What are the recommended dosing schedule, monitoring, and toxicity management for azacitidine in patients aged 65 years or older with myelodysplastic syndromes or newly diagnosed acute myeloid leukemia who are not candidates for intensive chemotherapy?

Azacitidine Dosing, Monitoring, and Toxicity Management in Older Adults with MDS/AML

Recommended Dosing Schedule

For patients aged ≥65 years with MDS or newly diagnosed AML who are not candidates for intensive chemotherapy, azacitidine should be administered at 75 mg/m² subcutaneously daily for 7 consecutive days every 28 days, with a minimum of 6 cycles required before assessing treatment efficacy. 1, 2, 3

Standard Regimen Details

• Route of administration: Subcutaneous injection is the standard and FDA-approved route 2, 3
• Cycle frequency: Repeat every 28 days (4 weeks) 1, 3
• Minimum treatment duration: At least 6 cycles are mandatory before evaluating efficacy, as most patients only respond after several courses 2, 4
• Alternative schedule: The "5-2-2" regimen (5 days on, 2 days off, 2 days on) is acceptable for practical reasons, though it has not demonstrated survival advantage over the 7-day regimen in higher-risk MDS 2

Treatment Duration and Continuation

• Continue treatment as long as the patient continues to benefit 3
• Do not discontinue before 6 cycles unless there is clear disease progression or unacceptable toxicity, as delayed responses are common 2
• Hematological improvement according to IWG 2006 criteria should be considered indicative of response and is associated with prolongation of survival 2

Clinical Efficacy Evidence

MDS Population

In higher-risk MDS patients with 20-30% bone marrow blasts (meeting 2008 WHO AML criteria), azacitidine demonstrated a median overall survival of 24.5 months versus 16 months with conventional care (HR 0.47, P=0.005), with 2-year survival rates of 50% versus 16%. 1

AML Population (>30% Blasts)

In older adults aged ≥65 years with newly diagnosed AML (>30% blasts), azacitidine increased median overall survival from 6.5 months to 10.4 months compared with conventional care regimens (HR 0.85), with 1-year survival rates of 46.5% versus 34.2%. 1

Monitoring Requirements

Hematologic Monitoring

• Monitor complete blood counts (CBC) frequently throughout treatment 3
• Assess for anemia, neutropenia, and thrombocytopenia, which are the most common adverse reactions 3
• Most common grade 3/4 adverse events include febrile neutropenia (19.5%), thrombocytopenia, and neutropenia 1

Organ Function Monitoring

• Monitor patients with renal impairment closely for toxicity, as azacitidine and its metabolites are primarily excreted by the kidneys 3
• Assess baseline risk for tumor lysis syndrome and monitor appropriately, as azacitidine can cause fatal or serious tumor lysis syndrome, including in MDS patients 3
• Patients with severe preexisting hepatic impairment are at higher risk for hepatotoxicity 3

Response Assessment Timeline

• Evaluate hematologic response after a minimum of 6 cycles 2, 4
• Peak plasma concentrations are achieved within 30 minutes of subcutaneous administration 4
• Maximum DNA methylation effect occurs at day 15 of each cycle 5

Toxicity Management

Myelosuppression (Most Common Toxicity)

The most common adverse reactions (>30%) in adult MDS patients receiving subcutaneous azacitidine are: nausea, anemia, thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, injection site erythema, constipation, neutropenia, and ecchymosis. 3

• Grade 3/4 thrombocytopenia: 27% 1
• Grade 3/4 neutropenia: 24% 1
• Grade 3/4 febrile neutropenia: 21% 1
• Grade 3/4 anemia: 21% 1

Dose Modifications

• Delay or reduce dosage as appropriate for hematologic toxicity and renal toxicity 3
• The 30-day mortality rate with azacitidine is approximately 9% 1

Supportive Care Measures

• Premedicate for nausea and vomiting 3
• Grade 3/4 nausea occurs in 7.3% of patients 5
• Grade 3/4 vomiting occurs in 7.3% of patients 5
• Grade 3/4 diarrhea occurs in 12.2% of patients (dose-limiting toxicity at 600 mg oral dose) 5

Injection Site Reactions

• Injection site erythema is common with subcutaneous administration 3
• Rotate injection sites to minimize local reactions 4

Patient Selection Criteria

Appropriate Candidates

• Higher-risk MDS patients (IPSS-R intermediate, high, or very high risk) without major comorbidities 2, 6
• Patients >70 years or younger patients without a donor for allogeneic stem cell transplantation 2
• Older adults aged ≥65 years with newly diagnosed AML (>30% blasts) who are not candidates for intensive chemotherapy 1, 3

Contraindications

• Advanced malignant hepatic tumors 3
• Hypersensitivity to azacitidine or mannitol 3

Special Clinical Scenarios

Bridge to Transplant

• 2-6 cycles of azacitidine are commonly used before hematopoietic stem cell transplantation to reduce bone marrow blasts or for logistical reasons 2
• Fit patients ≤70 years with a donor should proceed to allogeneic stem cell transplantation, preceded or not by azacitidine 2

Combination Therapy

Venetoclax combined with azacitidine (75 mg/m² daily for 7 days of each 28-day cycle) is FDA-approved for newly diagnosed AML in adults aged ≥75 years or those with comorbidities precluding intensive chemotherapy, with CR/CRi rates of 67% and median overall survival of 17.5 months. 1

• The venetoclax dose is 400 mg daily when combined with azacitidine 1
• This combination showed superior efficacy compared to azacitidine monotherapy 1

Critical Pitfalls to Avoid

Treatment Duration Errors

• Do not discontinue treatment before 6 cycles unless there is clear disease progression or unacceptable toxicity, as delayed responses are common 2
• Responses may not be apparent until after several courses of therapy 2, 4

Product Substitution Error

• Do not substitute azacitidine for injection for oral azacitidine - the indications and dosing regimens differ 3
• Oral azacitidine has different bioavailability (6.3-20%) and is used for maintenance therapy in different clinical contexts 5

Inappropriate Use in Low-Risk MDS

• Do not use azacitidine in low-risk MDS simply because a patient has transfusion-dependent anemia 6
• First optimize erythropoiesis-stimulating agent (ESA) therapy and consider lenalidomide if del(5q) is present 6
• Azacitidine has demonstrated survival benefit only in higher-risk MDS (IPSS intermediate-2 or high risk) 6, 7

Post-Transplant Maintenance

• Do not use azacitidine maintenance after allogeneic HSCT outside clinical trials - this is Level V, Grade D evidence 8
• Azacitidine maintenance should not replace allogeneic HSCT in transplant-eligible candidates 8

Inadequate Monitoring

• Do not fail to monitor for tumor lysis syndrome, particularly in patients with high blast counts 3
• Do not neglect renal function monitoring in patients with baseline renal impairment 3

Pregnancy and Reproductive Considerations

• Azacitidine can cause fetal harm 3
• Advise female patients and male patients with female partners of reproductive potential to use effective contraception 3
• Advise patients not to breastfeed during treatment 3