Authored by Ann Liu, PhD
Medically Reviewed by Brian Koffman, MDCM (retired), MSEd
The Bottom Line:
Patients with CLL / SLL who were treated with zanubrutinib continue to experience deep sustained responses six years out with no new safety issues.
Who Performed the Research and Where Was it Presented:
Dr. Constantine Tam from Alfred Hospital and Monash University and colleagues presented the results at the American Society for Hematology (ASH) Annual Meeting 2024.
Background:
Bruton tyrosine kinase (BTK) inhibitors are very effective in treating chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Still, they must be taken continuously, which can lead to side effects over time. Ibrutinib was the first BTK inhibitor approved for use in CLL / SLL, but it can cause cardiovascular side effects like abnormal heart rhythm and high blood pressure. Next-generation covalent BTK inhibitors acalabrutinib and zanubrutinib have maintained the efficacy of ibrutinib while improving safety. Zanubrutinib is the newest of the covalent BTK inhibitors. In this study, researchers looked at the long-term safety and efficacy of zanubrutinib in patients with CLL / SLL.
Methods and Participants:
AU-003 and GA-101 were the first clinical studies to test zanubrutinib in patients with B cell cancers, including patients with CLL / SLL. AU-003 evaluated zanubrutinib monotherapy, and GA-101 evaluated zanubrutinib in combination with obinutuzumab. These studies were conducted almost 10 years ago. At the end of each study, eligible patients could enroll in a long-term extension study to continue treatment with zanubrutinib or for long-term follow-up.
Results:
- In total, 170 patients were treated with zanubrutinib in AU-003 and GA-101, and 117 of those patients enrolled in the long-term extension study.
- The median follow-up for both studies is about 6.5 years.
- There were no new, unexpected side effects with prolonged therapy past two years.
- The only side effect that was consistently seen in years two to six was an increased risk of infections.
- Prevalence of atrial fibrillation (abnormal heart rhythm) remained low (2-5%).
- The prevalence of high blood pressure was between 15% and 20%, which was not unexpected because blood pressure tends to increase with age, and the median age of patients in these studies was 71 years.
- 100% of treatment-naïve patients with CLL responded to zanubrutinib, and 92-94% of patients with relapsed / refractory CLL / SLL responded to treatment.
- The complete response rate has improved over time and is now 36% for treatment-naïve patients. MRD (measurable residual disease) results were not presented.
- Three in four treatment-naïve patients are still progression-free at six years of follow-up.
- The median progression-free survival for patients with relapsed / refractory CLL / SLL is seven years.
Conclusions:
This study provides reassuring data that six years out, the responses to zanubrutinib are durable, and the safety profile remains similar to what was originally seen. Interestingly, the proportion of patients with CLL / SLL who experienced complete remissions has actually increased over time. It seems that when BTK inhibitors are used as a first-line treatment and for a prolonged period of time, a subset of patients can reach complete remission.
Links and Resources:
Watch the interview on the abstract here:
You can read the actual ASH abstract here: Deep and Sustained Responses in Patients with CLL Treated with Zanubrutinib or Zanubrutinib + Obinutuzumab in Phase 1/2 AU-003 and Phase 1b GA-101 Studies: A Report from the Zanubrutinib Extension Study
