Paper Details

ABSTRACT

Background

Venetoclax plus hypomethylating agents (VEN+HMA) is a standard frontline treatment for older or unfit patients with acute myeloid leukemia (AML), but suboptimal remission depth, delayed hematologic recovery, and relapse remain important clinical challenges. Anthracyclines are a cornerstone of intensive AML therapy; however, treatment-related myelosuppression and cumulative cardiotoxicity limit their use in older or medically unfit patients. Aclarubicin (ACLA) is a distinct anthracycline with antileukemic activity and a favorable safety profile, including reduced cardiotoxic potential. We evaluated whether adding ACLA to VEN+HMA could improve remission quality and clinical outcomes in this population (NCT05264883).

Methods

In this multicenter, open-label, randomized phase 2b trial, patients with newly diagnosed AML aged 60–80 years, as well as younger patients who were ineligible for or declined intensive induction chemotherapy, were randomly assigned 1:1 to VEN+HMA or VEN+HMA+ACLA in 28-day cycles. VEN was administered at 100 mg on day 1, 200 mg on day 2, and 400 mg daily thereafter, with dose adjustments as clinically indicated. HMA consisted of azacitidine 75 mg/m²/day on days 1–7 or decitabine 20 mg/m²/day on days 1–5, according to institutional practice. Patients in the experimental arm additionally received ACLA 10 mg/m²/day on days 1–3. FLT3 or IDH1/IDH2 inhibitors were permitted in genotype-selected patients. Efficacy was analyzed in the intention-to-treat population. The primary endpoint was composite complete remission (CRc; complete remission [CR] or CR with incomplete hematologic recovery [CRi]). Secondary endpoints included CR before cycle 2, measurable residual disease (MRD) negativity, overall survival (OS), disease-free survival (DFS), hematologic recovery, and safety.

Results

Between October 8, 2021, and August 7, 2023, 215 patients were screened at four hospitals in China, of whom 187 were randomized to VEN+HMA+ACLA (n=94) or VEN+HMA (n=93). The median age was 63 years (IQR, 57–69) in the VEN+HMA+ACLA group and 65 years (IQR, 59–72) in the VEN+HMA group. The CRc rate was higher with VEN+HMA+ACLA than with VEN+HMA (84.0% [79/94; 95% CI, 75–91] vs 69.8% [65/93; 95% CI, 59–79]; P=0.021). The overall CR rate was also higher with VEN+HMA+ACLA (80.9% [95% CI, 71.4–88.2] vs 48.4% [95% CI, 37.9–59.0]; P<0.001), whereas CRi was less frequent (3.2% vs 22.0%; P<0.001). CR before cycle 2 was achieved in 68.1% versus 36.6% of patients, respectively (P<0.001). Among patients achieving CRc, MRD negativity was observed in 90% versus 68%, respectively (P<0.001).

Hematologic recovery was also faster with VEN+HMA+ACLA. Median time to neutrophil recovery to ≥500/μL was 18 versus 24 days (P<0.001), while median time to platelet recovery to ≥20,000/μL was 19 versus 21 days. Concurrent neutrophil and platelet recovery within 3 weeks occurred in 61% versus 31% of patients (P<0.001).

At a median follow-up of 25.8 months, median OS was 44.8 months with VEN+HMA+ACLA versus 17.0 months with VEN+HMA (HR, 0.54; 95% CI, 0.35–0.83; P=0.004). Median DFS was 37.3 versus 15.5 months, respectively (HR, 0.65; 95% CI, 0.40–1.04; P=0.069). Exploratory subgroup analyses showed a higher CR rate in FAB-M5 AML (92.9% vs 50.0%; P=0.014), whereas patients with t(8;21) AML showed a numerical improvement in CRc (75.0% vs 25.0%; P=0.098).

Early mortality was similar between groups (3.2% vs 2.2%). Grade ≥3 respiratory infections (43% vs 51%), pneumonia (16% vs 18%), and sepsis (6% vs 5%) were comparable, and grade ≥3 cardiac events were uncommon (2% vs 1%).

Conclusions

Adding ACLA to VEN+HMA was associated with earlier and deeper remission, faster hematologic recovery, and longer OS without an apparent increase in severe toxicity. These findings support further evaluation of this regimen in older or unfit patients with newly diagnosed AML.