In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms of action, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

On September 1, 2020, azacitidine tabletswere approved for continued treatment of patients with acute myeloid leukemia (who achieved first complete remission or complete remission with incomplete blood cell count recovery following intensive induction chemotherapy and are not able to complete intensive curative therapy.^1,2

Azacitidine tablets should not be substituted for intravenous (IV) or subcutaneous (SC) azacitidine. The indications and dosing regimen for azacitidine tablets differ from those of IV and SC azacitidine.

Supporting Efficacy Data

Approval was based on findings in the phase III, double-blind QUAZAR trial (ClinicalTrials.gov identifier NCT01757535).² In the trial, 472 patients who achieved complete remission or complete remission with incomplete blood cell count recovery with intensive induction chemotherapy with or without receiving subsequent consolidation therapy were randomly assigned to receive azacitidine tablets at 300 mg (n = 238) or placebo (n = 234) on days 1 to 14 of each 28-day cycle. The main efficacy outcome was overall survival.

For the azacitidine vs placebo groups, median patient age was 68.0 vs 68.0 years (72% vs 71% aged ≥ 65 years), 50% vs 54% were male, and 91% vs 84% were White. Eastern Cooperative Oncology Group performance status was 0 or 1 in 91% vs 93%, 85% vs 87% had intermediate and 15% vs 13% had poor cytogenetic risk, and 89% vs 92% had primary acute myeloid leukemia. Response to induction was complete remission in 79% vs 84% and complete remission with incomplete blood cell count recovery in 21% vs 16%, and cycles of consolidation following induction were none in 22% vs 18%, one in 46% vs 44%, two in 29% vs 33%, and three in 3% vs 6%.

Median overall survival was 24.7 months (95% confidence interval [CI] = 8.7–30.5 months) in the azacitidine group vs 14.8 months (95% CI = 11.7–17.6 months) in the placebo group (hazard ratio = 0.69, 95% CI = 0.55–0.86; P = .0009). A subgroup analysis showed consistency in the overall survival benefit with azacitidine for patients with both complete remission and complete remission with incomplete blood cell count recovery.

How It Works

Azacitidine is a pyrimidine nucleoside analog of cytidine that inhibits DNA/RNA methyltransferases. Azacitidine is incorporated into DNA and RNA following cellular uptake and enzymatic biotransformation to nucleotide triphosphates. Incorporation of azacitidine into the DNA of cancer cells in vitro, including acute myeloid leukemia cells, inhibited DNA methyltransferases, reduced DNA methylation, and altered gene expression, including reexpression of genes regulating tumor suppression and cell differentiation. Incorporation of azacitidine into the RNA of cancer cells, including leukemic cells, inhibited RNA methyltransferases, reduced RNA methylation, decreased RNA stability, and decreased protein synthesis. Antileukemic activity of azacitidine was demonstrated by reduction of cell viability and induction of apoptosis in acute myeloid leukemia cell lines in vitro. Azacitidine decreased tumor burden and increased survival in leukemic tumor models in vivo.

How It Is Used

Azacitidine tablets should not be substituted for IV or SC azacitidine. Treatment of patients using IV or SC azacitidine at the recommended dosage of azacitidine tablets may result in a fatal adverse reaction. Treatment of patients using azacitidine tablets at the doses recommended for IV or SC azacitidine may not be effective.

Azacitidine is a hazardous drug. Applicable special handling and disposal procedures must be followed.

The recommended dosage of azacitidine in tablet form is 300 mg, once daily, on days 1 through 14 of 28-day cycles, with treatment continuing until disease progression or unacceptable toxicity. An antiemetic should be administered 30 minutes prior to each dose for the first two cycles; antiemetic prophylaxis may be omitted after two cycles if there has been no nausea and vomiting. Azacitidine tablets should not be administered if the absolute neutrophil count is < 0.5 Gi/L on day 1 of a cycle; the start of the cycle should be delayed until the absolute neutrophil count is at least 0.5 Gi/L.

Due to risk of myelosuppression, complete blood cell counts should be monitored every other week for the first two cycles and prior to the start of each cycle thereafter. Monitoring should be increased to every other week for two cycles after any dose reduction for myelosuppression.

Prescribing information provides detailed instruction for dosage modifications, including dose reduction and interruption and discontinuation of treatment for adverse reactions, including myelosuppression, gastrointestinal toxicity, and other grade 3 or 4 adverse reactions.

Safety Profile

Among patients in the QUAZAR trial receiving azacitidine, 71% were exposed for at least 6 months and 49% for at least 1 year. The most common adverse events of any grade (≥ 20%) among patients receiving azacitidine tablets in the trial were nausea (65% vs 24% in placebo group), vomiting (60% vs 10%), diarrhea (50% vs 21%), fatigue/asthenia (44% vs 25%), constipation (39% vs 24%), pneumonia (27% vs 17%), and abdominal pain (22% vs 13%). The most common grade 3 or 4 adverse events included febrile neutropenia (11% vs 8%), pneumonia (9% vs 5%), and diarrhea (5% vs 1%). Laboratory abnormalities that worsened from grade 0 to 2 at baseline to grade 3 or 4 postbaseline included neutropenia (49% vs 23%), thrombocytopenia (23% vs 10%), and anemia (4% vs 3%).

Serious adverse events occurred in 15% of patients who received azacitidine, the most common being pneumonia (8%) and febrile neutropenia (7%). Adverse events led to interruption of azacitidine in 35% of patients and led to dose reduction in 14%. Treatment was permanently discontinued due to adverse events in 8% of patients, and adverse events led to death in one patient due to sepsis.

Azacitidine tablets have warnings/precautions for risks of substitution with other azacitidine products, myelosuppression, and embryo-fetal toxicity. Azacitidine tablets are contraindicated in patients with known severe hypersensitivity to azacitidine or its components. Patient should be advised not to breastfeed while receiving azacitidine. 

REFERENCES

1. U.S. Food and Drug Administration: FDA approves Onureg (azacitidine tablets) for acute myeloid leukemia. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-onureg-azacitidine-tablets-acute-myeloid-leukemia. Accessed September 8, 2020.

2. U.S. Food and Drug Administration: Highlights of prescribing information for Onureg (azacitidine) tablets for oral use. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/214120s000lbl.pdf. Accessed September 8, 2020.