Authored by Ann Liu, PhD
Medically Reviewed by Brian Koffman, MDCM (retired), MSEd
The Bottom Line:
The first-line combination pirtobrutinib, venetoclax, and obinutuzumab produces deep remissions with high rates of uMRD in the majority of patients with CLL. This study is still ongoing, so researchers will continue to monitor patients to see how durable their remissions are.
Who Performed the Research and Where Was it Presented:
Dr. Nitin Jain from The University of Texas MD Anderson Cancer Center and colleagues presented the results at the American Society for Hematology (ASH) Annual Meeting 2024.
Background:
Treatments that have combined covalent BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib) with BCL2 inhibitors (venetoclax, sonrotoclax) have produced high rates of undetectable measurable residual disease (uMRD) in patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). These combination treatments are time-limited and produce deep remissions, making them a potentially attractive option. In this study, researchers evaluated noncovalent BTK inhibitor pirtobrutinib, which has a very good safety profile, in combination with venetoclax and obinutuzumab as a first-line treatment for CLL.
Methods and Participants:
This is a phase 2 clinical trial of a combination of pirtobrutinib, venetoclax, and obinutuzumab in patients with previously untreated CLL. Patients received pirtobrutinib and obinutuzumab for one month before starting venetoclax in order to reduce tumor burden and reduce the risk of tumor lysis syndrome. Measurable residual disease was evaluated in the blood and bone marrow after one year of treatment using next-generation sequencing (can detect 1 in 1 million cells, 10-6 sensitivity). Patients who were MRD-negative stopped therapy. Patients who were MRD-positive continued pirtobrutinib and venetoclax for an additional year. After ending therapy, patients continued to be monitored with regular evaluation of MRD status in the blood.
Results:
- A total of 74 patients enrolled in the study, and the median follow-up is about 10 months.
- After one year of therapy, 89% of patients had uMRD in the blood, and 81% had uMRD in the bone marrow.
- The main serious side effects were low neutrophil count (58%), which is typical of combination therapies, and low platelet count (18%).
- These side effects can usually be managed by temporarily holding the drug, reducing the dose, or providing growth factor support to boost white blood cell counts.
- The study is still ongoing, and patients will continue to be monitored for several years to determine the durability of their remissions.
Conclusions:
A combination of pirtobrutinib, venetoclax, and obinutuzumab produces deep remissions in most patients with CLL as a first-line treatment. This study is still ongoing, so researchers will continue to monitor patients for a long time to see how durable their remissions are. These results are encouraging since we have seen in previous studies that getting to uMRD is associated with longer progression-free survival.
Several questions remain about how to use combination therapies in clinical practice. What is the best combination? How many drugs should patients start on for their first treatment? How should treatments be sequenced? This is especially pertinent for the use of pirtobrutinib as a frontline therapy because it is now only used in the relapsed setting. How will its use before an irreversible covalently binding BTK inhibitor affect the development of resistance mutations and the ability to use both reversible and irreversible BTKi in the same patients? While we may not have answers to these questions yet, the promising results from clinical trials suggest that these new treatment combinations will help patients with long-term disease control.
Links and Resources:
Watch the interview on the abstract here:
You can read the ASH abstract here: Combined Pirtobrutinib, Venetoclax, and Obinutuzumab As First-Line Treatment of Patients with Chronic Lymphocytic Leukemia (CLL)
