Early Bone Marrow Evaluation of Venetoclax Plus Hypomethylating Agents in Acute Myeloid Leukemia Patients

Introduction

Venetoclax plus hypomethylating agents (VEN-HMAs) has been approved for the first-line treatment of acute myeloid leukemia (AML) and shown excellent efficacy. The standard duration of Venetoclax in VEN-HMAs is 28 days and the recommended bone marrow evaluation is approximately 21st to 28th day after stopping therapy. However, some patients developed severe myelosuppression during treatment and had to terminate the medication or reduce the dose. Some studies have indicated that shorter duration of venetoclax administration to 14 days has the same efficacy and better safety profile in treatment of AML. Therefore, we tried to investigate that early bone marrow evaluation on the 15th day of VEN-HMAs in the first cycle might evaluate bone marrow response earlier and make timely adjustments to the following regimens. In this study, we collected 52 patients who underwent bone marrow evaluation on the 15th day in the first VEN-HMAs cycle and observed the efficacy of early bone marrow evaluation.

Method

This study collected clinical data from 52 patients with AML who received the VEN-HMAs at the First Hospital of China Medical University from September 2019 to March 2024. The study was divided into newly diagnosed (ND) and relapsed/refractory (R/R) groups to evaluate basic information, ELN 2022 risk group classification, treatment response, duration of myelosuppression, the following regimens and survival outcomes. All the patients received 15th day of bone marrow. The primary endpoints were MLFS (Morphologic leukemia-free state) and complete remission (CR). The secondary endpoints were MRD (minimal residual disease), overall survival (OS) and relapse free survival (RFS). Statistical analyses were performed using SPSS 22.0 and R language 4.2.2. Survival curves were drawn with Kaplan-Meier and survival analysis between groups were performed using Log-rank test. P-values less than 0.05 were indicated statistical difference.

Results

A total of 52 patients completed the study, with 40 in the ND group and 12 in the R/R group. The median age of patients in the two groups were 66.0 years and 54.5 years. A total of 46 (88.5%) de novo AML and 6 (11.5%) secondary AML patients were included in this study. According to the 2022 ELN criteria, 11(21.2%), 15 (28.8%), and 26 (50.0%) patients were grouped to favorable, intermediate, and adverse risk groups, respectively. The total myelosuppression duration in two groups were 29.65 (±3.82) and 43.0 (±10.61) days.

The data showed that 29 patients (72.5%) in ND AML patients obtained MLFS on the 15th day of VEN-HMAs in the first cycle. Among them, 19 patients received VEN for 14 days (VEN-14) due to severe myelosuppression or infection, and 10 patients continued VEN until 28 days (VEN-28). In the VEN-14 group, 63.2% (12/19) patients obtained CR MRD-, while 70% (7/10) patients in the VEN-28 group obtained CR MRD- (P=0.203). Based on the basic information containing age, sex, ELN risk stratification, bone marrow and peripheral blood count without statistical difference between the two groups, we compared the OS and RFS of VEN-14 group and VEN-28 group without statistical significance (OS: P=0.446, mOS had not been reached in both group; RFS: P=0.669, mRFS: 12m vs. 6m). Median follow-up time was 12 months. The myelosuppression duration in the VEN-14 and VEN-28 group were 33.5 (±6.12) and 23.5 (±3.76) days (P=0.271). Among the remaining 11 patients in ND group, 3 patients achieved partial response (PR) and 8 patients showed no response (NR) after 28 days of oral venetoclax without or with additional agents (3 cases, Cytarabine or Homoharringtonine) by re-evaluation of bone marrow.

In the R/R group, 8 (66.7%) patients achieved MLFS in the early evaluation, including 2 with VEN-14 and 6 with VEN-28. 4 patients with NR or PR continued oral venetoclax to 28 days. The final CR MRD- rate was 41.6% (5/12) and CR/CRi (CR with incomplete hematologic recovery) rate was 75% (9/12).

Conclusion

Our real-world study indicated that early bone marrow evaluation is recommended in the AML target therapy, which can enhance clinical decision-making. For patients experiencing severe myelosuppression who have achieved MLFS, timely suspension of venetoclax is beneficial to the recovery of myelosuppression and doesn't affect short-term efficacy and long-term survival. Conversely, for patients with inadequate therapeutic efficacy, it allows for timely adjustments or changing treatment options.

No relevant conflicts of interest to declare.