Page 220 - 2021_12-Haematologica-web

Letters to the Editor
Oral azacitidine preserves favorable level of fatigue and health-related quality of life for patients with acute myeloid leukemia in remission: results from the phase III, placebo-controlled QUAZAR AML-001 trial
Despite relatively high remission rates with intensive chemotherapy (IC), most patients with acute myeloid leukemia (AML) will relapse, and overall survival (OS) in relapsed AML is dismal.1 In the phase III, placebo-con- trolled QUAZAR AML-001 trial, oral azacitidine (Oral- AZA [CC-486]) significantly prolonged OS versus placebo (P=0.0009; median 24.7 vs. 14.8 months from randomiza- tion) and relapse-free survival (RFS) (P=0.0001; 10.2 vs. 4.8 months) as maintenance therapy for patients with AML in first remission after intensive chemotherapy (IC), and was associated with a manageable safety profile.2 Health-related quality of life (HRQoL) and fatigue gener- ally improve over time for patients with AML in remis- sion; an ideal maintenance treatment should prolong sur- vival without compromising HRQoL.3,4
The impact of Oral-AZA on patient-reported fatigue and HRQoL, a key secondary endpoint in QUAZAR AML-001, was assessed using the self-administered Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale and EuroQoL EQ-5D-3L instru- ments. We hypothesized that Oral-AZA treatment would not meaningfully worsen fatigue or overall HRQoL from baseline, and that mean changes from baseline in fatigue and HRQoL scores in the Oral-AZA arm would be com- parable (i.e., not inferior) to those in the placebo arm.
Topline HRQoL outcomes of this study are described briefly elsewhere.2 At study entry, patients reported gen- erally favorable levels of fatigue and overall HRQoL. Mean FACIT-Fatigue and EQ-5D-3L health utility index (HUI) scores remained similar to baseline over time dur- ing Oral-AZA treatment, with similar changes between the Oral-AZA and placebo arms.2 We describe previously unreported HRQoL results from QUAZAR AML-001, including longitudinal analyses using linear mixed-effect models for repeated measures (MMRM), outcomes in patient subgroups defined by prognostic baseline charac- teristics, and rates of clinically meaningful deterioration in HRQoL scores.
QUAZAR AML-001 was a randomized, double-blind, placebo-controlled phase III trial. Study design and end- points are reported in detail elsewhere.2 Briefly, patients aged ≥55 years, with intermediate- or poor-risk cytoge- netics at diagnosis, ECOG PS ≤3, and ineligible for trans- plant, were randomized to Oral-AZA 300 mg or placebo once-daily for 14 days/28-day cycle within 4 months after achieving first CR or CR with incomplete hemato- logic recovery (CRi) with IC (induction ± consolidation). Patients who relapsed on-study with 5-15% blasts could
receive an escalated 21-days/cycle dosing schedule at the discretion of the treating investigator.
The FACIT-Fatigue Scale is a 13-item questionnaire that measures an individual’s level of fatigue during daily activities over the previous week. The EQ-5D-3L is a generic instrument that includes a descriptive question- naire that assesses impairment across five dimensions (mobility, self-care, pain/discomfort, usual activities, anx- iety/depression) at three severity levels (none, moderate, severe), and a visual analogue scale (VAS) that asks patients to rate their perceived HRQoL from 0-100. Higher scores indicate lower fatigue (FACIT-Fatigue) and better health state (EQ-5D-3L). Both instruments were completed on day 1 of each cycle and end-of-treatment (EOT). HRQoL-evaluable patients had non-missing assessments at baseline and ≥1 post-baseline visit.
In order to interpret changes from baseline, we used predefined thresholds for clinically meaningful changes within/between treatment arms (i.e., minimally impor- tant differences [MID]) and5at the individual level (i.e., responder definitions [RD]). Thresholds used to define clinically meaningful improvement and deterioration from baseline, respectively, were score changes of +3/–3 on the FACIT-Fatigue Scale;6 +0.08/–0.10 on the EQ-5D- 3L HUI;7,8 and +11/–11 on the EQ-5D VAS.8
MMRM models were performed to confirm the hypothesized non-inferiority of Oral-AZA and placebo;9 these models used an unstructured covariance matrix and included the intercept and visit as random effects, and treatment arm, randomization stratification factors,2 baseline HRQoL score, visit, baseline-by-visit interaction, and treatment-group-by-visit interaction as fixed effects. The dependent variable was change in HRQoL score from baseline. Non-inferiority of Oral-AZA versus place- bo was demonstrated if the lower bound of the two- sided 95% confidence interval (CI) of the between-group difference in the overall least-squares (LS) mean change from baseline was greater than the MID for deterioration at each assessment.5,10
Empirical cumulative distribution frequency (eCDF) curves were generated showing FACIT-Fatigue score changes from baseline for individual patients within each treatment arm at cycles 3, 6, 12, and 24, using the prede- fined RD for clinically meaningful improvement and deterioration (+3/–3 points). Time to confirmed deterio- ration was assessed for each patient from the time of ran- domization until the first of ≥ 2 consecutive visits with a change from baseline surpassing the RD for clinically meaningful deterioration, or until death. Time to con- firmed deterioration was estimated using Kaplan-Meier product-limit methods and compared between treatment arms using a stratified Cox proportional hazards regres- sion model with treatment group and baseline score as covariates.
Table 1. Mixed-effect models for repeated measures analyses: overall least-squares mean changes from baseline within in each arm, between-group differences in overall least-squares mean changes, and prespecified minimally important differences for each assessment.
Assessment
FACIT-Fatigue scale
EQ-5D-3L health utility index
EQ-5D visual analogue scale
Overall LS mean [95%CI] change from baseline
Difference in overall LS mean change, Oral-AZA vs. placebo, mean [95%CI]*
–0.89 [–2.37, 0.59]
–0.01 [–0.03, 0.01]
–0.95 [–4.38, 2.47]
Prespecified MID
for clinically meaningful worsening
–3
–0.10
–11
Oral-AZA
–0.60 [–2.19, 0.99]
–0.01 [–0.03, 0.01]
2.64 [–0.59, 5.86]
Placebo
0.29 [–1.44, 2.02]
0.00 [–0.02, 0.02]
3.59 [0.01, 7.17]
*Mixed-effect models for repeated measures (MMRM) analyses confirmed the noninferiority of Oral-AZA effects on fatigue and overall HRQoL vs. placebo, as the lower bounds of the 95% confidence interval (CI) for between-group differences in least-square (LS) mean changes from baseline did not exceed the predefined minimally important difference (MID) for worsening on any assessment. AZA: azacitidine; FACIT: functional assessment of chronic illness therapy.
3240
haematologica | 2021; 106(12)