Treatment of TP53-mutated myelodysplastic syndrome and acute myeloid leukemia with low-intensity metronomic decitabine and venetoclax.

Venetoclax (Ven) in combination with hypomethylating agents (HMA) (azacitidine or decitabine) is the standard of care for elderly or unfit patients with acute myeloid leukemia (AML) and is being explored in high-risk myelodysplastic syndrome (HR-MDS). However, currently approved dosing of HMA/Ven is associated with prolonged cytopenias, without a clear improvement in survival for TP53-mutated myeloid malignancies. In order to reduce hospitalizations during COVID, a once-weekly, metronomic schedule of decitabine (0.2 mg/Kg) and ven (400 mg) was developed for patients with MDS and AML. Based on the encouraging results, a phase II trial was performed. In the current study, we analyzed response rates and survival for all patients with TP53-mutated disease treated on the metronomic schedule. In total, 40 patients with TP53-mutated MDS and AML (26 in a prospective trial and 14 in the retrospective cohort) were included; 26 had HR-MDS and 14 had AML. The median age was 76.5 years, 70% had complex cytogenetics, and 82% had bi-allelic TP53 mutations. The overall response rate for AML (complete remission [CR] + CR with incomplete blood count recovery) was 70% and 57% (CR + marrow CR) for MDS. With a median follow-up of 12.9 months, the median overall survival for the entire cohort was 11.3 months (11.6 months for AML, 9.9 months for MDS), and median overall survival in the 31 patients with bi-allelic mutated TP53 was 10.4 months. Transfusion independence was achieved in 58%. Neutropenic fever occurred in 15%, there were no therapy-related fatalities, and the 100-day mortality was 7.5%. Results showed that a non-cytotoxic metronomic dosing schedule of decitabine/Ven has a low toxicity profile in TP53-mutated myeloid malignancies.