Dr Wiestner on an Extended Follow-Up Study of Resistance Mutations With Acalabrutinib in CLL

Adrian Wiestner, MD, PhD, senior investigator, Lymphoid Malignancies, lead, Laboratory of Lymphoid Malignancies, Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, discusses an extended follow-up investigation into resistance mutations in patients with chronic lymphocytic leukemia (CLL) who were treated with acalabrutinib (Calquence). 

Data from this phase 2 study were presented at the 2023 ASH Annual Meeting. This trial investigated the use of acalabrutinib in patients with treatment-naive CLL or small lymphocytic lymphoma (SLL) who presented with 17p deletion, TP53 mutations, or NOTCH1mutations, as well as those with relapsed/refractory CLL/SLL.

This phase 2 clinical trial was a single-center exploration that studied the efficacy of acalabrutinib—a second-generation BTK inhibitor that offers a potentially favorable adverse effect (AE) profile, Wiestner begins. Notably, with a median follow-up of 6.5 years, the trial demonstrates treatment adherence, he states. The primary objective of this study is to determine the reasons for patient progression, Wiestner elucidates.

BTK inhibitor resistance often correlates with mutations in BTK that affect the cysteine residue that is crucial for drug attachment, or downstream mutations in PLCG2—an immediate signaling molecule, he expands. The study revealed that these mutations are present in approximately 80% of patients with CLL who progress, underscoring the dominant mechanism of resistance to BTK inhibitors, Wiestner explains. This clinical insight sheds light on potential CLL management strategies, he notes.

The findings from the phase 2 trial indicate a need to retarget the same signaling pathway affected by these mutations, Wiestner continues. Noncovalent BTK inhibitors, exemplified by pirtobrutinib (Jaypirca), have emerged as viable treatment options for patients with disease harboring 17p deletions, TP53 mutations, or NOTCH1 mutations, he states. Additionally, BTKdegraders utilizing the cellular proteasome system to degrade BTK are under investigation, Wiestner adds.

Understanding mechanisms of BTK inhibitor resistance, especially through comprehensive sequencing approaches, is important for informing the development of targeted and effective treatment strategies for patients with CLL, he concludes.