Effect of Azacitidine in the Treatment of Acute Myeloid Leukemia on Long-Term Patient Survival

Introduction

Despite all the progress in current treatment of acute myeloid leukemia, the chance of long-term survival of patients remains relatively low. The 5-year survival rate for patients aged 60–69 is around 22%, while for those older than 70 it is only 5%. Prognosis depends on many factors (age, comorbidities, cytogenetic abnormalities, gene mutations, and the success of chemotherapy). Hematopoietic stem cell transplantation is often used as a curative treatment for patients in remission, but for some patients, this therapy is not feasible. Therefore, other ways to extend remission and overall survival must be sought.

Study Methodology and Population

The randomized placebo-controlled Quazar AML-001 study included patients older than 55 years with low or intermediate cytogenetic risk profiles. Enrolled patients had to have achieved complete remission. Patients were divided into 2 groups in a 1:1 ratio. The first group received AZA at a dose of 300 mg orally once daily for 14 days repeatedly in 28-day cycles, while the second group received a placebo in the same regimen. The primary endpoint was overall survival (OS).

During the study, the presence of measurable residual disease (MRD) was monitored using flow cytometry, from cycles 3 to 24 every 3 cycles, and then every 6 cycles or as clinically needed. Remission was defined as MRD negativity (< 0.1%) in > 2 consecutive assessments.

Results

Out of the total of 472 patients (median age 68 years), 238 received azacitidine and 234 a placebo. 86% of the patients had intermediate cytogenetic risk, 29% had an NPM1 mutation, and 14% had an FLT3 mutation. At the start of the follow-up period, MRD was positive in 47% of the patients.

The median overall survival was 24.7 months in the AZA group compared to 14.8 months in the placebo group. The probability of 2-year survival was also higher in patients treated with AZA (50.6% vs. 37.1%). Long-term survival was further monitored after the main study phase ended. In this follow-up phase, 39 patients continued taking AZA while treatment was discontinued for placebo participants. 23% of patients in the AZA group were treated for > 3 years (≥ 36 cycles), and 14% received ≥ 60 cycles.

In March 2022, new results from the follow-up phase of the study (median follow-up 55.5 months) were published, with 25 patients still taking AZA. The median overall survival in both groups remained unchanged, with a higher probability of 3-year survival in the AZA group (37.4% vs. 27.9%), as well as 5-year survival (26.5% vs. 20.1%). 

To predict based on clinical and biological variability, 2 additional groups were newly created: long-term survivors (LTS) whose survival was over 3 years, and a non-LTS group with shorter survival. The LTS cohort included 140 patients, of which 83 belonged to the AZA group and 57 to the placebo group. Patients in the LTS cohort had a higher occurrence of intermediate cytogenetic risk variants (45% vs. 22%), and MRD positivity was lower in this group (34% vs. 53%).

Discussion and Conclusion

Results from the follow-up phase of the study revealed that the presence of intermediate cytogenetic risk variants correlates with long-term patient survival. Conversely, no relationship was found between the administration of consolidation therapy and survival time in both cohorts. Initial MRD negativity increased the chance of long-term survival in the placebo group, but not in the AZA group. 37% of patients with initially positive MRD responded to AZA treatment. MRD disappearance was linked to a significant extension in overall survival time in both cohorts. 

The Quazar AML-001 study demonstrated an increased probability of long-term survival in AML patients treated with azacitidine after achieving first remission. Favoring its use, a significant part of patients continued treatment even after the follow-up period without adverse effects or intolerance. AZA demonstrably reduces the occurrence of MRD positivity, one of the most important prognostic factors of AML. Therefore, it can be recommended for patients where hematopoietic stem cell transplantation is not possible for any reason. 

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Source: Wei A. H., Döhner H., Sayar H. et al. Long-term survival with oral azacitidine for patients with acute myeloid leukemia in first remission after chemotherapy: updated results from the randomized, placebo-controlled, phase 3 QUAZAR AML-001 trial. Am J Hematol 2023 Apr; 98 (4): E84−E87, doi: 10.1002/ajh.26847.

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2011-CZ-2300019