Comparing the Efficacy and Safety of VAC (Venetoclax, Azacitidine, Chidamide) and VA Regimens As Induction Therapy for Newly Diagnosed Patients with Immunophenotypically Mature Monocytic AML
Authors: Tan Kai-Wen , Pei Shanshan , Wang Miao , Dai Lan , Zhang Hao , Chen Chun-Yan , Huang Zhen-Qi , Dai Hai-Ping , Wang Ying , Miao Miao , Han Yue , Tang Xiaowen , Qiu Huiying , Chen Suning , Sun Aining , Wu Depei , Li Zheng , Xue Sheng-Li 
Published: December 2024

Introduction:

Venetoclax in combination with Azacitidine (VA) is the first-line induction regimen recommended by NCCN guidelines for AML patients who are ineligible or decline intensive chemotherapy. However, studies have identified multiple mechanisms developing resistance to the regimen. Among them, mature monocytic differentiation appears to be an important developmental event driving relapse/refractory responses to VA (Pei S et al. Cancer Discov, 2020; Bisaillon R et al. Leukemia, 2020), suggesting the need to further define the mature monocytic AML disease and design more effective treatment strategies. We propose to define Immunophenotypically mature Monocytic AML patients (Im-Mono AMLs) by a flow criteria where blasts and promonocytes express at least two monocytic markers including CD11b, CD14, CD36 and CD64 and are negative for at least one primitive marker: CD34 or CD117. In addition, given that the monocytic developmental hierarchy is sensitive to histone deacetylase inhibitors (HDACi) (Zeng AGX et al.Nat Med,2022), we add Chidamide (C), a selective HDACi, in combination with VA to form a newly designed VAC regimen. In this study, we compare the efficacy and safety of VAC versus VA as induction therapy for the newly diagnosed (ND) Im-Mono AMLs who are unfit or decline intensive chemotherapy.

Methods:

Patients with ND Im-Mono disease, identified by the flow cytometry criteria described above, were enrolled in this study. Participants were drawn from a clinical trial (NCT05566054), and due to the limited number of cases, additional cases were included from a retrospective cohort. The patients were divided into two groups: VA group, receiving Azacitidine (75mg/m2 on days 1-7) and Venetoclax (escalated doses of 100mg, 200mg, and 400mg by day 28), and VAC group, receiving Chidamide (10mg/day on days 1-7) combined with VA. Patients who did not respond to the 1st cycle of treatment were allowed to receive alternative induction regimen. For post-remission therapy, patients could continue with the original regimen, switch to other regimens, or undergo hematopoietic stem cell transplantation. The primary endpoint was ORR (CR+CRi+MLFS) after the 1st cycle. Secondary endpoints included MRD-negative CR rate (defined as &lt; 1 × 10−3 by flow cytometry), overall survival (OS), and adverse events.

Results:

Between January 2021 and June 2024, a total of 48 patients were enrolled. 20 patients received VAC regimen, and 28 patients received VA regimen. There were no significant differences in baseline characteristics between the two groups of patients (P &gt; 0.1). At the end of the 1st cycle of treatment, the ORR in VAC group was 75%, which was significantly higher than the 46.4% in VA group (P = 0.048). The MRD-negative CR rate was 86.7% in VAC group and 84.6% in VA group (P = 1.000). At a median follow-up of 7.57 months (range, 0.9-24.7), the median OS was not reached in both groups. Besides, the incidence of grade 3 or higher febrile neutropenia (57.6% vs. 52.6%), infection (21.2% vs. 23.7%), and sepsis (9.1% vs. 13.2%) were not significantly different between VAC and VA group (P &gt; 0.1). Patients in VAC group required similar platelets (4.5U vs. 5U, P = 0.859) and red blood cell infusions (5.5U vs. 5U, P = 0.979) during induction as compared with those in VA group. Mechanistically, the laboratory experiments showed that Venetoclax and Chidamide exhibit strong synergistic anti-leukemic effects in Venetoclax resistant monocytic cell line THP-1 harboring NRAS, KMT2A-rearrangment and TP53 mutations, all of which are known to be worse prognosis factors for VA. Moreover, Venetoclax and Chidamide could target primitive and monocytic leukemia subpopulations in primary AML samples, respectively, effectively treating the developmental heterogeneity of AML disease.

Conclusion:

Despite VA regimen being an active and promising strategy for AML, the inherent heterogeneity of AML contributes to primary or secondary resistance to VA, presenting major clinical challenges. It is crucial to better define the developmental heterogeneity and devise new treatment strategies. In this report, we newly defined Im-Mono AMLs who show poor responses to VA. In contrast, VAC regimen achieved a considerably higher remission rate without increased adverse effects in these patients. This provides proof-of-principle for combining HDAC and BCL2 inhibitors to address disease heterogeneity and improve AML treatment outcomes.