P554: results of a randomized placebo-controlled phase 2 study of hypomethylating agents with or without eltrombopag in elderly aml patients (delta)

Background: Hypomethylating agents (HMA) belong to the standard backbone for the treatment of AML in elderly patients who are not suitable for intensive chemotherapy. However, treatment responses are limited and treatment-associated cytopenia, particularly thrombocytopenia, put patients at risk of bleeding and led to treatment delay. Eltrombopag (EPAG) is an oral thrombopoietin receptor (TPO) agonist that, stimulates megakaryopoiesis and is able to reduce platelet counts in AML and MDS patients. Moreover, previous data indicate a synergistic antileukemic effect of HMA and EPAG. Therefore, combining HMA with EPAG represents a promising therapeutic approach. Aims: We conducted a phase 2 clinical trial to evaluate the efficacy and safety of HMA with or without EPAG in elderly AML patients. Methods: In this randomized placebo-controlled phase 2 study (DELTA), we included newly diagnosed AML patients (>/=65 years) with a platelet count <75 Gpt/L, who were not eligible for intensive chemotherapy. Patients received either standard-dose decitabine (DAC) for 5 days, or azacitidine (AZA) for 5 + 2 days, combined with EPAG (starting dose 200mg) or placebo on days 12 to 25 of each HMA cycle. Primary endpoint was Treatment-change-free survival (TCFS), defined as time from randomization until death or day one of a new disease modifying treatment. The study was terminated prematurely in June 2020 due to the EMA approval of the HMA-venetoclax combination as new treatment standard in elderly AML, resulting in ethical conflicts treating patients with HMA monotherapy. Results: Between 2015 and 2020, 131 patients were randomized (1:1) to HMA+EPAG (n=66) or HMA+placebo (n=65). Median age was 78 years. Favorable, intermediate and adverse risk (ELN 2017) was present in 14.5%, 45.5% and 40% of patients, respectively. 84/131 (68.3%) patients were platelet transfusion dependent at study entry. With regards to the primary endpoint Treatment change-free survival (TCSF) the combination therapy of HMA+EPAG revealed no significant improvement compared to HMA+placebo in elderly AML patients (4 months vs 4.9 months; HR 1.2, 95%-CI, 0.85-1.8; p=0.26). Median overall survival was 4.4 months in HMA+EPAG compared to 5.6 months in HMA+placebo (HR 1.3, 95%-CI, 0.89-2.0; p=0.17). Overall response rates (complete or partial response, stable disease) were 28.6% in the HMA+EPAG group and 33.0 % for the HMA+placebo group (p=0.472). There were neither significant differences in the incidence of clinically significant bleeding events (n= 13% versus 15%, p=0.52), nor in platelet transfusion rates between both groups (p= 0.72). The most common adverse events (AEs) were infection (17.4 % in the EPAG group and 15.2% in the placebo group), fever (7.6 % and 5.1 %,), and bleeding events (5.5% and 3.0%), respectively. Summary/Conclusion: The addition of eltrombopag to HMA did not improve outcomes of AML treatment in the elderly AML population. No new safety concerns regarding AML progression were noted in the EPAG containing combination therapy. Image:Keywords: MDS/AML, AML, Acute myeloid leukemia