Oral azacitidine may prolong survival in patients with acute myeloid leukemia

In newly diagnosed acute myeloid leukemia (AML), intensive chemotherapy (IC) can achieve high response rates, but the duration of response is usually brief
.

Clinical trials have investigated a variety of treatments, including demethylating drugs, for maintenance therapy in patients with AML in remission
.

Although some therapies in maintenance therapy have been shown to prolong disease-free survival (DFS) or recurrence-free survival (RFS) after IC, until recently, no significant effect on overall survival (OS) has been shown in large randomized studies.
) have a significant impact
.

In the randomized QUAZAR AML-001 phase 3 trial (NCT01757535), oral azacitidine (AZA) significantly prolonged compared with placebo in patients with AML in first remission after induction chemotherapy (≥55 years; with or without subsequent consolidation) treatment; not suitable for hematopoietic stem cell transplantation [HCT]) with a median OS of 9.
9 months (24.
7 vs 14.
8 months) and an RFS of 5.
3 months (10.
2 vs 4.
8 months)
.

Oral AZA is generally well tolerated and does not reduce the good health-related quality of life in these patients
.

Based on these results, oral AZA was recently approved in the United States, Canada, and the European Union for the treatment of adult patients with AML in first remission after IC (unable to complete IC, such as HCT)
.

The presence of measurable residual disease (MRD) in AML patients in remission after IC has been consistently shown to predict relapse and is a poor prognostic marker that may help guide treatment decisions
.

Therefore, the duration of MRD negativity and the transition of post-IC MRD+ patients to MRD- status may be important features of an effective AML maintenance strategy, for which prospective data are lacking
.

Given the prognostic impact of MRD on AML, we assessed MRD by multiparameter flow cytometry (MFC) in samples collected serially during screening and treatment in the QUAZAR AML-001 trial, based on MRD status at screening, MRD+ to MRD- transition, and persistence of MRD negativity during treatment were further evaluated for survival endpoints
.

Methods Eligible patients were ≥55 years of age, had intermediate- or low-risk cytogenetic risk at diagnosis, and achieved first complete remission (CR) or incomplete hematologic recovery after IC (induction therapy with or without consolidation) CR (CRi) and are not suitable to receive HCT
.

Within 4 months (± 7 days) of achieving CR/CRi, patients were randomized 1:1 to receive oral AZA 300 mg or placebo on Days 1 to 14 of each cycle (28-day cycle ) administered once a day
.

MRD (≥0.
1% leukemia cells in bone marrow) was assessed by MFC in serial samples collected at baseline and on day 1 of every 3 cycles
.

The primary and key secondary endpoints were OS and RFS, respectively
.

All MRD analyses were exploratory endpoints
.

Results >>>>Patient Baseline Characteristics The MRD-evaluable cohort included 463/472 (98.
1%) randomised patients (oral AZA group, n=236; placebo group, n=227) whose bone marrow samples were available for MFC assessment
.

At baseline, 44% (n=103) of the oral AZA group and 51% (n=116) of the evaluable patients in the placebo group were MRD+
.

Baseline characteristics of MRD+ and MRD- patients were broadly similar (see Table 1 for details)
.

Table 1 >>>> Baseline MRD status is a prognostic indicator of survival In each treatment group, baseline MRD+ patients had significantly shorter median OS than MRD- patients (Figure 1), confirming MFC-defined ≥0.
1% MRD+ threshold Adverse prognostic effect; HRs for OS between MRD+ and MRD- subgroups were 1.
7 (95% CI, 1.
3, 2.
4) and 1.
9 (95% CI, 1.
5, 2.
7) for oral AZA and placebo, respectively
.

Likewise, patients who were MRD+ at baseline had lower RFS in both the oral AZA (HR, 1.
8 [95% CI, 1.
4, 2.
5]) and placebo (2.
2 [1.
7, 3.
0]) groups
.

Multivariate analysis confirmed that, when controlling for treatment groups, baseline MRD status (MRD+ vs.
MRD-) was associated with OS (HR, 1.
85 [95% CI, 1.
49, 2.
31]) and RFS (HR, 2.
04 [1.
65, 2.
53]) There was a significant independent association (oral AZA or placebo) (Table 2)
.

Figure 1 Table 2 >>>> Oral AZA improves survival regardless of baseline MRD status Regardless of post-IC MRD status, oral AZA improves OS from randomization compared to placebo, oral AZA and placebo Median OS was 14.
6 months vs 10.
4 months for MRD+ patients at baseline (HR, 0.
69 [95% CI, 0.
51 to 0.
93]), and 30.
1 vs 24.
3 months for MRD- patients at baseline ( HR, 0.
81 [0.
59, 1.
12]) (Fig.
1A)
.

Median RFS was also prolonged with oral AZA compared with placebo in two MRD subgroups: 7.
1 and 2.
7 months in MRD+ patients at baseline (HR, 0.
58 [95% CI, 0.
43, 0.
78]), MRD-patients were 13.
4 and 7.
8 months (0.
71 [0.
52, 0.
98]), respectively (Fig.
1B)
.

Multivariate analysis confirmed that oral AZA was significantly associated with OS (HR, 0.
74 [95% CI, 0.
59, 0.
92]) and RFS (0.
63 [0.
51, 0.
78]) compared with placebo when controlling for baseline MRD status independent benefit (Table 2)
.

>>>>Oral AZA treatment increases MRD-negative conversion rates For MRD+ patients at baseline, oral AZA (37%) was almost twice as likely to convert to MRD- status on-study as placebo (19%) (OR, 2.
50 [ 95% CI, 1.
35, 4.
61]) (Table 3)
.

For MRD-negative patients, the median time from randomization to first observed MRD-assessment was 61 days (oral AZA group) and 59.
5 days (placebo group)
.

However, some patients treated with oral AZA achieved MRD negativity even after long-term MRD positivity: 9/38 (24%) of MRD-negative patients in the oral AZA arm had MRD-persistence for more than 6 months after randomization (most 13.
1 months longer) and only 1 patient in the placebo group (5%; 8.
1 months) (Table 3)
.

Table 3 >>>> Oral AZA prolongs the duration of MRD negativity In all patients, the median overall duration of MRD negativity increased by 6 months with oral AZA compared with placebo (11.
0 months vs 5.
0 months, respectively ) (Figure 2)
.

For patients who were MRD- at baseline (median time 26.
4 and 10.
4 months, respectively) and MRD+ at baseline who achieved MRD- status on study (median time not reached and 12.
9 months, respectively] ), oral AZA prolonged the duration of MRD negativity compared with placebo
.

Figure 2.
Conclusions of the study compared with placebo, demethylating drug oral AZA significantly prolonged OS and RFS in AML patients ≥55 years old (not suitable for hematopoietic stem cell transplantation; first remission after intensive chemotherapy)
.

Although the presence or absence of MRD is a strong prognostic indicator of OS and RFS, oral AZA maintenance therapy increased survival benefit in patients with AML independent of patients' MRD status at baseline
.

Reference source: Gail J.
Roboz, Farhad Ravandi, Andrew H.
Wei, et al.
Oral azacitidine prolongs survival of patients with AML in remission independently of measurable residual disease status.
Blood (2022) 139 (14): 2145–2155.
https ://doi.
org/10.
1182/blood.
2021013404.
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