Journal: Haematologica
Study question
Can a low-intensity, once-weekly “metronomic” regimen of decitabine plus venetoclax provide meaningful responses with less toxicity in TP53-mutated high-risk MDS and AML, a group that typically does poorly with standard HMA/venetoclax?
Design and patients
- Phase 2 prospective trial plus retrospective cohort, total n=40 with TP53-mutated myeloid malignancies
- Diagnoses: 26 high-risk MDS, 14 AML
- Median age: 76.5 years
- High-risk biology: 70% complex karyotype; 82% bi-allelic TP53 mutations
- Treatment: once-weekly decitabine 0.2 mg/kg + venetoclax 400 mg
Efficacy
- Overall response
- AML: 70% composite CR (CR + CRi)
- MDS: 57% (CR + mCR)
- Median follow-up: 12.9 months
- Median overall survival
- Entire cohort: 11.3 months
- AML: 11.6 months
- MDS: 9.9 months
- Bi-allelic TP53 subset (n=31): 10.4 months
- Transfusion independence: achieved in 58%
Safety and tolerability
- Neutropenic fever: 15%
- No therapy-related deaths
- 100-day mortality: 7.5%
- Overall toxicity profile: low, without the prolonged, severe cytopenias typically seen with standard HMA/venetoclax schedules
Clinical takeaway
A non-cytotoxic, once-weekly decitabine/venetoclax regimen yields comparatively high response rates and ~10–11 months median survival in very high-risk, predominantly bi-allelic TP53-mutated MDS/AML, with substantially reduced infectious complications and early mortality. This schedule appears to be a tolerable option for older/unfit TP53-mutated patients, warranting further comparative study.