A Phase I Study of Chidamide in Combination with Dcag and Venetoclax in Acute Myeloid Leukemia: Clinical Safety, Efficacy, and Correlative Analysis

Background Acute myeloid leukemia (AML) is a highly heterogeneous hematopoietic malignancy characterized by elevated mortality rates and unfavorable prognoses. Epigenetic therapy plays an essential role in the treatment of AML. However, the clinical outcome of the combination of multiple epigenetic agents alongside conventional chemotherapy remains unclear.

Methods We conducted a Phase I study to evaluate the clinical safety and efficacy of chidamide combined with DCAG and venetoclax (referred to as CACAG+VEN) in patients with acute myeloid leukemia (NCT05659992). Patients received induction treatment with intravenous aclarubicin (10mg/m²/d on day 1, 3, 5), subcutaneous azacitidine (75 mg/m² on day 1–7), intravenous cytarabine (75 mg/m²/bid on day 1-5), oral chidamide (30mg, twice/week for two week), and oral venetoclax (100 mg on day 1, 200 mg on day 2, 400 mg on day 3-14). Granulocyte colony-stimulating factor (G-CSF) 5μg/kg/day until granulocyte recovery. This study emploied single-cell RNA sequencing to provide an in-depth analysis of transcriptional dynamics in acute myeloid leukemia cells, spanning diagnosis to post-treatment.

Findings

Between Junrary 1, 2020, and August 1, 2024, a total of 32 patients were screened for the study, of whom 30 patients met all inclusion and exclusion criteria. The median age of the patients was 51.5 years (range, 27–72 years). Twenty-seven patients (90%) had De novo AML and 3 patients (10%) had therapy-related AML. The ECOG scores of the patients were all below 3. Fifteen patients (50%) were classified as NCCN adverse-risk category. Among the patients, NPM1 was mutated in 23.3%, ASXL1 in 20.0%, FLT3-ITD in 16.7%, and NRAS in 16.7% of patients. All patients received at least one treatment with CACAG+VEN regimen, 13 patients (43.3%) received only one cycle, 17 patients (56.7%) received two cycles. Seventeen patients (56.7%, 17/30) received allo-HSCT after chemotherapy. The ORR after one cycle of CACAG+VEN regimen was 96.7 (95% CI, 83.3-99.8), with a CRc rate of 93.3% (95% CI, 78.7-98.9). Among the patients receiving two cycles of regimen, the CRc rates were 100% (17/17; 95% CI, 81.6-100) for those receiving the CACAG+VEN, and 83.3% (5/6; 95% CI, 43.7-99.1) for those receiving other regimens (excluding allo-HSCT) (P=0.085). Four patients of 30 patients died from relapse of AML. The 6-monthOS, EFS, and DOR were 93.2% (95% CI: 75.5-98.3), 72.7% (95% CI: 52.7- 85.3), and 70.7% (95% CI: 49.8- 84.1). No treatment-related deaths occurred. After one cycle of CACAG+VEN regimen, a shift in bone marrow cell populations was observed, with a reduction in hematopoietic stem cell/Tumor and an expansion of granulocyte- macrophage progenitor, neutrophil, and monocyte clusters. Tumor cells exhibited increased expression of genes related to proliferation, self-renewal, and migration. Treatment resulted in decreased expression of BCL2A1 and HOXA genes, and increased PTPRM expression.

Interpretation This study proposed the CACAG+VEN regimen as an efficacious induction therapy for newly diagnosed AML, attaining a high CRc rate, predominantly in NCCN adverse-risk patients. And it provided insights into the transcriptional dynamics of AML during treatment with the CACAG+VEN regimen.