The prognosis for patients with acute myeloid leukemia (AML) remains poor with high mortality rates. It is often not possible to achieve complete remission with current therapy and relapse following treatment is common. New and more targeted treatment approaches are therefore needed to improve outcomes for patients. AML progression and treatment resistance has been associated with overexpression of BCL2. Venetoclax, a BH3 mimetic targeting BCL2, has been shown to effectively target AML cells and induce cell death. It has been approved for the treatment of AML but as with other AML treatments not all patients respond, and others develop treatment resistance. Research has therefore focussed on exploring combination therapies for Venetoclax. Our group has previously shown that mitochondrial transfer from mesenchymal stromal cells (MSC) to AML blasts promotes AML growth and is mediated by CD38. Daratumumab targets CD38 and inhibits this transfer, which results in impaired AML growth and improved animal survival. Here, we investigate the effect of inhibiting both CD38 with daratumumab and BCL2 with Venetoclax on the survival of AML. Primary AML blasts and MSC were isolated from patients' bone marrow in accordance with the Declaration of Helsinki. Flow cytometry was used to measure CD38 and BCL2 expression in AML blasts compared to normal CD34+ progenitor cells. BCL2 expression was significantly higher in AML blasts and CD38 expression was also increased. Cell viability was significantly reduced following treatment with Venetoclax alone, whilst Daratumumab alone or in combination with Venetoclax did not affect AML survival further. However, the action of daratumumab relies on the bone marrow microenvironment and AML blasts were therefore co-cultured with MSC and then treated with Venetoclax or daratumumab or in combination. After 24 hours cells were stained with Annexin V-FITC/PI and flow cytometry was used to assess levels of apoptosis. Combination treatment with Venetoclax and Daratumumab resulted in significantly more apoptosis in AML cells compared to AML cells treated with single agent. Finally, the effect of combination treatment with Venetoclax and Daratumumab was assessed in vivo using an NSG xenograft mouse model of AML. Mice were engrafted with MV411-luc or patient derived AML and then treated with vehicle control (PBS) or daratumumab alone (5mg/kg on day 7 and 14) or Venetoclax alone (100mg/kg/day) or both daratumumab and Venetoclax. Bioluminescence imaging was used to assess disease engraftment and progression before and after treatment. Combining treatment with Daratumumab and Venetoclax in vivo significantly reduced tumour burden and improved animal survival compared to control or single agent.
This data supports that combination treatment with Venetoclax and Daratumumab could have an important clinical application in the treatment of AML.
Citation Format: Charlotte Hellmich, Jayna J. Mistry, Amelia Lambert, Jamie A. Moore, Aisha Jibril, Angela Collins, Kristian M. Bowles, Stuart A. Rushworth. Targeting BCL-2 and CD38 in models of acute myeloid leukemia reduces tumour burden [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1048.