DECIDER-2: Prospective randomized multicenter phase III trial of decitabine and venetoclax administered in combination with all-trans retinoic acid or placebo in patients with acute myeloid leukemia who are ineligible for induction chemotherapy.

Acute myeloid leukemia (AML) is predominantly a disease of older patients with a poor long-term survival. Approval of the combination of venetoclax (VEN) with azacitidine (AZA) or decitabine (DAC) in the European Union in 2021 for the treatment of patients with newly diagnosed AML who are ineligible for induction chemotherapy has become the treatment backbone for older, medically non-fit AML patients. Based on in vitro priming of AML cells to all-trans retinoic acid (ATRA) by DAC, we had previously conducted a randomized phase II trial (DECIDER, AMLSG 14 - 09) in 200 elderly, non-fit AML patients on the effect of ATRA as add-on to DAC. Median overall survival (OS) was 8.2 months with ATRA versus 5.1 months without ATRA (hazard ratio, 0.65; 95% CI, 0.48 to 0.89; P = 0.006). Notably, ATRA did not add toxicity, the combination was active also in patients with adverse genetics, and prolonged time to treatment resistance. Investigating a triple combination of DAC, VEN and ATRA was a logical next step. This randomized double-blind phase III trial compares the efficacy of ATRA versus placebo as add-on to the backbone treatment (DAC and VEN) with respect to OS, objective best response, quality of life and safety. The accompanying translational research will contribute to identify molecular markers for drug efficacy and better tailoring epigenetic therapy. DECIDER-2 (AMLSG 32 - 21) is a prospective, randomized, double-blind, placebo-controlled, parallel group, multicenter trial. The primary study objective is to compare the efficacy of ATRA versus placebo as add-on to the backbone treatment (DAC and VEN) in terms of OS. The target population is adult AML patients unfit for standard induction chemotherapy. Patients are randomized (1:1) to receive backbone treatment in combination with either ATRA or placebo. Four interim safety analyses were planned with the involvement of the Data Monitoring Committee. This trial investigates whether the in vitro cooperativity of DAC, VEN, and ATRA prolongs OS in unfit AML patients compared to placebo, offering a novel, low-toxicity triplet combination with a promising risk-benefit ratio. EU CT number: 2020-005495-36/2023-507461-26-00 (registered 18.11.2020); German clinical trials registry number: DRKS00023646 (registered 23.08.2022).