Idelalisib addition has neutral to beneficial effects on quality of life in bendamustine/rituximab-treated patients: results of a phase 3, randomized, controlled trial

Abstract

Background: In a phase 3 randomized, double-blind, placebo-controlled trial, treatment with idelalisib, a phosphoinositol-3 kinase δ inhibitor, + bendamustine/rituximab improved progression-free survival (PFS) and overall survival (OS) in adult patients with relapsed/refractory chronic lymphocytic leukemia (R/R CLL). Here we report the results of health-related quality of life (HRQL) analyses from this study.

Methods: From June 15, 2012 to August 21, 2014, 416 patients with R/R CLL were enrolled; 207 patients were randomized to the idelalisib arm and 209 to the placebo arm. In the 416 patients randomized to receive bendamustine/rituximab and either oral idelalisib 150 mg twice-daily or placebo, HRQL was assessed at baseline and throughout the blinded part of the study using the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu) and EuroQoL Five-Dimension (EQ-5D) visual analogue scale (VAS) questionnaires. The assessments were performed at scheduled patient visits; every 4 weeks for the first 6 months from the initiation of treatment, then every 8 weeks for the next 6 months, and every 12 weeks thereafter until end of study. Least-squares mean changes from baseline were estimated using a mixed-effects model by including treatment, time, and treatment-by-time interaction, and stratification factors as fixed effects. Time to first symptom improvement was assessed by Kaplan-Meier analysis.

Results: In mixed-effects model analysis, idelalisib + bendamustine/rituximab treatment led to clinically meaningful improvements from baseline in leukemia-associated symptoms. Moreover, per Kaplan-Meier analysis, the proportion of patients with symptom improvement was higher and time to improvement was shorter among patients in the idelalisib-containing arm compared with those who did not receive idelalisib. The physical and social/family FACT-Leu subscale scores, along with the self-rated health assessed by EQ-VAS, showed improvement with idelalisib over placebo, but the difference did not reach statistical significance. The functional and emotional FACT-Leu subscale scores remained similar to placebo.

Conclusions: Addition of idelalisib to bendamustine/rituximab, apart from improving PFS and OS, had a neutral to beneficial impact on HRQL in patients with R/R CLL, particularly by reducing leukemia-specific disease symptoms.

Trial registration: Clinicaltrials.gov NCT01569295. Registered April 3, 2012.

Keywords: Health-related quality of life; Idelalisib; Patient-related outcomes; Randomized phase 3 study; Relapsed/refractory CLL.

Conflict of interest statement

MM reports research grants, personal fees, and nonfinancial support from Gilead Sciences, Inc.; as well as personal fees from Janssen, Roche, and Novartis. AI, ASP, ME, and WJ report institutional research grants from Gilead Sciences, Inc. TR reports research support and personal fees from Gilead Sciences, Inc. MW reports nothing to disclose. JD reports consulting and lecturing fees from Gilead Sciences, Inc.; Janssen; Roche; and GSK-Novartis. FM reports personal fees from Celgene; Genentech/Roche; Gilead Sciences, Inc.; and Janssen. AS reports honoraria from AbbVie; Gilead Sciences, Inc.; Janssen; and Roche; and nonrestricted educational grants from Gilead Sciences, Inc.; and Janssen. HE reports honoraria from Gilead Sciences, Inc.; AbbVie; Genentech; Pharmacyclics; and Janssen; consulting or advisory roles with Gilead Sciences, Inc.; AbbVie; Genentech; Pharmacyclics; and Janssen; speakers’ bureau fees from Gilead Sciences, Inc.; AbbVie; Genentech; Pharmacyclics; and Takeda; and research funding from Gilead Sciences, Inc.; AbbVie; Genentech; Pharmacyclics; Roche; Celgene; Novartis; Kite; GlaxoSmithKline; AstraZeneca; ATARA; BeiGene; TG Therapeutics; and Verastem. SS is an employee of Gilead Sciences, Inc.; and may hold stock. JCB reports consulting or advisory roles with Pharmacyclics/AbbVie; Janssen; Genentech; and Gilead Sciences, Inc.; honoraria from Janssen; and institutional research funding from Pharmacyclics/AbbVie and Gilead Sciences, Inc. ADZ reports honoraria from Genentech/Roche; Gilead Sciences, Inc.; Celgene; Janssen; Amgen; Novartis; and Adaptive Biotech; consulting or advisory roles with Genentech/Roche; Gilead Sciences, Inc.; Celgene; Janssen; Amgen; Novartis; Adaptive Biotechnologies; and MEI Pharma; research funding from MEI Pharma; Genentech/Roche; Gilead Sciences, Inc.; BeiGene; and AbbVie; travel, accommodations, and expenses paid by Roche; Gilead Sciences, Inc.; and Celgene; and acting as a Data Monitoring Committee Chair for BeiGene.

Figures

Fig. 1

Mixed-effects model analysis of FACT-Leu. a, FWB; b, EWB; c, PWB; d, S/FWB; e, LeuS; f, TOI score; g, FACT-Leu total score. Curves above the x-axis indicate positive effects, and curves below the axis show negative effects. Gray area denotes MID range. aP = 0.0525 for treatment difference. bP = 0.0192 for treatment difference. cP = 0.0343 for treatment difference. CI confidence interval, EWB emotional well-being, FACT-Leu Functional Assessment of Cancer Therapy–Leukemia, FWB functional well-being, LeuS leukemia-specific symptoms, MID minimally important difference, PWB physical well-being, S/FWB social/family well-being, TOI trial outcome index

Fig. 2

Percent of patients with improvements in FACT-Leu subscales (Kaplan-Meier analysis). a, PWB; b, S/FWB; c, LeuS; d, EWB; e, FWB. EWB emotional well-being, FACT-Leu Functional Assessment of Cancer Therapy–Leukemia, FWB functional well-being, LeuS leukemia-specific symptoms, PWB physical well-being, S/FWB social/family well-being

Fig. 3

Mixed-effects model analysis of EuroQoL Five-Dimension VAS. CI confidence interval, VAS visual analogue scale