Decitabine and Cedazuridine Dosage and Use in Myelodysplastic Syndromes and Leukemia
Oral decitabine and cedazuridine (DEC-C) is recommended as a substitution for intravenous decitabine in patients with IPSS Intermediate-1 and above myelodysplastic syndromes, with the standard dosage being one tablet (35 mg decitabine and 100 mg cedazuridine) taken orally once daily on Days 1 through 5 of each 28-day cycle. 1, 2
Indications
Decitabine and cedazuridine (INQOVI) is FDA-approved for:
- Adult patients with myelodysplastic syndromes (MDS), including:
- Previously treated and untreated
- De novo and secondary MDS
- French-American-British subtypes:
- Refractory anemia
- Refractory anemia with ringed sideroblasts
- Refractory anemia with excess blasts
- Chronic myelomonocytic leukemia (CMML)
- International Prognostic Scoring System (IPSS) groups:
- Intermediate-1
- Intermediate-2
- High-risk 2
Dosage and Administration
- Standard dosage: 1 tablet (35 mg decitabine and 100 mg cedazuridine) taken orally once daily on Days 1 through 5 of each 28-day cycle 2
- Administration: Take on an empty stomach 2
- Treatment duration: Continue for a minimum of 4 cycles to assess response, with continued treatment as maintenance therapy in patients who show clinical benefit 1
Clinical Evidence for Equivalence to IV Decitabine
The oral combination has been proven bioequivalent to IV decitabine in clinical trials:
- The ASCERTAIN phase 3 trial demonstrated that oral decitabine-cedazuridine produced 98.93% (90% CI 92.66-105.60) of the systemic exposure compared to IV decitabine, indicating pharmacokinetic equivalence 3
- Similar DNA demethylation activity was observed between the oral and IV formulations, with differences in mean LINE-1 demethylation ≤1% 4
Safety Profile
Common adverse reactions (≥20%) include:
- Fatigue, constipation, hemorrhage, myalgia, mucositis, arthralgia, nausea, dyspnea, diarrhea, rash, dizziness, febrile neutropenia, edema, headache, cough, decreased appetite, upper respiratory tract infection, pneumonia, and increased transaminases 2
Most common Grade 3-4 laboratory abnormalities (≥50%):
- Decreased leukocytes, decreased platelet count, decreased neutrophil count, and decreased hemoglobin 2, 3
Monitoring and Dose Modifications
- Obtain complete blood counts prior to initiation, prior to each cycle, and as clinically indicated 2
- For hematologic toxicity:
- If recovery from previous cycle requires more than 6 weeks, delay next cycle and consider dose reduction
- For non-hematologic toxicity, delay treatment for:
- Serum creatinine ≥2 mg/dL
- ALT or total bilirubin ≥2 times ULN
- Active or uncontrolled infection 5
Clinical Positioning in Treatment Algorithm
According to NCCN Guidelines:
- Oral decitabine and cedazuridine is recommended for patients with:
- Clinically significant cytopenias
- Clinically relevant thrombocytopenia or neutropenia
- IPSS Intermediate-1 and above 1
Advantages Over IV Decitabine
- Equivalent pharmacokinetic exposure and clinical efficacy compared to IV decitabine 3, 4
- Oral administration eliminates the need for IV access and infusion-related complications
- Potential for improved quality of life and reduced healthcare resource utilization
- Particularly valuable during the COVID-19 pandemic and for patients with limited access to infusion centers
Emerging Combination Therapies
Recent research shows promising results for combining oral decitabine-cedazuridine with venetoclax:
- In higher-risk MDS and CMML, this combination showed a 95% overall response rate in a phase 1/2 study 6
- In older or unfit AML patients, the combination demonstrated 64% overall response rate in newly diagnosed patients and 46% in relapsed/refractory disease 7
Important Considerations and Precautions
- Myelosuppression: Fatal and serious myelosuppression and infectious complications can occur 2
- Embryo-Fetal Toxicity: Can cause fetal harm; advise patients of reproductive potential to use effective contraception 2
- Drug Interactions: Avoid coadministration with drugs metabolized by cytidine deaminase 2
- Lactation: Advise patients not to breastfeed during treatment 2
The oral formulation represents a significant advancement in the treatment of MDS and related disorders, providing equivalent efficacy to IV decitabine with the convenience of oral administration, potentially improving patient quality of life while maintaining clinical outcomes.