The Evolution of BTK Inhibitors in B-Cell Lymphoma

Wojciech Jurczak, MD, PhD, head of the department of oncology at Maria Sklodowska-Curie National Research Institute of Oncology in Warsaw, Poland, ​​discusses advancements in B-cell lymphoma therapy, focusing on novel treatments like immunotherapy and molecular-targeted agents, particularly BTK (Bruton's tyrosine kinase) inhibitors.

BTK inhibitors are key in lymphoma subtypes such as chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), where BTK is chronically upregulated. These inhibitors help overcome resistance, including chemotherapy resistance linked to P53 mutations. While BTK inhibition typically involves time-unlimited therapy, combining it with BCL-2 inhibitors can offer time-limited treatment options.

The evolution of BTK inhibitors began with ibrutinib (Imbruvica), followed by second-generation inhibitors like acalabrutinib (Calquence), which received accelerated approval from the FDA for the treatment of adult patients with MCL who have received at least 1 prior regimen in October 2017, and zanubrutinib (Brukinsa), which was also granted an accelerated approval for the treatment of adult patients with MCL who have received at least 1 prior therapy, in November 2019. These BTK inhibitors are more selective and less toxic, reducing adverse events such as atrial fibrillation.

Third-generation inhibitors, such as pirtobrutinib (Jaypirca), which was first approved in January 2023 for the treatment of adult patients with relapsed/refractory mantle cell lymphoma (MCL) who previously received at least 2 lines of systemic therapy, including a Bruton's tyrosine kinase (BTK) inhibitor, and nemtabrutinib, which is not yet approved, were developed to address resistance mechanisms, particularly in patients with CLL with cysteine mutations at position 481. These newer agents are highly selective, well-tolerated, and achieve 24-hour coverage with inhibitory concentrations above IC90, making them more effective even in non-mutated cases.

“It should be noted that these third-generation inhibitors not only overcome resistance but also have excellent tolerability and even greater selectivity than the second-generation products,” explains Jurczak.