What is the efficacy of Cedazuridine (Cedazuridine) and Decitabine versus Decitabine alone in the treatment of Myelodysplastic Syndromes (MDS)?

From the Guidelines

Cedazuridine/decitabine (ASTX727, Inqovi) is preferred over IV decitabine alone for myelodysplastic syndromes (MDS) treatment. This oral combination provides similar efficacy to IV decitabine but with the significant advantage of convenient at-home administration. The standard regimen is one tablet containing cedazuridine 100 mg and decitabine 35 mg taken once daily on days 1-5 of 28-day cycles. Cedazuridine works by inhibiting cytidine deaminase, an enzyme that rapidly degrades decitabine in the gastrointestinal tract and liver, thereby allowing oral decitabine to achieve similar blood levels as the IV formulation.

Key Points

• Clinical trials have demonstrated equivalent pharmacokinetics, DNA demethylation activity, and clinical responses between the oral combination and IV decitabine 1.
• Common side effects include myelosuppression (neutropenia, thrombocytopenia, anemia), fatigue, nausea, constipation, and diarrhea.
• Regular blood count monitoring is essential, and prophylactic antimicrobials may be needed during periods of neutropenia.
• Treatment typically continues until disease progression or unacceptable toxicity, with response assessment after 4-6 cycles.

Evidence Summary

The evidence from studies 1 suggests that cedazuridine/decitabine is a viable treatment option for MDS, with benefits including improved response rates and survival. However, the most recent and highest quality study 1 supports the use of cedazuridine/decitabine as a preferred treatment option due to its convenience and efficacy.

Clinical Considerations

When considering treatment options for MDS, it is essential to weigh the benefits and risks of each treatment, including the potential for improved response rates and survival, as well as the risk of adverse effects. The use of cedazuridine/decitabine should be individualized based on patient-specific factors, including disease severity, performance status, and comorbidities.

From the FDA Drug Label

INQOVI is a combination of decitabine, a nucleoside metabolic inhibitor, and cedazuridine, a cytidine deaminase inhibitor, indicated for treatment of adult patients with myelodysplastic syndromes (MDS), including previously treated and untreated, de novo and secondary MDS with the following French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, and chronic myelomonocytic leukemia [CMML]) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups. (1)

The efficacy of Cedazuridine and Decitabine versus Decitabine alone in the treatment of Myelodysplastic Syndromes (MDS) is not directly compared in the provided drug labels 2 and 2. The labels indicate that INQOVI, a combination of decitabine and cedazuridine, is used for the treatment of adult patients with MDS, but they do not provide a direct comparison with decitabine alone. Key points:

• INQOVI is indicated for the treatment of MDS
• The labels do not provide a direct comparison with decitabine alone
• Efficacy comparison is not available in the provided drug labels

From the Research

Efficacy of Cedazuridine and Decitabine versus Decitabine alone in MDS

• The combination of oral decitabine plus cedazuridine has been investigated as a treatment for higher-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia 3.
• A phase 1/2 study found that the combination of oral decitabine plus cedazuridine and venetoclax was safe and had encouraging activity in patients with higher-risk MDS and chronic myelomonocytic leukemia 3.
• The development of oral decitabine plus cedazuridine has been driven by the need for more convenient and effective treatments for MDS, with the goal of achieving synergistic activity and better patient outcomes 4, 5.
• A phase 3 study compared the safety and pharmacokinetics of oral decitabine plus cedazuridine versus intravenous decitabine in patients with MDS or chronic myelomonocytic leukemia, and found that oral decitabine-cedazuridine was pharmacologically and pharmacodynamically equivalent to intravenous decitabine 6.
• While there is no direct comparison between cedazuridine and decitabine versus decitabine alone in the provided studies, a meta-analysis comparing decitabine and azacitidine found that azacitidine had higher overall response rates and better survival benefits than decitabine in patients with MDS 7.

Safety and Pharmacokinetics

• The most common grade 3-4 adverse events associated with oral decitabine plus cedazuridine were thrombocytopenia, neutropenia, and febrile neutropenia 3, 6.
• The safety profiles of oral decitabine-cedazuridine and intravenous decitabine were similar, with the most frequent adverse events of grade 3 or worse being thrombocytopenia, neutropenia, and anaemia 6.
• The incidence of serious adverse events was higher with oral decitabine-cedazuridine than with intravenous decitabine in the first two cycles of treatment 6.

Clinical Implications

• The use of oral decitabine plus cedazuridine may offer a convenient and effective alternative to intravenous decitabine for the treatment of MDS or chronic myelomonocytic leukemia 5, 6.
• Further studies are needed to fully evaluate the efficacy and safety of cedazuridine and decitabine versus decitabine alone in the treatment of MDS.