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Pirtobrutinib for Patients with Chronic Lymphocytic Leukemia (CLL) Previously Treated with a Covalent BTK Inhibitor

In science and medicine, information is constantly changing and may become out-of-date as new data emerge. All articles and interviews are informational only, should never be considered medical advice, and should never be acted on without review with your health care team.

Medically reviewed by Dr. Brian Koffman

The Bottom Line:

A newly published paper in the New England Journal of Medicine found that pirtobrutinib shows efficacy in patients with heavily pretreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who had received a covalent Bruton tyrosine kinase inhibitor (BTKi). Pirtobrutinib may be an important option to extend the benefit of BTK inhibition among patients who progressed on previous BTKi.

Who Performed the Research and Where Was it Presented:

Dr. Jennifer Woyach from the Ohio State University, Dr. Anthony Mato of Cayuga Health, and colleagues published their findings in the prestigious New England Journal of Medicine in 2023.


While we have previously reported on the results of the BRUIN trial with Dr. Jennifer Woyach and with Dr. Nirav Shah, the most recent findings were recently published in the New England Journal of Medicine. Pirtobrutinib is a non-covalent (reversible) BTKi, which binds to BTK in a different way and at a different site than covalent (irreversible) BTKi such as ibrutinib, acalabrutinib, and zanubrutinib. Pirtobrutinib’s ability to inhibit BTK is not dependent on the binding structure of C481, the common site of resistance mutations for covalent BTKi.

Methods and Participants:

The BRUIN study was a phase 1/2 study of daily pirtobrutinib in patients with relapsed/refractory B-cell cancers, including CLL and SLL.


  • 773 patients with B-cell cancers were enrolled in the trial, including 317 with CLL / SLL.
  • 247 patients with CLL / SLL had previously been treated with a BTK inhibitor.
  • The median number of prior therapies was three and included anti-CD20 antibody (88%), chemotherapy (79%), BCL2 inhibitors (41%), PI3K inhibitors (1%), chimeric antigen receptor (CAR) T-cell therapy (6%), and allogeneic stem-cell transplantation (2%).
  • Approximately 77% of patients had discontinued previous BTKi therapy due to disease progression, and 23% discontinued it due to adverse events or other reasons.
  • Among the patients who had previously received a BTKi, the overall response rate was 73%.
  • Among patients who had previously received both a BTK inhibitor and a BCL2 inhibitor, the overall response rate was 70%.
  • The median progression-free survival was approximately 20 months.
  • Among patients who had received all five classes of available CLL or SLL therapy, including BTK, BCL2, and PI3K inhibitors as well as chemoimmunotherapy, the median progression-free survival was 14 months.
  • Progression-free survival was similar regardless of BTK C481 mutation status or age.
  • The only factor shown to impact the response rate negatively was the downstream gain-of-function mutation of PLCɣ2, where surprisingly, 10 of 18 still responded. One would predict that since this mutation turns the B-cell receptor (BCR) pathway back on downstream from where the pirtobrutinib inhibits it, it wouldn’t work at all, but it clearly does more than half the time.
  • The most common adverse events were infections (71%), bleeding (43%), and low white blood cell counts (33%).
  • Only 3% of patients discontinued pirtobrutinib due to treatment-related adverse events.


Pirtobrutinib shows efficacy in patients with heavily pretreated CLL / SLL who had received a covalent BTK inhibitor. Moreover, it is very well tolerated, with only 3% of patients discontinuing therapy due to  intolerance. This is much better than seen with other BTK inhibitors. Pirtobrutinib may be an important option to extend the benefit of BTK inhibition among patients who progressed on previous BTK inhibitors.

Pirtobrutinib already has been approved for mantle cell lymphoma, so there is reason to expect it will be available “off-label” for CLL / SLL, especially since in June of 2023, the National Comprehensive Cancer Network (NCCN) recommended pirtobrutinib as second-line or third-line therapy in various clinical settings. Full CLL approval is expected after the completion of the Phase 3 trial.

Pirtobrutinib is an important addition to the CLL therapeutic armamentarium, but where its final place in treatment sequencing is still being explored.

Links and Resources:

While the entire article is currently paywalled, here is where you can read the abstract: Pirtobrutinib after a Covalent BTK Inhibitor in Chronic Lymphocytic Leukemia

Take care of yourself first.

Ann Liu, PhD