Real-world experience with front-line metronomic low-dose weekly decitabine and venetoclax in elderly and/or frail patients with MDS or AML

Abstract Background: Hypomethylating agents (HMAs) with and without venetoclax (Ven) have improved outcomes in elderly and less fit patients with high-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). However, standard dosing schedules are associated with high mortality during the induction period largely related to treatment toxicities. Low-dose weekly decitabine (Dec) and Ven demonstrated improved tolerability and a comparable median OS (mOS) of 16.1 months (mos) in a diverse elderly and frail cohort (Goldfinger et al, 2024). The improved tolerability was primarily attributed to non-cytotoxic / non-myelosuppressive properties of the regimen. We conducted a retrospective review to assess real-world outcomes in elderly and/or frail patients who received the weekly low-dose Dec-Ven regimen at Northwell Health. Methods: We retrospectively reviewed patients with newly diagnosed AML or high-risk MDS ineligible for standard dose HMA-Ven who received weekly low-dose Dec-Ven as front-line therapy between August 2022 and March 2025. Induction therapy included Ven (400 mg) on Days 1, 8, 15, and 22, and subcutaneous Dec (0.2 mg/kg) on Days 2, 9, 16, and 23 on a 28-day cycle for 3 cycles. Key outcomes included: completion of three uninterrupted cycles without dose modification, QOL assessed by transfusion independence and incidence of non-hematologic adverse events, days not hospitalized during the treatment period, overall response rate (ORR), hematologic complete response (CR) rate and overall survival (OS). Results: Twenty-nine patients were identified (20 AML; 9 high-risk MDS) with a median age of 82 years (range: 66.9-91) and median ECOG performance status (PS) of 2. Notable comorbidities included malignancy (n=10, 34.5%) on active non-hematologic cancer treatment for metastatic disease (n=7, 24%), chronic kidney disease (n=5, 17%), and dementia (n=2, 7%). High-risk features included TP53 mutations (n=8; 28%) or complex karyotype (n=6; 21%). Among these patients, the ORR was 8/29 (28%), with a CR/CRi rate of 6/29 (21%). For AML patients, the ORR was 35% (7/20) with CR/CRi of 30% (6/20); for MDS patients, the ORR was 11% (1/9) with no CR/CRi. Adverse genetics correlated with poorer outcomes, with mOS of 3.7 mos in TP53-mutated and/or complex karyotype cases (n=10), and 4.2 mos in adverse/high-risk subgroups (n=17). Full count recovery was achieved in 25% (5/20) of AML patients. Fourteen patients (47%) completed the 3-cycle induction without interruptions. Those with AML (n=9) had a median age of 82 years, mPS of 2, mOS of 8.1 mos, transfusion independence of 44% (4/9), neutrophil recovery of 67% (6/9), and median time spent at home of 8.0 months, together reflecting considerable improvement in QOL over the course of treatment. In contrast, those with MDS who completed 3 cycles of therapy (n=5) had a median age of 77 years, mPS of 3, mOS of 5.2 mos, transfusion independence in 20% (1/5), and median time spent at home of 5.3 mos. Discussion: In this retrospective real-world analysis of elderly and/or frail patients with MDS or AML where supportive care or hospice were reasonable options in the setting of standard therapies, the low-dose weekly Dec-Ven regimen demonstrated acceptable tolerability and modest efficacy. While differences in patient populations likely attributed to lower mOS and ORR in the entire cohort, patients completing induction had longer survival than expected with supportive care alone with meaningful time spent at home and not hospitalized. Despite the presence of disease related cytopenias, there were no treatment-related deaths with many AML patients achieving transfusion independence and neutrophil recovery. This regimen offers a viable, low-intensity alternative for patients unfit for standard HMA-Ven, providing an opportunity for treatment in a population with few options, and merits further prospective evaluation in tailored settings.