This article has been medically reviewed by Dr. Brian Koffman on May 7, 2023.
The Bottom Line:
Pirtobrutinib can extend the benefits of Bruton tyrosine kinase inhibitors (BTKi) in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who are resistant to covalent BTKi. However, for those who eventually become resistant to pirtobrutinib, results from laboratory cell culture studies suggest that combination therapies may be the most effective next step.
Who Performed the Research and Where Was it Presented:
Dr. Bill Wierda from MD Anderson Cancer Center and colleagues presented the results at the American Society for Hematology Annual Meeting in 2022.
Background:
Covalent Bruton tyrosine kinase inhibitors (BTKi) such as ibrutinib, acalabrutinib, and zanubrutinib are highly effective therapies for CLL / SLL. Still, these treatments can fail if the patient develops resistance (usually through a mutation at the C481 position of BTK) or intolerance. Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi, which inhibits both wildtype and C481-mutant BTK. As previously reported, pirtobrutinib has clinical activity in patients who have previously been treated with a covalent BTKi and in patients who have C481-mutant BTK. However, after approximately 19 months, about half of the patients treated with pirtobrutinib had developed progressive disease.
In this video, Dr. Matthew Davids, Director of the Center for Chronic Lymphocytic Leukemia (CLL) at Dana-Farber Cancer Institute, interviewed Dr. Bill Wierda, a Professor of Medicine in the Department of Leukemia at MD Anderson Cancer Center in Houston, Texas. They discussed the results of a laboratory study of cells from CLL patients who developed resistance to pirtobrutinib.
Methods and Participants:
This study used a subset of patients from the BRUIN trial, a phase 1/2 clinical trial testing pirtobrutinib in patients with previously treated B-cell malignancies, including those with CLL / SLL. In addition, this study specifically used samples from patients with CLL who progressed on pirtobrutinib. Tumor samples were taken from these patients, and these cells were then used in laboratory experiments where they were exposed to different drugs.
Results:
- Thirteen patients with CLL developed progressive disease while on pirtobrutinib.
- At the start of therapy, 11 of these patients had mutant BTK (85%), and two patients had wildtype-BTK (15%), suggesting that mutant BTK may be more likely to have disease recurrence while on pirtobrutinib therapy.
- Samples of CLL cells were obtained from patients after progression, and the cells were incubated with different drugs, including ibrutinib, venetoclax, APR-246 (a glutathione inhibitor), AZD5991 (an MCL1 antagonist), or double or triple combinations.
- Among single-agent treatments, venetoclax was the most effective at inducing cell death, but overall single, agent treatments weren’t great at killing these highly resistant cells.
- Combinations treatments (e.g., ibrutinib plus venetoclax or venetoclax plus AZD5991) were much more effective than single agents, which may warrant further study in the clinic.
- These laboratory results give us insight into the next steps for patients who progress on pirtobrutinib.
Conclusions:
For patients with CLL / SLL who eventually become resistant to pirtobrutinib, results from laboratory cell culture studies suggest that combination therapies may be the most effective next step.
Links and Resources:
Watch the interview on the abstract here:
You can read the actual ASH abstract here: Pharmacological Profiling of Cells from Patients with Chronic Lymphocytic Leukemia (CLL) Treated with Pirtobrutinib.
Take care of yourself first.
Ann Liu, PhD
