Abstract PR009: Decitabine/venetoclax reduced-toxicity induction: a very effective bridge-to-transplant in older AML patients with non-favorable genetics

Abstract Background HMAs have finally become the mainstay for AML and MDS patients (pts) ineligible for more intensive therapy, due to their favorable safety profile and activity also in adverse-genetic disease. Given these advantages over standard, intensive induction chemotherapy („7+3“) we and others have demonstrated good feasibility of HMAs as bridge-to-transplant (Lübbert et al., J. Clin. Onc. 2013). In the EORTC AML21 randomized phase III trial we compared 10-day decitabine (DAC) monotherapy (300 pts) vs. 7+3 (300 pts) in AML pts >60 years fit for 7+3. Pts achieved similar overall survival (OS) in both arms, we noted a remarkably high transplant rate after limited pre-treatment, and similar 3-year survival from transplant (50/51%, Lübbert et al., Lancet Haematol. 2023). DAC resulted in fewer toxicities, and maintained quality-of-life, compared to 7+3 (Efficace et al., Blood 2024). Venetoclax (VEN) added to an HMA has remarkably improved OS of AML pts (DiNardo et al., N. Engl. J. Med. 2020). Here we report a single-center experience of AML pts allografted already after a limited number of DAC+VEN treatment cycles. Patients and Methods Between 2/2019 and 2/2023, 20 consecutive newly diagnosed AML pts ineligible for 7+3 received DAC (20 mg/m2 x 5 days i.v.) + VEN (for up to 28 days) at our center and were planned for allo-tx. Median age: 67 (range, 47–74), int. /adverse risk genetics were present in 10/8 pts (3 pts with a TP53 mutation, 4 pts with complex-monosomal karyotype), 6 pts had prior MDS, 17 pts had ECOG performance status 0/1. Results Of 20 pts, 18 proceeded to allografting (tx) within a median of 2.5 mths (1 pt died of sepsis prior to tx, 1 pt continued DAC+VEN). Median number of cycles: 2; 16 pts received only 1 (5) or 2 (11) cycles. Before tx, 8 pts (44%) had attained complete remission (CR), CRi or a marrow leukemia-free state. 10 and 7 pts received a treosulfan- or melphalan-based conditioning regimen, resp. Three, 12 and 3 pts received grafts from matched-sibling, matched-unrelated and haploidentical donors, resp. At day +30, all 18 pts had attained a CR, 15/18 a molecular remission (complete chimerism). After a median follow-up of 3.6 years, 16/18 pts are alive and in continued hematologic remission (1 pt died after relapse, 1 from GvH after relapse), resulting in a 3-year survival of 79% (median survival not reached). Conclusions The transplant outcome after 1-2 cycles of DAC+VEN bridging is superior to that attained in the EORTC AML21 trial (10-day DAC monotherapy). A randomized comparison of an HMA+VEN bridging approach vs 7+3 induction appears warranted and is pursued by the EORTC Leukemia Group. It will be of great interest to see whether the dual treatment will prove superior to 7+3, as our single-arm study results suggest. As regards TP53-mutated pts, all-trans retinoic acid combined with an HMA holds promise (Bresser et al., Eur. J. Haematol. 2024), hence we have opened a randomized phase III trial comparing DAC+VEN+ATRA vs. DAC+VEN+placebo (DECIDER-2), also as bridge-to-transplant, in AML pts aged >18 years. Citation Format: Michael Lübbert, David Alber, Christoph Rummelt, Francesca Biavasco, Gabriele Ihorst, Reinhard Marks, Justus Duyster, Ralph Wäsch, Claudia Wehr, Jürgen Finke. Decitabine/venetoclax reduced-toxicity induction: a very effective bridge-to-transplant in older AML patients with non-favorable genetics [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Methylation, Clonal Hematopoiesis, and Cancer; 2025 Feb 1-4; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2025;85(3 Suppl):Abstract nr PR009.