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Pirtobrutinib and Prior BCL2 Inhibitor Exposure in CLL

In science and medicine, information is constantly changing and may become out-of-date as new data emerge.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:

Long-term follow-up shows that pirtobrutinib is effective in patients with CLL who have received multiple prior lines of therapy, including BCL2 inhibitors. It is well-tolerated, and side effects are limited.

Who Performed the Research and Where Was it Presented:

Dr. Jennifer Woyach and colleagues from Ohio State University presented the results at the American Society for Hematology (ASH) Annual Meeting 2023.


Pirtobrutinib is a noncovalent (reversible) Bruton tyrosine kinase inhibitor (BTKi) that blocks the same pathways as covalent (irreversible) BTK inhibitors ibrutinib, acalabrutinib, and zanubrutinib. Pirtobrutinib can effectively treat chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) even after patients have developed resistance mutations to covalent BTK inhibitors because they bind differently. In December 2023, the FDA approved pirtobrutinib for treating relapsed or refractory CLL and SLL in patients who have already received a covalent BTK inhibitor and a BCL2 inhibitor. In this study, researchers looked at patient responses to pirtobrutinib after over two years of follow-up and whether prior BCL2 inhibitor exposure affected responses.

Methods and Participants:

The BRUIN study was a phase 1/2 clinical trial of pirtobrutinib in patients with relapsed / refractory CLL or SLL


  • The study included 282 patients previously treated with a covalent BTK inhibitor.
  • Of these patients, 55% had not received prior BCL2 inhibitor therapy, and 45% had previously been treated with a BCL2 inhibitor.
  • The median follow-up was approximately 30 months (over two years).
  • The median progression-free survival is a little over 19 months with pirtobrutinib treatment.
  • Patients exposed to BCL2 inhibitors and patients who were BCL2 inhibitor-naïve responded similarly to pirtobrutinib with response rates of around 80%.
  • The time in remission (progression-free survival) was longer in patients who were BCL2 inhibitor-naïve (23 months) compared with patients who were BCL2 inhibitor-exposed (16 months), which may be due to them having been exposed to fewer lines of treatment previously.
  • Pirtobrutinib was generally well-tolerated, and the most common side effects included fatigue (37%), diarrhea (28%), cough (27%), and bruising (26%).


Pirtobrutinib is effective in patients with CLL who have received multiple prior lines of therapy, including BCL2 inhibitors. It is well-tolerated, and side effects are limited. If you are interested in participating in a clinical trial using pirtobrutinib, these are some phase 3 clinical trials that are currently enrolling participants:

  1. A Study of Pirtobrutinib (LOXO-305) Versus Ibrutinib in Participants With Chronic Lymphocytic Leukemia (CLL)/​Small Lymphocytic Lymphoma (SLL) (BRUIN-CLL-314)
  2. A Trial of Pirtobrutinib (LOXO-305) Plus Venetoclax and Rituximab (PVR) Versus Venetoclax and Rituximab (VR) in Previously Treated Chronic Lymphocytic Leukemia/​Small Lymphocytic Lymphoma (CLL/​SLL) (BRUIN CLL-322)

    Several smaller trials are also being conducted at various sites throughout the US, so it is worth checking on to see if there are any near you.

    Links and Resources:

    Watch the interview on the abstract here:

    Pirtobrutinib and Prior BCL2 Inhibitor Exposure in CLL – ASH 2023 Dr. Jennifer Woyach

    You can read the ASH abstract here: Pirtobrutinib in Post-cBTKi CLL / SLL: ~30 Months Follow-up and Subgroup Analysis With/Without Prior BCL2i from the Phase 1/2 BRUIN Study.

    Take care of yourself first.

    Ann Liu, PhD