What is the recommended use and dosage of Azacytidine (Vidaza) for older adults with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML), particularly those with impaired renal or hepatic function, or a history of cardiovascular or pulmonary disease?

Azacitidine for Older Adults with MDS/AML

Azacitidine at 75 mg/m² subcutaneously for 7 consecutive days every 28 days is the recommended first-line treatment for older adults with higher-risk MDS (IPSS-R intermediate/high/very high) or AML with >30% bone marrow blasts who are ineligible for allogeneic stem cell transplantation, and this regimen has demonstrated superior overall survival compared to conventional care regimens. 1, 2

Patient Selection and Risk Stratification

Appropriate Candidates

• Higher-risk MDS patients (IPSS-R intermediate, high, or very high risk) without major comorbidities who are not immediately eligible for allogeneic transplantation should receive azacitidine 1, 3
• Older adults >70 years or younger patients without a transplant donor are suitable candidates for azacitidine therapy 1, 3
• AML patients ≥65 years with >30% bone marrow blasts who are ineligible for intensive chemotherapy or transplantation benefit from azacitidine 2, 4

Patients Who Should NOT Receive Azacitidine

• Lower-risk MDS patients (IPSS-R low or very low) should not receive azacitidine, as there is no survival benefit demonstrated in this population 3
• These patients have median survival of 5.3-8.8 years and should instead receive supportive care, erythropoiesis-stimulating agents, or lenalidomide for del(5q) 3

Standard Dosing Regimen

Primary Dosing Schedule

• 75 mg/m² subcutaneously daily for 7 consecutive days every 28 days is the FDA-approved and guideline-recommended regimen 1, 5, 2
• Subcutaneous injection is the standard route of administration 5, 2

Alternative Acceptable Regimen

• "5-2-2" regimen (5 days on, 2 days off, 2 days on) is considered acceptable and often easier to apply in clinical practice, though it has not demonstrated survival advantage over the 7-day regimen in higher-risk MDS 1, 5

Treatment Duration and Response Assessment

Minimum Treatment Duration

• At least 6 cycles are mandatory before evaluating treatment efficacy, as most patients only respond after several courses 1, 5
• The median number of cycles administered in pivotal trials was 9 cycles (range 1-39) 2

Response Criteria

• Complete remission (CR), partial remission (PR), or hematological improvement (HI) according to IWG 2006 criteria should be assessed 1, 5
• Achievement of HI is associated with prolongation of survival compared with supportive care 1, 5
• In pivotal trials, azacitidine demonstrated median overall survival of 24.5 months versus 15.0 months with conventional care (hazard ratio 0.58, p=0.0001) 2

Transfusion Independence

• 45% of transfusion-dependent patients at baseline became transfusion-independent on azacitidine treatment, with median duration of independence of 13.0 months 2

Special Populations and Dose Modifications

Renal Impairment

• The FDA label does not specify dose adjustments for renal impairment, though azacitidine is rapidly absorbed and metabolized 2, 6
• Clinical judgment should guide dose reductions in patients with severe renal dysfunction experiencing excessive toxicity 2

Hepatic Impairment

• No specific dose adjustments are provided in the FDA label for hepatic impairment 2
• Monitor closely for toxicity and consider dose reductions if needed 2

Cardiovascular or Pulmonary Disease

• Azacitidine can be administered to patients with cardiovascular or pulmonary comorbidities, as these were not exclusion criteria in pivotal trials 2
• The most common grade 3-4 adverse events are hematologic (neutropenic fever 19.5%) and gastrointestinal (diarrhea 12.2%, nausea/vomiting 7.3%) rather than cardiopulmonary 2, 7

Frail or Very Elderly Patients

• Doses can be reduced in relatively frail patients, though specific reduction schedules are not standardized 1
• Very frail patients may be better served with supportive care alone 1

Special Clinical Scenarios

Bridge to Transplantation

• 2-6 cycles of azacitidine are commonly used before hematopoietic stem cell transplantation to reduce bone marrow blasts or for logistical reasons 1, 5
• Fit patients ≤70 years with a donor should proceed to allogeneic transplantation, preceded or not by azacitidine 1, 8
• Continue azacitidine as bridging therapy until transplant for patients who have achieved disease control 8

Treatment Failure

• Patients who fail to respond to azacitidine or are primary refractory have extremely poor survival (median <6 months) except for those eligible for transplantation 1
• Enrollment in clinical trials is recommended for treatment failures 1, 8

Critical Pitfalls to Avoid

Premature Discontinuation

• Do not discontinue treatment before 6 cycles unless there is clear disease progression or unacceptable toxicity, as delayed responses are common 1, 5
• This is the most common error in azacitidine management 5

Inappropriate Use in Low-Risk Disease

• Do not use azacitidine in low-risk MDS simply because a patient has transfusion-dependent anemia—first optimize erythropoiesis-stimulating agent therapy and consider lenalidomide if del(5q) is present 3
• Do not extrapolate higher-risk MDS survival data to justify azacitidine use in truly low-risk patients 3

Inadequate Supportive Care

• Anticipate and manage myelosuppression with growth factors, antibiotics, and transfusions as needed 2
• Monitor for neutropenic fever and pneumonia, the most common serious adverse events 2, 9