What is the role of oral azacytidine in the treatment of Acute Myeloid Leukemia (AML)?

Oral Azacitidine in Acute Myeloid Leukemia

Oral azacitidine (CC-486) is specifically indicated as maintenance therapy for AML patients ≥55 years who achieve complete remission (CR/CRi) after intensive chemotherapy but are not candidates for allogeneic hematopoietic stem cell transplantation (HSCT). 1

Primary Role: Post-Remission Maintenance Therapy

Oral azacitidine demonstrated improved overall survival in the QUAZAR AML-001 trial, showing a median OS advantage of 9.9 months versus placebo in patients who achieved first remission after intensive induction chemotherapy. 2 This represents the first maintenance therapy to show meaningful OS benefit in this setting, addressing a long-standing unmet need. 2

The drug should be administered for 14 days of each 28-day cycle, a dosing schedule not feasible with injectable formulations. 2 This extended exposure allows for sustained hypomethylating activity and convenient outpatient administration. 3

Key Eligibility Criteria

• Age ≥55 years 1
• Achievement of CR or CRi following intensive chemotherapy 1, 2
• Not eligible for immediate allogeneic HSCT 4
• Sufficient performance status to tolerate continued therapy 1

Critical Contraindications and Limitations

Oral azacitidine must NOT replace allogeneic HSCT in transplant-eligible candidates. 4 The drug is specifically designed for patients who cannot proceed to transplant due to age, comorbidities, or lack of suitable donor. 4

Maintenance with hypomethylating agents after allogeneic HSCT cannot be recommended outside clinical trials (Level V, Grade D evidence). 1, 4 While phase I/II data showed a 21% one-year relapse rate post-HSCT, this approach may increase toxicity without therapeutic benefit in patients curable with HSCT alone. 1, 4

Alternative First-Line Role (Not Maintenance)

Injectable azacitidine (with or without venetoclax) serves as first-choice therapy for newly diagnosed AML patients ineligible for intensive chemotherapy. 1 This represents a distinct indication from the maintenance setting and should not be confused with oral azacitidine's post-remission role. 4

For unfit patients, injectable azacitidine at 75 mg/m² daily for 7 days every 28 days is recommended. 1, 5 Treatment continues until disease progression, relapse, or intolerance, but may be terminated after at least 4 consecutive cycles without response or clinical benefit. 1

Comparative Real-World Outcomes

Recent real-world data comparing intensive chemotherapy followed by oral azacitidine maintenance (IC→Oral-AZA) versus frontline venetoclax plus injectable azacitidine (VEN-AZA) showed:

• Median relapse-free survival: 14.9 months (IC→Oral-AZA) versus 8.1 months (VEN-AZA), p=0.027 6
• Median overall survival: 18.7 months versus 15.2 months, p=0.034 6

This suggests that for patients who can tolerate intensive chemotherapy and achieve remission, the IC→Oral-AZA strategy provides superior outcomes compared to upfront lower-intensity therapy. 6

Pharmacokinetic Advantages

Oral azacitidine achieves approximately 17.4% bioavailability compared to subcutaneous administration. 7 The extended 14-day dosing schedule provides sustained drug exposure and hypomethylating activity not achievable with 7-day injectable regimens. 3, 2 This eliminates injection-site reactions and facilitates long-term adherence. 3

Common Pitfalls to Avoid

• Do not delay or replace allogeneic HSCT with oral azacitidine in transplant-eligible patients 4
• Do not use oral azacitidine as first-line therapy in treatment-naive patients—this is not an approved indication 4
• Do not routinely prescribe HMA maintenance post-HSCT outside clinical trials despite encouraging phase I/II data 1, 4
• Do not confuse the maintenance indication (oral formulation, post-remission) with first-line therapy in unfit patients (injectable formulation) 4

Monitoring and Duration

Treatment should continue until disease progression, relapse, or unacceptable toxicity. 5 Regular bone marrow evaluations and MRD monitoring help guide treatment duration and detect early relapse. 8 The median treatment duration in pivotal trials was 9 cycles, though some patients continued for up to 39 cycles. 5

Future Directions

Ongoing clinical trials are evaluating oral azacitidine in combination with other oral agents including venetoclax, IDH inhibitors, and FLT3 inhibitors, potentially enabling all-oral combination regimens. 9, 2 Pre-emptive treatment when mixed chimerism or MRD appears post-HSCT may be more rational than prophylactic maintenance. 1, 4