What is the role and indications of maintenance azacitidine (hypomethylating agent) in acute myeloid leukemia (AML)?

Maintenance Azacitidine in Acute Myeloid Leukemia

Oral azacitidine (CC-486) is indicated for maintenance therapy in AML patients ≥55 years who achieve complete remission after intensive chemotherapy but are not candidates for allogeneic stem cell transplantation, as it significantly improves both overall survival and relapse-free survival. 1

Primary Indication: Post-Intensive Chemotherapy Maintenance

For patients ≥55 years in first complete remission (CR or CRi) after intensive induction and consolidation chemotherapy who cannot proceed to allogeneic HSCT, oral azacitidine maintenance is the evidence-based standard. 1 The landmark QUAZAR AML-001 trial demonstrated:

• Median overall survival: 24.7 months vs 14.8 months with placebo (p<0.001) 1
• Median relapse-free survival: 10.2 months vs 4.8 months with placebo (p<0.001) 1
• Dosing: 300 mg orally once daily for 14 days per 28-day cycle 1

This represents the only non-targeted therapy approved by both FDA and EMA specifically for maintenance in this setting. 2

Important Distinction: Subcutaneous vs Oral Formulations

Subcutaneous azacitidine showed improved disease-free survival but NOT overall survival in older AML patients, making it a less compelling option than oral azacitidine. 3 The oral formulation (CC-486) is not bioequivalent to injectable azacitidine and demonstrated superior survival outcomes. 1

Contraindications and Limitations

Maintenance azacitidine should NOT replace allogeneic HSCT in transplant-eligible candidates. 3 The treatment is specifically for patients who:

• Are not immediate candidates for HSCT 2
• Have achieved CR or CRi after intensive chemotherapy 1
• Are ≥55 years of age 1

Post-Transplant Setting: Not Recommended

Maintenance with hypomethylating agents after allogeneic HSCT cannot be recommended outside clinical trials. 3 The ESMO guidelines explicitly state this as Level V, Grade D evidence. 3

The rationale against routine post-HSCT HMA maintenance includes:

• Unclear whether prophylactic HMA treatment prevents relapse 3
• May increase toxicity without therapeutic benefit in patients curable with HSCT alone 3
• Phase I/II data showed 21% 1-year relapse rate but lacks randomized controlled evidence 3

Pre-emptive treatment when mixed chimerism or MRD appears may be more rational than prophylactic maintenance post-HSCT. 3

Alternative First-Line Role: Unfit Patients

Azacitidine (with or without venetoclax) serves as first-choice therapy for newly diagnosed AML patients ineligible for intensive chemotherapy, not as maintenance in this population. 3 This is a distinct indication from maintenance therapy. 3

Toxicity Profile and Quality of Life

The most common adverse events with oral azacitidine maintenance are:

• Grade 1-2 gastrointestinal events (most frequent) 1
• Grade 3-4 neutropenia (41% vs 24% placebo) 1
• Grade 3-4 thrombocytopenia (22% vs 21% placebo) 1

Overall health-related quality of life is preserved during CC-486 treatment, making it tolerable for prolonged maintenance. 1

Emerging Data: Combination Strategies

Low-dose azacitidine (50 mg/m² for 5 days) plus venetoclax (400 mg for 7-14 days) shows promise as maintenance therapy following both intensive and low-intensity induction, with 2-year relapse-free survival of 65%. 4 However, this remains investigational and is not guideline-recommended. 4

Real-world data suggest intensive chemotherapy followed by oral azacitidine maintenance provides superior relapse-free survival (14.9 vs 8.1 months) and overall survival (18.7 vs 15.2 months) compared to frontline venetoclax-azacitidine in patients potentially eligible for either approach. 5

Duration and Monitoring

Continue oral azacitidine maintenance until disease progression or intolerance. 1 The QUAZAR trial design supports prolonged maintenance therapy. 1

Monitor for neutropenia and thrombocytopenia, which are the primary grade 3-4 hematologic toxicities requiring dose adjustments. 1

Common Pitfalls to Avoid

• Do not use subcutaneous azacitidine maintenance based solely on disease-free survival benefit when oral formulation shows overall survival advantage 3, 1
• Do not delay or replace allogeneic HSCT with azacitidine maintenance in transplant-eligible patients 3
• Do not routinely use HMA maintenance post-HSCT outside clinical trials despite phase I/II data 3
• Do not confuse first-line azacitidine therapy in unfit patients with maintenance therapy in fit patients achieving remission 3