Dosing decitabine and venetoclax for terminal differentiation to improve outcomes in TP53 mutant MDS and AML.

Abstract

6514 Background: Mutations in the tumor suppressor TP53 gene are common in elderly patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) and confer resistance to conventional chemotherapeutic DNA damaging agents. Venetoclax (Ven) added to the hypomethylating agents (HMA) of Decitabine or Azacitidine is the current standard of care for elderly patients with AML and is frequently used in high-risk MDS (HR-MDS). Currently approved dosing schedules of HMA/Ven rely on cytotoxicity and have not improved outcomes in the TP53 mutant population. The efficacy and tolerability of metronomic weekly dosing of Decitabine and Ven in HR-MDS and AML were previously described (Goldfinger et al, Blood 2024). Mechanistically, metronomic dosing relies on terminal differentiation, rather than cytotoxicity making it an attractive regimen for TP53 mutant MDS/AML. Methods: Patients with histologically confirmed AML or MDS and a TP53 mutation received a once-weekly dose of decitabine 0.2 mg/kg subcutaneously and one dose of Ven 400 mg on days 1, 8, 15 and 22 of a 28-day cycle. Results: Between April 2020 and January 2025, 40 patients with TP53 mutated myeloid malignancies were treated with metronomic weekly low-dose Decitabine/Ven (14 AML, 26 MDS). Twenty-four patients were followed prospectively as part of a clinical trial (NCT05184842), and 16 were treated off-trial and had data collected retrospectively. Median age at diagnosis was 76.5 years, 13 (32%) were from minority backgrounds, 28 (70%) had complex cytogenetics and 31 (82%) had biallelic TP53 mutations (median VAF 36%). All AML patients were ELN-poor risk, 21 MDS patients (82%) were R-IPSS high or very high risk. The median time on therapy was 5.8 months, with 10 (25%) patients still on therapy at time of data cut-off. Four patients in the AML and five in the MDS cohorts were not evaluable (2 withdrew consent, 1 lost to follow-up and 6 did not have a BM biopsy for evaluation). Of the evaluable AML patients, 7 (70%) achieved a complete remission (CR), 3 (30%) did not respond. In the evaluable MDS patients, 9 (43%) achieved a CR and 3 (15%) a marrow CR, 4 (19%) with stable disease, 5 (24%) with no response. Of the 26 patients who were transfusion-dependent at the start of therapy, 15 (58%) became transfusion-independent. For the entire cohort (n=40), the median overall survival (OS) was 11.3 months. For the AML and MDS cohorts, the OS was 11.6 and 9.9 months, respectively. In patients who underwent allogeneic stem cell transplant (n=6), OS was 16 months. Non-heme therapy-related adverse events of ≥ grade 3 was seen in 13 (54%) of patients. Conclusions: In this cohort, of elderly patients with poor risk TP53 mutated MDS and AML the use of a non-cytotoxic dosing schedule of Decitabine and Ven resulted in over half the patients achieving a CR and transfusion independence. The median OS of 11.3 months compares favorably to currently approved cytotoxic dosing of HMA/Ven. Clinical trial information: NCT05184842 .