Jurczak on BTK Inhibitors and the Future of B-Cell Lymphoma Therapy

Wojciech Jurczak, MD, PhD, head of the department of oncology at Maria Sklodowska-Curie National Research Institute of Oncology in Warsaw, Poland, ​​discusses the future of B-cell lymphoma therapy, with a focus on Bruton's tyrosine kinase (BTK) inhibitors and degraders.

BTK inhibitors are used across lymphoma subtypes, including chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), where BTK is chronically upregulated. The first BTK inhibitor approved was ibrutinib (Imbruvica), followed by second-generation inhibitors like acalabrutinib (Calquence), and zanubrutinib (Brukinsa). According to Jurczak, these BTK inhibitors have shown to be more selective and less toxic than other agents, reducing adverse events such as atrial fibrillation.

While currently approved for relapsed/refractory settings, ongoing studies may expand their use to earlier treatment lines. However, repeated BTK pathway inhibition, even with advanced drugs, may lose efficacy over time. Jurczak emphasizes that the future of lymphoma therapy may involve transitioning from BTK inhibitors to BTK degraders, a promising new drug class.

Further, Jurczak explains that the choice of BTK inhibitor often depends on physician preference and patient-specific factors. Ibrutinib remains notable for its efficacy and cost, while second- and third-generation inhibitors are favored for their improved safety profiles.

“Ibrutinib will always be praised for its unique action and its price. It is supposed to be very well marketed in the near future,” Jurczak states. “The second-generation BTK inhibitors, like acalabrutinib, could be marketed for their exemplary adverse event profile, but so would pirtobrutinib and nemtabrutinib. Therefore, the choices will be difficult and will depend on the personal experience of the doctor.”

In lymphomas where BTK inhibition is less effective, such as follicular lymphoma, zanubrutinib combined with rituximab (Rituxan) is a key option.

“For lymphomas where BTK inhibition is less effective, like follicular lymphoma, we need a very strong BTK inhibitor. Currently, only zanubrutinib in combination with rituximab is approved in this setting,” he continues.