Preclinical Evaluation of the Novel BTK Inhibitor Acalabrutinib in Canine Models of B-Cell Non-Hodgkin Lymphoma

Abstract

Acalabrutinib (ACP-196) is a second-generation inhibitor of Bruton agammaglobulinemia tyrosine kinase (BTK) with increased target selectivity and potency compared to ibrutinib. In this study, we evaluated acalabrutinib in spontaneously occurring canine lymphoma, a model of B-cell malignancy similar to human diffuse large B-cell lymphoma (DLBCL). First, we demonstrated that acalabrutinib potently inhibited BTK activity and downstream effectors in CLBL1, a canine B-cell lymphoma cell line, and primary canine lymphoma cells. Acalabrutinib also inhibited proliferation in CLBL1 cells. Twenty dogs were enrolled in the clinical trial and treated with acalabrutinib at dosages of 2.5 to 20mg/kg every 12 or 24 hours. Acalabrutinib was generally well tolerated, with adverse events consisting primarily of grade 1 or 2 anorexia, weight loss, vomiting, diarrhea and lethargy. Overall response rate (ORR) was 25% (5/20) with a median progression free survival (PFS) of 22.5 days. Clinical benefit was observed in 30% (6/20) of dogs. These findings suggest that acalabrutinib is safe and exhibits activity in canine B-cell lymphoma patients and support the use of canine lymphoma as a relevant model for human non-Hodgkin lymphoma (NHL).

Mantle cell lymphoma: 2019 update on the diagnosis, pathogenesis, prognostication, and management

“…The relevance of BTK (Bruton's tyrosine kinase) inhibitors in canine lymphoma models by Honigberg and colleagues was a breakthrough in the treatment of B‐cell NHL . This initial report paved the way for landmark clinical trials of ibrutinib in MCL and other B‐cell NHLs .…”

The specific Bruton tyrosine kinase inhibitor acalabrutinib (ACP-196) shows favorable in vitro activity against chronic lymphocytic leukemia B cells with CD20 antibodies

“…Based on our data, we propose that inhibition of IL-6 and TNF-α release by the BTK inhibitors acalabrutinib and ibrutinib may help to mitigate the immediate toxicities associated with anti-CD20 treatment, as shown for ibrutinib during therapy with chimeric antigen receptor T cells. 12 Acalabrutinib monotherapy has shown promising activity in animal models of CLL and lymphoma 13,14 and in CLL patients. 1,15 Like ibrutinib, acalabrutinib is already being tested in combination with anti-CD20 monoclonal antibodies, in particular in B-cell non-Hodgkin lymphoma (www.clinicaltrials.com).…”

New Molecular and Therapeutic Insights into Canine Diffuse Large B Cell Lymphoma Elucidates the Role of the Dog As a Model for Human Disease

“…1 The BCL2 inhibitor venetoclax and the BTK inhibitors ibrutinib and acalabrutinib are examples of drugs that benefited from such a model. [2][3][4] Clinical heterogeneity of canine DLBCL (cDLBCL) is known and early insights into its biological and molecular mechanisms, revealing similarities with the human counterpart, have been reported, but a genomic characterization of this tumor has never been provided. Furthermore, a complete understanding of the molecular mechanisms driving the pathogenesis of cDLBCL is necessary to take more accurate advantage of this comparative model and, also, to improve the clinical outcome of the dogs.…”

“…5 These data fit with the reported frequent inactivation of the NF-kB negative regulator TRAF3 in canine B-cell lymphomas 6 and the anti-tumor activity of BTK inhibitors, specifically active in the human activated B-cell subtype of DLBCL and experimentally used in canine B-cell lymphomas. 3,4 The protein-encoding gene LIN28B appeared as the most upregulated transcript in tumors. While LIN28B does not seem to be a relevant gene for human DLBCL, it is involved in the activation of the NF-kB pathway and MYC in different human and mouse tumor models and its overexpression causes murine peripheral T-cell lymphomas.…”