Further analysis from the QUAZAR AML-001 trial: MRD status and subsequent therapies

The phase III QUAZAR AML-001 trial (NCT01757535), which investigated oral azacitidine in elderly patients with acute myeloid leukemia (AML) in first complete remission, has been comprehensively reported on by the AML Hub. Briefly, oral azacitidine improved overall survival (OS) and relapse-free survival (RFS) in older patients when compared with the placebo.^1,2

This survival benefit was independent of NPM1 and FLT3-ITD/TKD mutational status. We previously reported the long-term survival data, which were also presented at the Society of Hematologic Oncology (SOHO) 2022 Annual Meeting by Ravandi,³ with estimated 3-year OS rates of 34.9% for patients receiving oral azacitidine and 27.9% for patients who received the placebo.

Below, we summarize two recent updates from this trail; one article published by Gail Roboz et al.¹ in Blood investigating the impact of measurable residual disease (MRD) status on survival outcomes in patients who received oral azacitidine, and a poster presented by Ravandi² at the 64th American Society of Hematology (ASH) Annual Meeting and Exposition assessing the survival outcomes for patients who received subsequent therapy following the QUAZAR AML-001 trial.

Impact of MRD status on survival outcomes with oral azacitidine¹

Methods

An overview of the study design from the QUAZAR AML-001 has been previously reported by the AML Hub. With regards to MRD assessment specifically:

• Patient MRD status was assessed by flow cytometry on Day 1 (+/− 7 days) of every 3 cycles up to Cycle 24, and then every 6 cycles.
• Upon two consecutive MRD assessments where the MRD status changed, MRD status was considered converted.
• The duration of MRD negativity was calculated as the time between randomization or the first conversion to MRD negative (MRD−) until conversion to MRD positive (MRD+) or treatment discontinuation.

Results

Of the 472 patients included in the QUAZAR AML-001 trial, 98.1% were evaluable for MRD assessments. At baseline, 44% and 51% of patients were MRD+ in the oral azacitidine and placebo arms, respectively (Table 1).

Table 1. Baseline MRD status and MRD positivity*

MRD, measurable residual disease. *Adapted from Roboz, et al.1
MRD status, %	All patients (N = 463)	Oral azacitidine (n = 236)	Placebo (n = 227)
MRD− (<0.1%)	53	56	49
MRD+ (≥0.1%)	47	44	51
Degree of MRD positivity
0.1–0.5%	29	27	30
≥0.5–1.0%	8	7	9
>1.0%	11	10	12

Survival benefit with oral azacitidine was independent of MRD status

The median OS and RFS were worse in patients who were MRD+ compared with patients who were MRD− across both treatment arms.

• Oral azacitidine improved OS vs placebo in the MRD+ group (14.6 vs 10.4 months) and in the MRD− group (30.1 vs 24.3 months).
• Similarly, RFS was longer in patients who received oral azacitidine vs placebo, in both the MRD+ (7.1 vs 2.7 months) and MRD− (13.4 vs 7.8 months) groups.
• This benefit was confirmed by multivariable analysis (Table 2).

Table 2. Multivariate analysis of OS and RFS*

CI, confidence interval; HR, hazard ratio; MRD, measurable residual disease; OS, overall survival; RFS, relapse-free survival. *Adapted from Roboz, et al.1
Parameter	HR (95% CI)	p value
OS
Baseline MRD status                (MRD+ vs MRD−)	1.85 (1.49–2.31)	<0.0001
Treatment arm                (Oral azacitidine vs placebo)	0.74 (0.59–0.92)	0.0067
RFS
Baseline MRD status                (MRD+ vs MRD−)	2.04 (1.65–2.53)	<0.0001
Treatment arm                (Oral azacitidine vs placebo)	0.63 (0.51–0.78)	<0.0001

Oral azacitidine treatment was associated with increased MRD responses and duration of MRD negativity

Among patients who were MRD+ at baseline, the conversion rate to MRD− was 37% in the oral azacitidine arm, compared with 19% in the placebo arm (odds ratio, 2.50; 95% confidence interval, 1.35–4.61). In the oral azacitidine arm, 24% of responders were MRD− >6 months after randomization (up to 13.1 months), compared with 5% of responders in the placebo arm.

