The Efficacy and Safety of Homoharringtonine Added to Venetoclax and Azacitidine in the Frontline Treatment of Newly Diagnosed Acute Myeloid Leukemia, a Multi-Center Exploratory Cohort Study

Purpose Our previous study showed that homoharringtonine added to venetoclax and azacitidine (HVA) improved the response compared to VA in the treatment of relapsed/refractory acute myeloid leukemia (AML) with well toleration. In this study we aimed to assess the efficacy and safety of HVA in the frontline treatment of newly diagnosed (ND) AML. Methods Patients with ND AML who were frontline treated with HVA (combined with FLT3 inhibitors in FLT3-mutated patients) for at least one cycle and had response assessment were included. The endpoint of the study was to evaluate the rate of overall response, composite complete remission (CRc), measurable residual disease (MRD), event-free survival (EFS), overall survival (OS), relapse and adverse events (AEs), and compare the efficacy and safety with that in the fit patients with “7+3” treatment and unfit patients with VA, respectively. Results 101 patients, including 73 fit and 28 unfit, with male to female 59/42, median age of 50(14-74) years, from the South China Hematology Alliance database were analyzed. After two cycles of induction, 84(83.2%) patients acquired response, 81(80.2%) CRc, 56(55.4%) MRD-negatve, including 61(83.6%), 59(80.8%) and 41(56.2%) in the fit patients, and 23(82.1%), 22(78.6%) and 15(53.6%) in the unfit patients, respectively. Patients with low risk (LR) versus (vs) intermediate risk (IR) vs high risk (HR) according to ELN 2022 or de novo vs secondary/therapy-related AML had comparable rate of CRc and MRD-negative. In the HR cohorts, HVA acquired higher response than “7+3” regimens in the fit patients (CRc 81.6% vs 56.8%) and VA in the unfit patients (CRc 77.3% vs 60.5%). Patients with N/KRAS (mutation 12/20 vs wild type 69/81, P=0.011) or PTPN11 mutations (1/5 vs 80/96, P=0.001) responded poorly to HVA treatment, while patients with IDH1/2 mutation (22/23 vs 59/78, P=0.034) had better response. With a median follow-up of 5(0.3-35.2) months, 37(36.6%) patients were bridged to allogenetic hematopoietic stem cell transplantation (allo-HSCT), 20/84(23.8%) relapsed, 21(20.8%) died. The expected rates of one year-OS and EFS were 95.5±2.6% and 89.4±4.1% in the fit patients, and 75.1±8.9% and 59.0±18.5% in the unfit patients. Multivariate analysis showed that TP53 mutation was the independently negative factor while bridging to allo-HSCT was the protective factor of OS. The most common grade ≥3 AEs were neutropenia (81.2%), anemia (71.3%), thrombocytopenia (68.4%), febrile neutropenia (52.5%), gastrointestinal reactions (30.7%), pneumonia (14.9%) and sepsis (5.0%), which were comparable between the fit and unfit patients, presenting lower incidence of infection than “7+3” regimens while similar to VA. Conclusions HHT added to VA in the frontline treatment of ND AML had high response, and might excel the standard treatment in the patients with HR AML, with well toleration. A multi-center randomized controlled trial of HVA vs “7+3” in fit patients and VA in unfit patients with HR AML has been initiated. Key words homoharringtonine, venetoclax/azacitidine, acute myeloid leukemia, efficacy, safety