CLL cells can sometimes mutate and develop resistance to treatment, but researchers are working to overcome this challenge.

• Understanding resistance mechanisms: By studying how CLL cells evolve, scientists are identifying the specific genetic changes that lead to drug resistance. For example, mutations in the BTK or PLCG2 genes can lead to resistance to BTK inhibitors.
• Developing next-generation therapies: Non-covalent BTK inhibitors, like pirtobrutinib, are designed to target CLL cells even if they have developed resistance to covalent BTK inhibitors like ibrutinib,  acalabrutinib, and zanubrutinib. However, CLL cells can also become resistant to pirtobrutinib.
• Exploring alternative pathways: Researchers are investigating drugs that work through different mechanisms, such as PI3K inhibitors and SYK inhibitors, to provide more options for patients with resistant CLL.