Impact of idelalisib on health-related quality of life in patients with relapsed chronic lymphocytic leukemia in a phase 3 randomized trial.

Patients with chronic lymphocytic leukemia (CLL) have overtly impaired well-being relative to healthy controls. Factors associated with lower overall health-related quality of life (HRQoL) in patients with CLL include older age, greater fatigue, severity of comorbid health conditions, advanced disease stage, and ongoing treatment for CLL. The use of standardized patient-reported outcomes has become an increasingly important component of therapeutic assessment in clinical trials, allowing for determination of the impact of treatment on HRQoL. Idelalisib, a potent, highly selective, oral small-molecule inhibitor of phosphoinositol-3 kinase δ, is approved by the US Food and Drug Administration and the European Medicines Agency, in combination with rituximab, for the treatment of relapsed CLL. In the pivotal randomized, double-blind, placebo-controlled trial of 220 elderly patients with relapsed or refractory CLL and comorbid conditions, idelalisib plus rituximab demonstrated statistically significant and clinically meaningful improvements in overall response rate, progression-free survival, and overall survival, with an acceptable toxicity profile compared with the placebo plus rituximab control. Grade ≥3 diarrhea, rash, and hepatic transaminase elevations were more frequent in the idelalisib plus rituximab arm. A prespecified analysis evaluated the impact of idelalisib plus rituximab versus rituximab plus placebo on HRQoL in the absence of the typical chemotherapyrelated toxicity using the 44-item Functional Assessment of Cancer Therapy–Leukemia (FACT-Leu) scale. The FACT-Leu instrument has well-established psychometric properties that yield a total score and subscales for physical well-being (PWB), functional wellbeing (FWB), social/family well-being (SWB), and emotional well-being (EWB), and a diagnosis-specific measure for patients with leukemia-specific symptoms (LeuS) such as fevers, chills, night sweats, nodal swelling and fatigue. The FACT-Leu total score is the sum of all subscales, and the trial outcome index is the sum of the scores for PWB, FWB, and LeuS. Higher scores reflect better HRQoL. The number of items, scoring ranges, and minimally important differences (MID) for each subscale are listed in Online Supplementary Table S1. The survey was administered every 2 weeks until week 8, every 4 weeks until week 24, every 6 weeks until week 48, and every 12 weeks thereafter until unblinding on November 8, 2013. No HRQoL or performance status data were collected after CLL disease progression. To avoid biasing HRQoL results, the FACT-Leu was administered in person at each visit before other procedures were performed, and before any study information was conveyed to the patient. FACT-Leu was scored based on the Functional Assessment of Chronic Illness Therapy-3 scoring guideline and user manual. Questionnaire compliance was defined as the proportion of patients who answered at least one question at a scheduled time point relative to all patients available at that time point (i.e., not including patients excluded for other reasons). Missing items in a subscale were imputed. Data collected from the FACT-Leu instrument were not reconciled with adverse event or laboratory data. Repeated measures mixed-effects models were used to assess mean change from baseline within and between treatment arms. Since a significant portion of the patients had progression of CLL during the study, and no HRQoL or performance status data were collected after disease progression, the duration of data collection varied. Missing data were not imputed for patients lost to follow-up without progression. The varied durations of FACT-Leu score collection were handled by the repeated measure mixed-effects model, which provides robust estimates by analyzing the observed data when data missing at random were reasonably assumed. Kaplan-Meier methods and log-rank tests were applied for each of the FACT-Leu subscale scores, assessing time to changes for each variable. The trial was registered at: clinicaltrials.gov NCT01539512; EudraCT 2011-005180-24. Between May 2012 and August 2013, 220 patients were enrolled. The study was stopped due to superior efficacy of idelalisib plus rituximab over placebo plus rituximab. Upon study termination and unblinding,