Authored by Ann Liu, PhD
Medically Reviewed by Brian Koffman, MDCM )retired), MSEd
The Bottom Line:
First-line treatment with combination pirtobrutinib, venetoclax, and obinutuzumab produces deep remissions in patients with CLL. The vast majority of patients achieved undetectable measurable residual disease after one year of treatment.
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 in 2025.
Background:
As the treatment landscape for chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) has changed, combination therapies have become increasingly popular. Combination therapies are given for a limited time, giving patients a break from the burdens of active therapy. Combining a BTK inhibitor (ibrutinib, acalabrutinib, zanubrutinib) with a BCL2 inhibitor (venetoclax) has been shown to produce deep remissions in patients with CLL / SLL. While combination therapies were initially used in the relapsed / refractory setting, they are now being tested as first-line therapies, and the combination of acalabrutinib and venetoclax recently won FDA approval for use in previously untreated CLL. This study examined the efficacy of the triple combination of pirtobrutinib, venetoclax, and obinutuzumab as a first-line therapy for CLL.
Methods and Participants:
This was a phase 2 clinical trial of time-limited, combination therapy with pirtobrutinib, venetoclax, and obinutuzumab (PVO) as first-line treatment for patients with CLL. Measurable residual disease status was measured both by next-generation sequencing, which can detect cancer cells at 1 in a million cells (1 x 10-6), and by flow cytometry, which can detect cancer cells at 1 in 10,000 cells (1 x 10-4). Therapy was given for one year, with the option of a second year of pirtobrutinib plus venetoclax if patients were still MRD+ at the end of one year.
Results:
- A total of 80 patients were enrolled in the study, and the median follow-up at the time of analysis was 19 months.
- At the end of one year of treatment, MRD rates measured by next-generation sequencing (1 x 10-6) were 88% in the blood and 75% in the bone marrow.
- At the end of one year of treatment, MRD rates measured by flow cytometry (1 x 10-4) were 100% in the blood and 97% in the bone marrow.
- After one year, 86% of patients were able to discontinue therapy, and 10 patients were eligible to continue with an additional year of pirtobrutinib-venetoclax.
- Among patients who stopped therapy after one year, none had experienced MRD recurrence with a median follow-up of 9 months.
- PVO suppressed bone marrow activity, and 69% of patients had severely low neutrophil counts (neutropenia), but only 4 patients had the more serious condition of neutropenic fever. 19%of patients had severely low platelet counts.
- No patients in the study had disease progression or died.
Conclusions:
First-line treatment with PVO produced deep remissions in patients with CLL. The vast majority of patients achieved undetectable measurable residual disease after one year of treatment. This is a promising combination therapy for CLL, but there are still unanswered questions about its use. Is this therapy equally effective or better than the recently approved combination of acalabrutinib and venetoclax? Does using pirtobrutinib (a noncovalent BTK inhibitor) in the first-line setting affect the ability to use covalent BTK inhibitors in the future due to the possibility of BTK mutations? While we may not have answers to these questions yet, it definitely looks like combination therapies are here to stay.
Links and Resources:
Watch the interview on the abstract here:
You can read the actual ASH abstract here: Time-limited pirtobrutinib, venetoclax, and obinutuzumab combination in first-line chronic lymphocytic leukemia
