A Metabolically Optimized, Noncytotoxic Low-Dose Weekly Decitabine/Venetoclax in MDS and AML

Area of Science:

• Hematology
• Oncology
• Pharmacology

Background:

• Venetoclax (VEN) combined with hypomethylating agents (HMA) is standard for elderly acute myeloid leukemia (AML) and being studied in myelodysplastic syndrome (MDS).
• Standard HMA/VEN dosing relies on cytotoxicity, often causing severe myelosuppression impacting normal blood cell production.
• A weekly low-dose decitabine (LDDec) regimen has shown efficacy in myeloid malignancies.

Purpose of the Study:

• To evaluate a once-weekly low-dose decitabine (LDDec) and venetoclax (VEN) regimen.
• To overcome the severe myelosuppression associated with standard HMA/VEN therapy.
• To assess this regimen in elderly or frail patients less tolerant to myelosuppression.

Main Methods:

• Retrospective, single-center analysis of patients with AML, MDS, or chronic myelomonocytic leukemia.
• Treatment involved a once-weekly LDDec/VEN regimen.
• Comparison with a cohort receiving standard HMA/VEN dosing.

Main Results:

• Overall response rates for first-line AML and MDS were 88% and 64% respectively with LDDec/VEN.
• In TP53-mutated patients, composite complete response was 71% with a median overall survival of 10.7 months.
• LDDec/VEN patients had longer therapy duration (175 vs. 78 days; P=0.014) and a trend toward higher transfusion independence (47% vs. 26%).

Conclusions:

• The weekly LDDec/VEN regimen demonstrates activity in myeloid malignancies.
• This approach allows frequent, sustained drug exposure, potentially overcoming limitations of standard HMA/VEN.
• Preliminary data suggest improved treatment duration and tolerability, especially in vulnerable patient populations.