The duration of MRD negativity was 11.0 months in the oral azacitidine arm and 5.0 months in the placebo arm. When compared with the placebo arm, oral azacitidine prolonged the duration of MRD negativity in patients who were MRD− at baseline (median, 26.4 months vs 10.4 months) and in patients who achieved MRD negativity during the study (median, not reached vs 12.9 months).

Multivariate analyses revealed:

• A higher number of pre-study consolidation cycles was associated with MRD conversion from MRD+ to MRD− in the placebo arm (0 vs 2–3; p = 0.0049) but not in the oral azacitidine arm (p = 0.45).
• Poor-risk cytogenetic features were negatively associated with MRD conversion from MRD+ to MRD− in the placebo arm (p = 0.035); however, poor-risk cytogenetic features had no impact on MRD conversion in the oral azacitidine arm.
• Presence of an NPM1 mutation was associated with MRD conversion in the oral azacitidine arm (p = 0.0029) but not in the placebo arm (p = 0.20).

The impact of subsequent treatment on the survival benefit of oral azacitidine²

Methods

Post-discontinuation of the study drug, patients were monitored for OS even if they received subsequent treatment.

Post hoc analyses were performed to assess survival outcomes in patients in QUAZAR AML-001 who relapsed and received subsequent treatment for AML.

Results

In the oral azacitidine arm, 10% of patients received a hematopoietic stem cell transplant, compared with 18% in the placebo arm. A breakdown of subsequent therapies is shown in Table 3.

Table 3. First subsequent therapy received after discontinuation of study drug*

FLAG-IDA, fludarabine, cytarabine, idarubicin, and granulocyte colony-stimulating factor; HIDAC, high-dose cytarabine; HMA, hypomethylating agents; LDAC, low-dose cytarabine; MEC, mitoxantrone, etoposide, and cytarabine. *Adapted from Ravandi.2
Subsequent therapy, %	Total	Oral azacitidine	Placebo
Intensive chemotherapy	44.3	43.1	45.3
FLAG-IDA and similar regimens	21.7	19.0	23.8
MEC and similar regimens	12.6	16.1	9.9
HIDAC	3.6	2.9	4.1
Other intensive chemotherapies	6.5	5.1	7.6
Lower-intensity therapy	47.6	49.6	45.9
HMA	28.5	24.8	31.4
LDAC	8.4	13.9	4.1
Other lower-intensity therapies	10.7	10.9	10.5
Not classified	1.3	1.5	1.2
Best supportive care	6.1	5.8	6.4

Survival outcomes

The median follow-up time was 51.7 months. In patients who received subsequent AML-directed therapy, azacitidine was associated with longer OS from time of randomization compared with the placebo arm (median OS, 17.9 vs 12.5 months). The median OS from time of first subsequent therapy in the azacitidine arm was similar to the placebo arm (median OS, 5.3 vs 5.8 months).

Considering the type of first subsequent treatment received:

• In patients who went on to receive intensive chemotherapy, the median OS was comparable between patients who had been treated with oral azacitidine (4.9 months) and placebo (7.3 months).
• In patients who went on to receive non-hypomethylating agents lower-intensity regimens, the median OS in patients receiving oral azacitidine (3.8 months) was also similar to placebo (4.0 months).
• In patients who received injectable hypomethylating agents, the median OS was longer in patients who received oral azacitidine (8.2 months) than placebo (4.9 months).

Conclusion

The QUAZAR AML-001 trial showed the survival benefits of oral azacitidine compared with placebo in older patients who were in complete remission. These further analyses consolidate the initial results, demonstrating that the survival benefit provided by oral azacitidine is independent of MRD status. In patients who went on to receive subsequent therapy, the survival benefits of oral azacitidine remain.

Patients treated with oral azacitidine were also found to be more likely to achieve MRD− status and sustain MRD negativity for longer. The survival of patients who received further AML-directed therapy was not affected by previous exposure to oral azacitidine, indicating that oral azacitidine maintenance therapy may not negatively impact the clinical benefit of subsequent therapies should patients relapse.