A Combined Histone Deacetylases Targeting Strategy to Overcome Venetoclax Plus Azacitidine Regimen Resistance in Acute Myeloid Leukaemia: Three Case Reports

Abstract

The management of patients with relapsed or refractory (R/R) acute myeloid leukaemia (AML) remains a challenge with few reliably effective treatments. Chidamide, a new selective HDAC inhibitor, has demonstrated some effectiveness in AML patients. Herein, we reported three patients with R/R AML who were unresponsive to venetoclax plus azacitidine (VA) but were successfully treated with VA when chidamide was added to the regimen. MCL1 is one of the anti-apoptotic proteins. Chidamide targets the MCL1 protein, which may permit venetoclax resistance when upregulated. We determined MCL1 protein expression in different AML cell lines, and chidamide could downregulate MCL1 expression in venetoclax resistance AML cells. In general, our experience showed that the chidamide/VA combination could improve the condition of R/R AML patients who are resistant to VA. Formally evaluating this regimen in R/R AML patients may be meaningful.

Keywords: R/R acute myeloid leukemia AML; chidamide; histon deacetylase inhibitors (HDACi); targeted therapy; venetoclax (BCL2 inhibitor).

Figure 1

Treatment process of patient 1 (A), patient 2 (B) and patient 3 (C). CR, complete remission; IA, cytarabine 100 mg/m² continuous infusion day1–7, idarubicin 12 mg/m² day1–3; HiDAC, cytarabine 2 g/m² over 3 h every 12 h on day1–3; CAG, cytarabine 10 mg/m² every 12 h, day1–14; aclarubicin 5–7 mg/m², daily on day1–8; and concurrent use of G-CSF 200 µg/m²/day; VA, venetoclax once daily (100 mg day1, 200 mg day2, 400 mg day3–28) and azacitidine 75 mg/m² day1–7; VAC, venetoclax once daily (100 mg day1, 200 mg day2, 400 mg day3–21), azacitidine 75 mg/m² daily day1–7, chidamide 5 mg daily day1–7.

Figure 2

Western blot for BCL2 and MCL1 from chidamide-treated AML cell lines. (A). Effect of chidamide (Chi) treatment on the protein expression of BCL2 and MCL1 in different AML cell lines. All the cell lines were treated with a suitable concentration of chidamide for 72 hours, and GAPDH was used as an internal control. (B). Venetoclax inhibited cell proliferation in different AML cell lines. All AML cell lines were exposed to different concentration of venetoclax (5 µM, 10 µM, 15 µM and 20 µM) for 72 h, and then cell viability was determined by a CCK-8 assay. (C). MCL1 protein levels were detected by western blot after 24 h of chidamide (0.5 µM) treatment or not. R-VEN (12 µM), U937 cell line resistant to 12 µM venetoclax.