Abstract CT225: AARON: An ongoing open-label phase I/II study of relatlimab (anti-LAG-3) with nivolumab (anti-PD-1) in combination with azacitidine ± venetoclax for the treatment of patients with relapsed/refractory and non-fit patients with newly di

Abstract The approval of venetoclax (VEN) in combination with hypomethylating agents (HMA) like Azacitidine (AZA) for newly diagnosed acute myeloid leukemia (AML) has significantly improved the outcomes of patients not fit for intensive chemotherapy. However, a considerable proportion of patients are primary refractory or relapse early with HMA/VEN, highlighting the need for novel combinatorial treatment options.Preclinical models have shown that blocking of the PD-1/PD-L1 pathway enhances antileukemic responses. However, in AML, single-agent efficacy of PD-1 inhibitors is limited. In preclinical findings, AZA upregulates PD-1 expression and the IFNγ signaling pathway. In relapsed/refractory (R/R) AML, AZA + Nivolumab demonstrated higher response rates and improved overall survival compared to historical outcomes (Daver et al 2019). We found that blocking the inhibitory immune checkpoint LAG-3 significantly increases anti-leukemic T-cell responses, in particular in combination with PD-1/PD-L1 blocking (Lichtenegger FS et al 2018). Here, we report interim results of a phase I/II trial designed to assess the safety and efficacy of AZA, nivolumab (anti-PD-1) and relatlimab (anti-LAG-3) in R/R AML, and of AZA+VEN in combination with nivolumab and relatlimab in non-fit patients with newly diagnosed wild-type IDH/NPM1 AML. In the AARON trial (NCT04913922), AZA±VEN (applied per standard of care) is combined with nivolumab (480mg) and relatlimab (160mg) q 4 weeks. To date, 12 r/r AML patients (pts) have been treated. We observed no CR/PR (response rate 0%), but acceptable tolerability. Immune adverse events occurred in 25% of pts, but were well manageable, also post-SCT. The 11 non-fit frontline pts (median age 78 years, range 62-86) treated to date had a very high risk profile (adverse risk profile per ELN 2022 criteria in 100%). These pts received a median of 3 cycles (range 1-10), and in 5/11 pts (45%) treatment is ongoing. Best response was CR/CRi in 7/10 evaluable pts (response rate 70%), MLFS in 1/10 (10%) and blast response in 1/10 (10%). Only one pt had primary refractory disease. Immune-related adverse events were seen in 3/11 pts (27%, transaminitis, myocarditis and rash, all G3) and rapidly reversible with steroid treatment. 30-day mortality was 9% (septic shock unrelated to study treatment in 1 pt). In 3/11 pts, nivolumab/relatlimab treatment was discontinued, whereas AZA+VEN was continued. In conclusion, AZA/VEN + LAG-3/PD-1 inhibition was safe in adverse risk frontline AML patients not fit for intensive chemotherapy and showed promising efficacy. We continue to enroll non-fit frontline patients. The ongoing comprehensive immunomonitoring program aims to elucidate mechanisms of treatment response. Citation Format: Veit Buecklein, Giulia Magno, Christian Rausch, Maximilian Warm, Alica-Joana Emhardt, Adrian Gottschlich, Karsten Spiekermann, Christian Schmidt, Sabine Witt, Michael Unterhalt, Naval Daver, Marion Subklewe. AARON: An ongoing open-label phase I/II study of relatlimab (anti-LAG-3) with nivolumab (anti-PD-1) in combination with azacitidine ± venetoclax for the treatment of patients with relapsed/refractory and non-fit patients with newly diagnosed acute myeloid leukemia - Interim analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT225.