Introduction

The small molecule BH3 mimetic venetoclax (VEN) leads to rapid apoptosis of human haematological cancers via BCL2 inhibition and is approved for treatment of relapsed/refractory chronic lymphocytic leukaemia (CLL) and acute myeloid leukaemia. In dogs, BCL2 is diffusely expressed in B-cell lymphoma, and may be over-expressed in peripheral T-cell lymphoma. This study assessed the ex vivo viability of primary canine haematological cancer cells following treatment with VEN and the dual BCL2/BCLxL inhibitor, navitoclax (NAV).

Methods

Peripheral blood mononuclear cells and/or lymph node and/or bone marrow samples were collected from dogs with lymphoma (LSA), leukaemia, and multiple myeloma (MM) from July 2019–March 2021. Cells were incubated with BH3 mimetics for 24 hours at various concentrations (2–10000nM). Viable cells were enumerated by flow cytometry using propidium iodide exclusion and surface staining of CD3 and CD21. Half maximal effective concentration (EC50) was determined.

Results

Nineteen dogs were included in the final analysis: 6 intermediate-large B cell LSA, 3 peripheral T-cell lymphoma (PTCL), 4 acute leukaemias, 2 T-cell CLL, 2 null-cell large cell LSA, 1 T-zone LSA (TZL), and 1 MM. All dogs with PTCL, TZL, and T-CLL showed marked sensitivity to VEN and NAV, whilst all intermediate to large B cell LSA, MM, and null cell LSA cells were resistant to VEN. Sensitivity in acute leukaemia varied, though 3 samples were sensitive to NAV.

Conclusion

Canine T cell malignancies are killed by BH3 mimetics at concentrations achievable in vivo, thus, VEN may be a novel therapeutic agent for treatment of these diseases.

Funding Information

Funding for the project was provided, in part, by The Canine Research Foundation and Dogs Victoria, and the University of Melbourne Resident Research Grant.