CC-486 maintenance preserves survival benefit, QoL in older AML patients

In older patients with acute myeloid leukaemia (AML), CC-486 maintenance therapy after intensive chemotherapy (CT) with or without consolidation CT led to improved survival regardless of MRD* status, and preserved baseline QoL status, according to the QUAZAR AML-001 trial presented at ASH 2020.

 

Although high remission rates may be achieved following intensive CT, the effect is mostly transient, noted presenting author Dr Gail Roboz from Weill Medical College of Cornell University New York-Presbyterian Hospital, New York, US. The hypomethylating agent CC-486, an oral formulation of azacitidine but not bio-equivalent to injectable azacitidine, allows for extended dosing schedules to prolong drug exposure over the treatment cycle. [N Engl J Med 2020;383:2526-2537]

 

This study comprised 472 adults (median age 68 years, 52 percent male) with de novo or secondary AML who were not candidates for HSCT**. Within 4 months of achieving first complete remission (CR) or CR with incomplete haematologic recovery following intensive CT ± consolidation CT, participants were randomized 1:1 to receive CC-486 300 mg or placebo QD for 14 days per 28-day treatment cycle.

 

A total of 463 participants from the overall sample comprised the MRD-evaluable cohort. Samples were obtained prior to randomization and throughout the study to evaluate the effect of MRD on survival, and the rates of conversion from MRD positivity to negativity. [ASH 2020, abstract 692]

 

At baseline, 43 percent of CC-486 recipients and 50 percent of those on placebo were MRD+. “[D]etectable residual disease in the bone marrow post-CT is predictive of early relapse. [Identifying] ≥0.1 percent MRD by MFC*** in patients with AML in remission after intensive CT is an important prognostic marker that may help guide treatment decisions,” said Roboz.

 

CC-486 outshined placebo in terms of improvement in overall survival (OS), be it among those who were MRD+ (median, 14.6 vs 10.4 months; hazard ratio [HR], 0.69) or MRD– at baseline (median, 30.1 vs 24.3 months; HR, 0.81).

 

Relapse-free survival (RFS) was also better with CC-486 vs placebo for both MRD+ (median, 7.1 vs 2.7 months; HR, 0.58) and MRD– groups (median, 13.4 vs 7.8 months; HR, 0.71).

 

On multivariate analyses, baseline MRD status (MRD+ vs MRD–) was significantly associated with OS and RFS (HRs, 1.85 and 2.04, respectively; p<0.0001 for both). CC-486 also showed a marked treatment benefit vs placebo in terms of OS and RFS (HR, 0.74; p=0.0067 and HR, 0.63; p<0.0001, respectively) independent of baseline MRD status.

 

CC-486 also prolonged the duration of MRD negativity vs placebo (median, 11.0 vs 5.0 months; HR, 0.62) and resulted in a higher rate of transition from MRD positivity to negativity (37 percent vs 19 percent).

 

About a quarter (24 percent) of CC-486 recipients achieved MRD negativity >6 months post-randomization, as opposed to only 5 percent of those on placebo. “[This suggests] that CC-486 could induce MRD negativity after prolonged MRD+ status,” noted Roboz.

 

The HRQoL^#-evaluable cohort comprised 444 patients from the overall sample. At baseline, participants generally had good HRQoL and low levels of fatigue. Overall mean baseline FACIT-FS^## and EQ-5D-3L HUI^### scores were 40.8 and 0.80, respectively. These values, according to Roboz, correlate with data from the US general population (43.6 [FACIT-FS] and 0.76 [EQ-5D-3L HUI]). [ASH 2020, abstract 214]

 

At any post-baseline visit, there were no clinically significant differences between CC-486 and placebo in terms of mean changes from baseline FACIT-FS score. Despite significant between-group differences in EQ-5D-3L HUI scores at cycles 22 and 23, Roboz noted that these might have been due to chance and were thus not deemed clinically meaningful.

 

Median times to deterioration in FACIT-FS (41 vs 44 weeks; p=0.70) and EQ-5D-3L HUI scores (200 vs 164 weeks; p=0.63) were also not significantly different between the CC-486 and the placebo arms.

 

These findings reveal that the favourable HRQoL and low fatigue levels at baseline were preserved throughout the maintenance therapy phase with CC-486. “[CC-486 effectively reduced] the risk of relapse and prolonged survival without compromising HRQoL or worsening fatigue,” said Roboz.