Authored by Ann Liu, PhD
Medically Reviewed by Brian Koffman, MDCM (retired), MSEd
The Bottom Line:
Pirtobrutinib as a first-line therapy significantly improved progression-free survival in patients with CLL / SLL compared with chemoimmunotherapy.
Who Performed the Research and Where Was it Presented:
Dr. Wojciech Jurczak from the National Research Institute of Oncology in Krakow, Poland, and colleagues presented the results at the American Society for Hematology (ASH) Annual Meeting in 2025.
Background:
Pirtobrutinib is a noncovalent Bruton tyrosine kinase inhibitor (BTKi) used to treat chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL). Noncovalent BTKi bind to BTK in a reversible manner, which is different from covalent BTKi, which bind irreversibly. Because of this difference in binding, pirtobrutinib has shown efficacy in patients who had developed resistance to covalent BTKi (ibrutinib, acalabrutinib, zanubrutinib). Pirtobrutinib first received FDA approval as a third-line therapy for patients who had relapsed after being treated with a covalent BTKi and a BCL2 inhibitor. More recently, the FDA removed the requirement of prior treatment with a BCL2 inhibitor, so now pirtobrutinib can be used directly after a covalent BTKi. In this study, researchers looked at the efficacy of pirtobrutinib as a first-line therapy compared with chemoimmunotherapy.
Methods and Participants:
The BRUIN-CLL 313 study is a phase 3, randomized, open-label clinical trial comparing pirtobrutinib with bendamustine-rituximab in previously untreated patients with CLL / SLL. Chemoimmunotherapy was still a standard treatment for CLL / SLL at the time that the trial was designed. High-risk patients with deletion 17p were excluded from the trial because it was already known that they do not respond as well to chemoimmunotherapy.
Results:
- A total of 282 patients were randomly assigned to receive pirtobrutinib or bendamustine-rituximab.
- At two years, 93% of patients in the pirtobrutinib group were progression-free, while 71% of patients in the bendamustine-rirtuximab group were progression-free.
- Pirtobrutinib reduced the risk of disease progression by 80% and improved overall survival.
- The rate of moderate to severe side effects was lower in the pirtobrutinib group (40%) vs the bendamustine-rituximab group (67%).
- Discontinuation rates due to side effects were lower in the pirtobrutinib group (4%) vs the bendamustine-rituximab group (15%).
Conclusions:
Pirtobrutinib as a first-line therapy significantly improved progression-free survival in patients with CLL / SLL compared with chemoimmunotherapy. It was also well-tolerated with low rates of discontinuation due to side effects. While pirtobrutinib is currently only approved as a second-line therapy after a covalent BTKi, data from this study suggest that it could potentially be used as a first-line therapy. As Dr. Jurczak discusses in the interview, first-line pirtobrutinib would likely be most appropriate for older patients with CLL / SLL, who are less likely to need multiple lines of therapy and may not be able to tolerate combination treatments. The concern is that we know that when pirtobrutinib is used in relapsed disease, it can lead to resistance mutations, specifically T474 and L528W, that make not only it, but all the covalent BTKi (ibrutinib, acalabrutinib, zanubrutinib) ineffective. That could limit later options. However, we do not yet know if that would be the case if it were used as a frontline therapy, as the induced resistance mutations might be different when it is used first. In other words, we know we can often get good responses with pirtobrutinib after patients progress on ibrutinib, acalabrutinib, and zanubrutinib, but we do not know if the sequencing was the reverse, and if pirtobrutinib was used frontline, would patients respond to later therapy with a covalent BTKi? Hence, use in older patients may make the most sense as they may never need a second line of therapy. The research is ongoing.
Links and Resources:
Watch the interview on the abstract here:
You can read the actual ASH abstract here: Pirtobrutinib vs bendamustine plus rituximab (BR) in patients with CLL / SLL: First results from a randomized phase III study Examining a non-covalent BTK inhibitor in untreated patients
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