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).
Highlights
B-cell receptor (BCR) signaling is a critical factor in the progression of many subtypes of B-cell non-Hodgkin lymphoma (NHL)
We investigated whether similar pathway inhibition could be achieved using acalabrutinib in canine lymphoma cells
The canine B-cell lymphoma line CLBL1 was treated with varying concentrations of acalabrutinib for 1 hour, and stimulated with anti-IgM and subjected to analysis of the BCR signaling pathway
Summary
B-cell receptor (BCR) signaling is a critical factor in the progression of many subtypes of B-cell NHL. This signaling is driven through a variety of mechanisms, including BCR binding to self or foreign antigen[1,2,3,4,5,6,7], overexpression or aberrant expression of signal transducers[8,9], and oncogenic somatic mutations driving distal signaling pathways[10,11]. Preclinical development of ibrutinib included treatment of dogs with B-cell lymphoma [17], perhaps because many similarities to human NHL are recapitulated in canine B-cell lymphoma, including histologic characteristics and response to chemotherapeutics. Similar to DLBCL in humans, differences in progression-free and overall survival were found between the ABC-like and GCB-like canine patients
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