How to Improve the Efficacy of Venetoclax and Azacitidine（VA）for Newly Diagnosed Acute Myeloid Leukemia？a Prospective, Single-Center, Single-Arm, Phase 2 Trial for New Diagnosed AML
Authors: Li Xuekai , Li Mengyun , Cui Wei , Chen Xiaoqian , Yu Yan , Chen Juan , Zhang Xin , Cui Qingya , Wu Depei , Tang Xiaowen 
Published: December 2024

BACKGROUND: Venetoclax is a targeted inhibitor of B-cell lymphoma-2 (BCL-2) that has demonstrated significant efficacy when combined with hypomethylating agents or low-dose cytarabine in acute myeloid leukemia (AML). This combination therapy offers a valuable treatment option for patients with AML, particularly the elder patients or unfit patients. However, the combination of venetoclax and the hypomethylating agent azacitidine results in a remission rate of approximately 60% and a notable subset of high-risk patients fails to achieve remission such as AML with TP53 aberrations, 11q23 abnormalities, t(8,21) and AML with a monocytic phenotype etc. Therefore, how to improve the efficacy of VA as induction regimen for newly diagnosed AML is necessary.

In this prospective study, we evaluated the efficacy and safety of venetoclax, azacitidine combined with HAAG as induction therapy in patients with newly diagnosed AML.

METHODS:Twenty-nine newly diagnosed AML patients were enrolled in this single-center, phase 2 clinical trial (NCT06394011) from January 1, 2021 to May 30, 2024. AML was diagnosed according to the 2016 WHO classification, Patients were treated with VA+HAAG regimen, which consists of venetoclax 100mg orally on days 1, 200mg orally on days 2, 400 mg orally on days 3–10, azacitidine 75mg/m2/d subcutaneous injection on days 1-7, homoharringtonine 1 mg/d intravenously on days 4- 10, aclarubicin 10 mg/d intravenously on days 4-7, cytarabine (Ara-C) 10 mg/m2 q12h subcutaneously on days 4-10, and granulocyte colony-stimulating factor (G-CSF) 50-300 µg/d subcutaneously on days 3-10. The primary endpoints were overall response rate (ORR) after induction treatment, including complete remission (CR) and complete remission with incomplete hematologic recovery(CRi). Secondary endpoints were adverse events (AEs) and survival.

RESULTS: This study included 29 patients (11 males and 18 females) with a median age of 43 years (range 19 to 59) . According to the 2022 ELN risk classification, 10 patients were classified as adverse risk, 6 patients were classified as intermediate risk and 13 patients were favorable risk. CEBPA was the most frequently mutated gene (24.0%), followed by FLT3-ITD (21.0%) , KIT (10.0%) , DNMT3A (10.0%) and NPM1-A (7.0%). Fourteen patients had fusion genes, including 4 CBFβ:: MYH11, 3 MLL rearrangement, 1 MLL-PTD and 2 RUNX1::RUNX1T1. Of all patients, complete remission (CR) rate was 93.10% (27/29) and overall response rate (CR and CRi) was 96.55% (28/29). The response rate was significantly higher in patients with favorable (100%) and intermediate risk (100%) as compared to those with adverse risk (90%). Of note, all 14 patients diagnosed as FAB-M4/M5 achieved CR. Four patients with 11q23 abnormalities achieved CR and particularly three of them achieved complete molecular remission(CMR). Concerning about the adverse events, the incidence of grade 3-4 neutropenia and thrombocytopenia was 100%. The median time to recovery of neutrophil and platelet counts were 16 (range 11 to 35) days and 22 (range 14 to 32) days. Meanwhile, the incidence of sepsis was 28% and the grade 3-4 non-hematologic AEs were not observed. The 3-month overall survival rate (OS) was 100% and the 3-month leukemia-free survival rate (LFS) was 93% (95% CI: 79.57-91.53). Fourteen patients received hematopoietic stem cell transplantation during the follow-up treatment.

CONCLUSIONS: In conclusion, the VA combined with HAAG regimen was effective and well-tolerated as induction therapy in patients with newly diagnosed AML. Moreover, this novel regimen demonstrated a higher CR rate in patients with adverse risk and FAB-M4/M5 subtype compared to the VA regimen.