Hypomethylating agents (HMAs) are the standard of care for patients with higher-risk myelodysplastic neoplasms (HR-MDS) and, in combination with venetoclax, for patients with acute myeloid leukemia (AML) who are not eligible for intensive chemotherapy (IC) or allogeneic stem cell transplantation (alloSCT). Nevertheless, responses occur only in around 50% of patients and are generally short-lived [1]. Thus, the majority of patients either do not respond to these agents or experience relapse, which associates a dismal outcome with a median survival of around 5 months [2]. Outside clinical trials, there are currently limited approved treatment options available for this patient population. The receptor tyrosine kinase AXL is linked to the pathogenesis of myeloid malignancies and mediates chemotherapy resistance [3, 4]. Moreover, recent studies have shown that AXL inhibition enhances anti-leukemic immune responses [4, 5]. Given that AXL is known to be upregulated on leukemic MDS and AML stem cells [5–7] AXL inhibition has been explored as a potential new targeted therapy for patients with myeloid malignancies in several clinical trials [4, 5, 8]. The BERGAMO multicenter phase 2 trial (NCT03824080) evaluated the safety and efficacy of the oral, selective, small molecule AXL inhibitor bemcentinib (BEM) in patients with HRMDS or AML not eligible for IC or alloSCT, refractory or relapsing after at least six cycles of azacitidine (AZA) or four cycles of decitabine (DAC). Patients were eligible if baseline bone marrow blast count by central morphology was≥ 5% and≥ 1 cytopenia according to IPSS-R was present. Patients received an initial loading dose of 400mg BEM orally once daily administered on days 1–3 of cycle 1 and a maintenance dose of 200 mg BEM on days 4–28 of cycle 1 and in subsequent 28-day treatment cycles. The primary efficacy endpoint was the overall hematological response rate (OHR) defined as complete response (CR), marrow complete response (mCR), partial response (PR), stable disease (SD) or hematologic improvement (HI) according to the modified IWG 2006 criteria [9] and 2017 European LeukemiaNet (ELN) recommendations, respectively [10], as assessed at week 17 after four BEM treatment cycles. In the intention-to-treat analysis, the primary hypothesis (OHR≤ 5% vs. OHR> 5%) was tested by one sample binomial test. Time to event endpoints were analyzed by Kaplan–Meier method. All patients who achieved CR, mCR, PR, SD or HI (HI-E, HI-P, HI-N) after the first four BEM treatment cycles were considered as responders and allowed to continue treatment for up to nine treatment cycles. Non-responding patients stopped BEM treatment after the first four cycles. Secondary endpoints were rate and grade of toxicity as measured by NCI CTCAE 5.0, overall survival (OS), progression-free-survival (PFS), time to treatment failure, duration of response (DOR) and best overall response. Exploratory analyses evaluated the role of potential molecular biomarkers to predict response to BEM treatment in MDS and AML. Responders and non-responders were compared with respect to presence of specific mutations by Fisher’s exact test. From 2018 to 2020, a total of 57 patients (MDS= 26, AML= 31) were screened at ten different trial sites in Germany and France within the ‘European Myelodysplastic Neoplasms Cooperative