(O29) BTK and BET Inhibition in Canine Lymphoma

Background – Canine B-cell lymphoma is a heterogenous group of neoplasms commonly treated with chemotherapy. Long-term remissions are uncommon and novel therapeutics are needed.

Hypothesis/Objectives – The goal of our research was to evaluate tolerability and efficacy of combined inhibition of BTK (Bruton’s tyrosine kinase) and BET (bromodomain and extraterminal domain) in dogs.

Animals – Three healthy, adult, research Beagles and 5 client-owned dogs with B-cell lymphoma.

Methods – First, a modified toxicity study was performed in research dogs. These dogs received the BET inhibitor mivebresib (0.1 mg/kg/day by mouth) and the BTK inhibitor ibrutinib (5 mg/kg/day by mouth) in combination for 4 weeks. Subsequently, 5 client-owned dogs received mivebresib (0.05 mg/kg/day by mouth) and ibrutinib (5 mg/kg/day by mouth) in an 8-week pilot study.

Results – During the modified toxicity study, 2 of 3 dogs experienced transient thrombocytopenia and one dog experienced self-limiting decreased stool consistency. Median treatment duration in client-owned dogs was 34 days (range, 7 – 57). Grade 2 diarrhea was the most common adverse event (n=3). Mivebresib dosage was reduced in 2 dogs. No grade 3 or 4 toxicities were observed. Two dogs with stage V disease experienced a clinical response, specifically a decrease in size of target lesions of 21% and 38%, with the date of maximum response occurring after 6 weeks of treatment in both dogs.

Conclusions and clinical importance – Inhibition of BTK and BET has clinical activity in canine B-cell lymphoma. Additional studies to fully define tolerability and efficacy are indicated.