Venetoclax, Azacitidine, Combined with Low-Dose Cytarabine in Older Newly Diagnosed Acute Myeloid Leukemia：the Result of a Prospective, Multicenter, Open, Randomized Controlled Trials

Background: Older patients with acute myeloid leukemia (AML) have a dismal prognosis. The combination of venetoclax with azacitidine had promising efficacy, but the minimal residual disease (MRD) negative rate is only 30-40%. In most cases measurable residual disease (MRD) positivity predicts hematologic relapse potentially allowing early therapeutic intervention. Meanwhile, venetoclax has poor therapeutic effect on monocytic AML because of low expression of BCL2 and high level of MCL1 in monocytes. Cytarabine synergizes with venetoclax by enhancing BH3 activity and suppressing MCL1 to increase anti-leukemic efficacy. This study compared the efficacy and safety of treatment with venetoclax, azacitidin administered with LDAC with venetoclax plus azacitidine in previously untreated patients with older (age≥60 years) AML.

Aims: To explore the efficacy and safety of Ven+AZA+LDAC induction therapy for older AML.

Methods: This is a prospective, multicenter, open, randomized controlled clinical trial. Adults age ≥60 years with newly diagnosed AML were enrolled. Included patients were randomized 1:1 via interactive response technology to the experimental and control group. The experimental group received induction treatment with venetoclax 100mg d1, 200mg d2, 400mg d3-28, azacytidine 75mg/m² d1-7, and cytarabine 10mg/m² q12h d1-7, while the control group received venetoclax 100mg d1, 200mg d2, 400mg d3-28, and azacytidine 75mg/m² d1-7. Venetoclax dose was adjusted based on concomitant CYP3A inhibitors. The primary observation was the remission rate (CR/CRi) and the negative rate of MRD after one course.

Results: The patients from six sites were enrolled between January 1, 2023, and May 31, 2024. Following the first course of VAA treatment, the outcomes were as follows: 24 patients (61.5%) achieved complete remission (CR) with negative minimal residual disease (MRD), 8 patients (20.5%) achieved CR with positive MRD, 2 patients (5.1%) experienced partial remission (PR), and 5 patient (12.8%) did not achieve remission (NR). The overall response rate (ORR) was 87.2%. However, only 12 patients (37.5%) hand achieved CR with negative MRD in control group (p=0.03) . Among them, 8 patients in VAA group and 1 patient in VA group underwent hematopoietic stem cell transplantation (p=0.03), and all HSCT patients were alive at the time of manuscript writing. Subgroup analysis revealed that out of the 13 AML-M4/5 patients, 9 (69.2%) and 4(28.6%) reached CR with negative MRD in the experimental and control group, respectively (p=0.03) . Follow up until June 30, 2024, overall survival (OS) rate were 97.4% and 75% in VAA and VA group, respectively. The estimated median overall survival (OS) for VAA group was 17.57 months (95% confidence interval 16.74-18.40 months), while the VA group was 14.61 months (95% confidence interval 12.31-16.90 months), which has statistical differences (p=0.011) .

Safety: All the 39 experience patients had anemia and thrombocytopenia, which controlled after therapy, without severe infection and bleeding complications. There were 7 patients in both VAA group and VA group who experienced transient elevation of total bilirubin. All enrolled patients have no treatment-related deaths occurred during the induction period.

Conclusion: The incidence of remission was higher among newly diagnosed older patients who received VAA, especially CR with negative MRD. Moreover, VAA regimen has shown an improved outcome of monocytic AML and a higher OS rate and make more patients had opportunities to undergo HSCT. Thirdly, treatment-related adverse reactions were not increased compared with the control group. However, it is necessary to further expand the sample size and extend the follow-up time to assess the long-term survival rate.