Medically reviewed by Dr. Brian Koffman
The Bottom Line:
Resistance mutations in BTK and PLCG2 are common in patients with CLL who progress on acalabrutinib.
Who Performed the Research and Where Was it Presented:
Dr. Clare Sun from the National Heart, Lung, and Blood Institute of NIH and colleagues presented the results at the American Society for Hematology (ASH) Annual Meeting 2023.
Background:
Bruton tyrosine kinase inhibitors (BTKi) are one of the main treatments for chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). They are very effective but must be taken continuously indefinitely as a single agent. Over time, patients can develop resistance mutations that reduce the efficacy of these drugs. Most studies of acquired resistance to covalent BTKi have looked at patients treated with ibrutinib. However, less is known about how resistance develops in patients treated with second-generation covalent BTKi, such as acalabrutinib and zanubrutinib.
Methods and Participants:
This study used patient samples from an ongoing phase 2 clinical trial of acalabrutinib for CLL / SLL. Patients had high-risk treatment-naïve disease or relapsed / refractory disease. Samples of peripheral blood mononuclear cells (mainly consisting of all the lymphocytes, cancerous or not, plus a few monocytes and other types of cells) were collected at the start of the study, six months after starting treatment, and then yearly until disease progression. When possible, paired bone marrow or lymph node samples were taken at progression.
Results
- The study enrolled 48 patients; the median follow-up is now 6.5 years.
- Median progression-free survival was 6 years.
- Thus far, 23 patients have developed progressive disease (20 CLL, 3 Richter’s transformation).
- At baseline, 91% of patients had mutations in CLL driver genes (genes that are important to CLL biology and survival).
- During acalabrutinib treatment, 31% of patients acquired a new CLL driver mutation (driver mutations offer an advantage to the clone and can expand it) while in remission.
- Among patients whose disease progressed, 79% had newly acquired mutations in CLL driver genes, most commonly BTK and PLCG2, at the time of progression. 55% of these patients had acquired mutations in BTK.
- Among patients with acquired BTK mutations, all had mutations in the C481 residue, where covalent BTKi bind and 20% also had mutations at the T474I residue.
- BTK mutations were not detected in patients who were in remission on acalabrutinib.
- PLCG2 was mutated in 25% of patients with progressive disease.
Conclusion:
Resistance mutations in BTK and PLCG2 are common in patients with CLL who progress on acalabrutinib. Mutations in the C481 binding site of BTK are a key factor in developing resistance to covalent BTKi. This information can help clinicians decide what would be an appropriate next therapy for patients who progress and plan the best sequencing of treatments.
Links and Resources:
Watch the interview on the abstract here:
You can read the ASH abstract here: Extended Follow-up and Resistance Mutations in CLL Patients Treated with Acalabrutinib.
Take care of yourself first.
Ann Liu, PhD
