Oral Azacitidine Prolongs Survival of AML Patients Regardless of Measurable Residual Disease
Intensive chemotherapy for patients newly diagnosed with acute myeloid leukemia (AML) often achieves high remission rates, although these remissions are often only temporary. Consolidation therapy with azacitidine (AZA) extends post-remission survival and disease-free intervals.
Azacitidine in AML Maintenance Therapy
Azacitidine is a hypomethylating agent that allows for extended dosing regimens and prolonged exposure during each treatment cycle. AZA affects mechanisms such as cytotoxicity against abnormal hematopoietic cells in the bone marrow and DNA hypomethylation influencing cell cycle regulatory genes.
Measurable Residual Disease
The presence of measurable residual disease (MRD) in AML patients in remission is a predictor of early relapse (RFS) and worse overall survival (OS). Post-remission maintenance therapy prolongs MRD-negative status or converts patients from MRD+ to MRD− state, thus potentially delaying or preventing relapse and extending OS.
QUAZAR Study Methodology and Parameters
The primary endpoints of the placebo-controlled, randomized phase III clinical study QUAZAR AML-001 were OS and RFS. A total of 472 AML patients aged ≥ 55 years, who achieved first disease remission with intensive chemotherapy and were ineligible for hematopoietic stem cell transplantation (HSCT), were enrolled. Stratified randomization by age, prior history, and genotoxicity was performed within 4 months of achieving remission in a 1:1 ratio to receive 300 mg AZA orally once daily (n = 236) or placebo (n = 227) for 14 days in each 28-day cycle.
MRD status (≥ 0.1% leukemic cells in bone marrow) was assessed using multiparametric flow cytometry in bone marrow aspirate samples taken at study onset, then on day 1 of every third cycle up to the 24th cycle, and subsequently every six cycles. Before starting maintenance therapy, MRD positivity was observed in 44% (n = 103) of patients in the AZA arm and 51% (n = 116) in the placebo arm.
Key Findings
Baseline MRD status strongly correlated with OS and RFS. Multivariable analyses showed that orally administered AZA significantly improved OS (24.7 vs. 14.8 months; p < 0.001) and RFS (10.2 vs. 4.8 months; p < 0.001) compared to the placebo arm, independent of MRD status post-induction therapy.
AZA treatment also extended the duration of MRD negativity by 6 months compared to placebo and led to a higher conversion rate of MRD+ patients to MRD− during maintenance therapy (37% vs. 19% in the placebo arm). In the azacitidine arm, 24% of patients achieved a prolonged MRD-negative period by > 6 months compared to placebo (11.0 vs. 5.0 months; p < 0.001) from the start of maintenance therapy.
Conclusion
The QUAZAR AML-001 study is the largest randomized clinical trial with azacitidine involving prospective centralized assessment of MRD status in older AML patients in first remission. The presence of measurable residual disease was a strong prognostic marker for OS and RFS; however, AZA provided benefit regardless of baseline MRD status. The results of this study were decisive for the registration of azacitidine in the EU, Canada, and the USA.
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Sources:
1. Roboz G., Ravandi F., Wei A. et al. Oral azacitidine prolongs survival of patients with AML in remission independently of measurable residual disease status. Blood 2022 Apr 7; 139 (14): 2145−2155, doi: 10.1182/blood.2021013404.
2. Čerňan M., Szotkowski T. Current trends in the treatment of acute myeloid leukemia – from induction chemotherapy "7+3" to targeted therapy. Clinical Pharmacology and Pharmacy 2021; 35 (3): 61−69.
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2011-CZ-2300020
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