Phase Ⅱ Study of Chidamide in Combination with Dcag and Venetoclax for Refractory/Relapsed Acute Myeloid Leukemia: Clinical Safety, Efficacy, and Correlative Analysis
Authors: Liu Qingyang , Wen Yanan , Zhang Xiawei , Gao Wenjing , Liu Daihong , Dou Liping 
Published: December 2024

Purpose:
Treatment options for relapsed and refractory acute myeloid leukemia patients (R/R AML) are limited. Based on the demonstrated synergistic effects of BCL-2 inhibitor venetoclax with hypomethylating agents (HMAs) and our previously clinical trial results about CDCAG regimen, the combination therapy involving venetoclax and CDCAG, was investigated for patients with R/R AML.
Patients and Methods:
We conducted a phase 2 trial (ChiCTR2200065634) to assess the safety and efficacy of venetoclax, chidamide, azacitidine, aclarubicin, cytarabine and G-CSF (CDCAG+VEN) combination therapy in R/R AML patients. The primary endpoint was overall response rate (ORR) following 1 course of CDCAG+VEN regimen. Molecular and cytogenetic analyses were performed using G- and R-banding analysis and next-generation sequencing (NGS). In addition, we performed single-cell RNA sequencing using bone marrow samples from 4 patients before and after CDCAG + VEN treatment.
Results:
From December 2, 2021, to June 8, 2024, a total of 39 patients were screened, with 34 eligible patients received the CDCAG + VEN regimen. The median age of the patients was 45.5 years (range, 15-74 years), comprising 50% (n=17) patients with refractory AML and 50% (n=17) patients with relapsed AML. In prior treatments, patients received the following: the conventional “7+3” chemotherapy regimen (76.5%), hypomethylating agents such as azacitidine or decitabine (58.5%), venetoclax (38.2%) and chidamide (11.8%). Risk classification by ELN 2022 criteria showed a distribution of 53.3% (n=18) with adverse-risk, 30% (n=10) with intermediate-risk, and 16.7% (n=6) with favorable-risk AML. Thirty-two patients completed the study, with an overall response rate (ORR) of 81.3% after one cycle of the CDCAG + VEN regimen, including 65.6% achieving complete remission or complete remission with incomplete count recovery (CR/CRi), and 15.6% achieving partial remission(PR). The ORR for the favorable risk group is 100%, for the intermediate risk group it is 70%, and for the adverse risk group it is 81.3%. In patients who had only prior used the “7+3” regimen without any epigenetic modifiers and venetoclax, the overall response rate could reach 100%. Measurable residual disease (MRD) as assessed by multiparametric flow cytometry was negative in 11 out of 21 (52%) patients who achieved CR/CRi. After treatment with CDCAG + VEN, 53% of patients underwent allogeneic hematopoietic stem cell transplantation, with 57% of CR/CRi patients receiving the transplant.
Mutation profiles were analyzed for 28 patients, with relevant mutations found in 21 patients. The ORR was 50% for patients with TP53 mutations and 75% for patients with ASXL1 mutations. Single-cell sequencing was performed on pre- and post-treatment samples from four patients with different responses to the CDCAG + VEN regimen; we analyzed 52,309 cells (BMMCs) derived from pre- and post-treatment samples. Our results revealed that copy number variation (CNV) clones decreased in post-treatment patients. And a total of 682 genes were significantly upregulated in tumor cells of NR patients. KEGG pathway enrichment analysis showed that the upregulated genes were enriched in the MAPK signaling pathway.
As of June 8, 2024, the median follow-up time was 232 days (range: 19-845 days), with six-month and one-year overall survival (OS) rates of 68.2% and 59.6%, respectively, and progression-free survival (PFS) rates of 82.3% and 77.4%. Patients who achieved CR/CRi and bridged to allogeneic hematopoietic stem cell transplantation (allo-HSCT) had better OS. No patients discontinued treatment due to adverse events (AE). For patients achieving CR/CRi, the median durations of neutropenia and thrombocytopenia were 17 days and 10.5 days, respectively. Grade 3 or 4 treatment-emergent adverse events (TEAEs) were reported in 44.1% of patients, including pneumonia, hyponatremia, hypokalemia, and hypocalcemia. One patient experienced early death due to infectious shock within 19 days of starting treatment.
Conclusion
In patients with R/R AML, the CDCAG + VEN regimen was well-tolerated and resulted in significant clinical benefit. Patients who have previously failed the standard “7+3” regimen may particularly stand to gain from the CDCAG plus VEN treatment approach.