
Allsup is a professor of hematology at the Hull York Medical School in Heslington, England.
Prior findings from the study’s interim analysis published in Lancet Oncology showed that at a median follow-up of 53 months (interquartile range, 41-61), patients treated with ibrutinib/rituximab (n = 386) achieved a median progression-free survival (PFS) that was not reached (NR) compared with 67 months (95% CI, 63-NR) for those treated with FCR (n = 385; HR, 0.44; 95% CI, 0.32-0.60; P < .0001).2 The 4-year PFS rates were 85.6% (95% CI, 81.3%-89.0%) and 73.0% (95% CI, 67.7%-77.5%), respectively.
Median overall survival (OS) was NR in both groups; the respective 4-year OS rates were 92.1% (95% CI, 88.6%-94.5%) and 93.5% (95% CI, 90.1%-95.7%).
FLAIR was a phase 3, open-label, randomized controlled trial conducted across 101 National Health Service hospitals in the United Kingdom that enrolled patients 18 to 75 years of age with previously untreated CLL requiring treatment.1 A WHO performance status of 2 or less was required, and patients with greater than 20% 17p deletion were not included.
Patients were randomly assigned 1:1 to receive ibrutinib plus rituximab or FCR. FCR was given for up to 6 cycles, in the absence of disease progression or unacceptable toxicity.2 Ibrutinib and rituximab were administered as a combination in the first 6 cycles before ibrutinib monotherapy continued for up to 6 years or until minimal residual disease (MRD) stopping rules were met.
HR-QOL was a prespecified secondary end point.1 Enrolled completed 3 validated patient-reported outcome (PRO) tools: the EORTC QLQ-C30, the CLL-specific EORTC QLQ-CLL16, and the EuroQoL EQ-5D-3L (including EQ-VAS). Questionnaires were collected at baseline, at the end of rituximab treatment, and every 6 months thereafter, up to 7 years post-randomization or until progressive disease. Data cut-off for this analysis was May 24, 2021.
Of 771 randomly assigned patients, 84.4% completed baseline PRO questionnaires and comprised the intention-to-treat population for this analysis, including 329 patients in the ibrutinib/rituximab arm and 322 patients in the FCR arm. Subsequent compliance ranged from 67.6% to 83.5%.
The authors acknowledged that the QOL instruments used were developed previously for chemoimmunotherapy and may lack sensitivity to detect differences relevant to BTK inhibitor therapy. The updated QLQ-CLL17 may have captured additional differences, and future trials should consider incorporating relevant items from the EORTC library.
Additional limitations include low representation of Black patients (1% in the HR-QOL cohort) and collection of HR-QOL data only up to disease progression. The authors called for improved ethnic minority recruitment and extension of HR-QOL assessment beyond first progression in future CLL trials.
"Newer BTK inhibitors may have a more positive impact on QOL, as may time-limited combinations of novel agents delivered in a personalized approach with MRD monitoring," Allsup and study authors concluded.
