Health-Related Quality of Life with CC-486 in Patients with Acute Myeloid Leukemia (AML) in First Remission Following Induction Chemotherapy (IC): Results from the Phase III QUAZAR AML-001 Maintenance Trial

INTRODUCTION: Effective AML maintenance treatment should decrease the risk of relapse and prolong survival without compromising health-related quality of life (HRQoL) or worsening fatigue. In the phase III randomized, double-blind, placebo-controlled QUAZAR AML-001 trial, CC-486, an oral hypomethylating agent, significantly improved overall survival (OS) and relapse-free survival (RFS) in patients with AML in first remission following IC. Here we present patient-reported HRQoL outcomes from QUAZAR AML-001.

METHODS: Eligible patients were aged ≥55 years, with intermediate- or poor-risk cytogenetics and Eastern Cooperative Oncology Group performance status (ECOG PS) scores ≤3; had achieved complete remission (CR) or CR with incomplete hematologic recovery (CRi) after IC ± consolidation; and were not candidates for hematopoietic stem cell transplant. Patients were randomized 1:1 to CC-486 300 mg or placebo, administered once-daily for 14 days per 28-day treatment cycle. HRQoL was assessed using two validated instruments, the Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale and the European Quality of Life–Five Dimensions–Three Levels (EQ-5D-3L) questionnaire. Each instrument was to be completed on day 1 of each treatment cycle and at the end of treatment (EOT). HRQoL endpoints included differences in mean score changes from baseline (BL) with CC-486 vs. placebo, and proportions of patients with clinically meaningful changes from BL (improvement, no change, deterioration) in FACIT-Fatigue and EQ-5D-3L health utility index (HUI) scores. Clinically meaningful improvement or worsening was defined as a change from BL of ≥3 points on the FACIT-Fatigue scale, and of +0.08 point (improvement) or –0.10 point (worsening) on the EQ-5D-3L HUI. Evaluable patients had an HRQoL assessment at BL and at ≥1 post-BL visit. Stratified ANCOVA models included treatment and BL scores as covariates. Longitudinal analysis using a mixed-effect model for repeated measures (MMRM) was performed to confirm the non-inferiority of CC-486 to placebo.

RESULTS: The HRQoL-evaluable population comprised 225/238 patients (95%) in the CC-486 arm and 219/234 patients (94%) in the placebo arm. Patient characteristics at BL were comparable between treatment arms. Most patients (61%) were 65–74 years of age. The median number of CC-486 treatment cycles was 12 and of placebo was 7. At BL, patients in CR/CRi in both treatment arms had comparable low levels of fatigue and generally good HRQoL. Overall mean [±SD] BL FACIT-Fatigue score was 40.8 [±8.4], similar to that of the US general population (43.6 [±9.4]; Cella, J Pain Symptom Manage, 2002) and of an age- and gender-matched German general population (43.2; Montan, Value Health, 2018). Patients also had generally good HRQoL at BL based on mean EQ-5D-3L HUI score (0.80 [±0.12]), which was comparable to a reference HUI value from the US general population aged 65–74 years (0.76). Compliance rates for questionnaire completion were >95% at BL and remained high (>85%) at all post-BL visits except for EOT.

No clinically meaningful differences occurred between CC-486 and placebo in mean changes from BL in FACIT-Fatigue scores at any post-BL visit (Figure A). Significant differences in EQ-5D-3L HUI scores between treatment arms at cycles 22 and 23 were not clinically meaningful and likely due to chance (no adjustment was made for multiplicity of testing) (Figure B). MMRM analysis also supported the non-inferior HRQoL with CC-486 relative to placebo. There was no statistically significant difference between treatment arms in proportion of patients with a clinically meaningful deterioration in FACIT-Fatigue score post-BL except at cycle 29 (again, likely due to chance), or in EQ-5D-3L HUI scores at any visit. No significant differences were observed between CC-486 and placebo in median times to deterioration in FACIT-Fatigue scores (41 vs. 44 weeks, respectively; P=0.70) or on the EQ-5D HUI (200 vs. 164 weeks; P=0.63).

DISCUSSION: Favorable HRQoL and low levels of fatigue were reported at BL and were preserved throughout CC-486 maintenance treatment. CC-486 significantly improved OS and RFS while maintaining HRQoL comparable to placebo.