Venetoclax Plus CACAG Regimen Demonstrates High Response Rates and Favorable Survival for R/R Acute Myeloid Leukemia
Key Clinical Summary
- Population and Design: Single-center phase 1 trial enrolled 34 patients with relapsed (n = 17) or refractory (n = 17) AML (median age 45.5 years) to evaluate CACAG + venetoclax as a salvage regimen, with a median follow-up of 461 days.
- Efficacy: ORR 76.5% (95% CI, 58.8 to 89.3) with CRc 73.5% and MRD negativity in 44% of responders. The 1-year OS was 82.3% (95% CI, 67.8 to 99.9) and PFS 79.8% (95% CI, 65.4 to 97.3), showing strong reinduction activity in both relapsed and refractory cohorts.
- Safety and Mechanistic Insights: Grade 3 to 4 myelosuppression in 44.1%, with median neutropenia and thrombocytopenia durations of 17 and 24 days, respectively. Single-cell RNA sequencing revealed downregulation of MCL1, HIF1A, and ABCC1, mitochondrial suppression, and p53 pathway activation, consistent with treatment response.
- Clinical Relevance: CACAG-VEN demonstrated high remission rates, durable 1-year survival, and manageable toxicity, supporting its role as an effective frontline salvage regimen for R/R AML following 3+7 induction failure, pending validation in larger, long-term studies.
The combination of chidamide, azacitidine, cytarabine, aclarubicin, G-CSF (CACAG), and venetoclax (VEN) showed high response rates and encouraging 1-year survival outcomes in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML), according to results published in Frontiers in Immunology.
Previous research has found an epigenetic modifier or a BCL2 inhibitor combined with cytotoxic agents may be a promising treatment regimen for patients with R/R AML. Researchers conducted a single-center, phase 1 trial to determine the efficacy and safety of CACAG plus venetoclax.
Patients received 1 cycle of CACAG-venetoclax and were followed for a median of 461 days. Venetoclax was administered orally (PO) on days 1 to 14 (100 mg for day 1, 200 mg for day 2, 400 mg for days 3 to 14), chidamide (30 mg) was administered orally on days 1, 4, 8, and 11, azacitidine (75 mg/m2) was administered subcutaneously on days 1 to 7. Cytarabine was administered intravenously (75 to 100 mg/m2/d) on days 1 to 5, aclarubicin (10 mg/m2/d) was administered on days 1,3, and 5, and granulocyte colony-stimulating factor (G-CSF; 300 mg/day) was administered until WBC > 20 × 109/L.
The primary end point was treatment-related adverse events and the overall response rate (ORR) after 1 cycle of CACAG-venetoclax. Secondary end points included composite complete response (CRc), partial response (PR) rate, no response (NR) rate, MRD negative rate after 1 cycle, overall survival (OS), progression-free survival (PFS), duration of response (DOR), and cumulative incidence of relapse.
Overall, 34 patients were included, of which 17 had relapsed disease and 17 had refractory disease. The median age was 45.5 years (range, 15 to 74). The median follow up was 461 days (range, 180 to 985). The ORR was 76.5% (95% confidence interval [CI], 58.8 to 89.3), with 73.5% achieving a CRc. Among responders, 44% attained MRD negativity. The estimated 1-year overall OS was 82.3% (95% CI, 67.8 to 99.9%) and the estimated 1-year PFS rates were 79.8% (95% CI, 65.4 to 97.3%).
Grade 3 or 4 myelosuppression occurred among 44.1% of patients, with median durations of neutropenia and thrombocytopenia of 17 and 24 days, respectively. Single-cell RNA sequencing of bone marrow samples before and after treatment revealed downregulation of MCL1, HIF1A, and ABCC1, as well as suppression of mitochondrial activity and activation of the p53 signaling pathway.
The researchers concluded, “Generally, CACAG-VEN represents an effective reinduction regimen for R/R-AML, with particular utility as a frontline salvage regimen in R/R patients who only failed the “3+7” regimen.”
They added, “Confirmation of a longer follow-up period with a greater durability of responses and long-term survival is necessary to confirm the safety and effectiveness.”
Source:
Wen Y, Yang J, Zhang X, et al. Phase 1 study of chidamide in combination with venetoclax, azacitidine, aclarubicin, cytarabine and G-CSF for refractory/relapsed acute myeloid leukemia: clinical safety, efficacy, and correlative analysis. Frontiers in Immunology. Published online December 10, 2025. doi:10.3389/fimmu.2025.1698710
