Authored by Ann Liu, PhD
Medically Reviewed by Ed Ratner, MD
The Bottom Line:
Adding pirtobrutinib to venetoclax–rituximab improved progression-free survival and undetectable measurable residual disease rates in patients with relapsed / refractory CLL.
Who Performed the Research and Where Was it Presented:
Dr. Matthew Davids from Dana-Farber Cancer Institute and colleagues presented the results at the European Hematology Association (EHA) Annual Meeting in 2026.
Background:
Many patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) receive a covalent BTK inhibitor (ibrutinib, acalabrutinib, zanubrutinib) as their first-line therapy. If they develop relapsed / refractory disease at a later date, next-line therapy options can include BCL2 inhibitors (venetoclax) or noncovalent BTKi (pirtobrutinib). Venetoclax in combination with an anti-CD20 monoclonal antibody (rituximab, obinutuzumab) has been a standard-of-care therapy for relapsed / refractory CLL. Pirtobrutinib is a noncovalent BTKi, recently fully approved in the US for those resistant to covalent BTKi (after the Bruin CLL-321 trial). Here, researchers wanted to test whether adding pirtobrutinib to venetoclax-rituximab would improve outcomes for patients with relapsed / refractory CLL.
Methods and Participants:
The BRUIN CLL-322 trial was a phase 3 clinical trial in which patients with relapsed / refractory CLL were randomly assigned to receive either:
- Pirtobrutinib plus venetoclax and rituximab (PVR)
- Venetoclax and rituximab (VR)
Patients received treatment for a fixed-duration of approximately two years.
Results:
- A total of 639 patients enrolled in the study, and the median follow-up was 27 months.
- 80% of patients had previously been treated with a covalent BTKi, and 71% had their disease progress on covalent BTKi.
- At 24 months, 87% of patients in the PVR group were progression-free, and 72% of patients in the VR group were progression-free, which was a statistically significant improvement.
- The improvement in progression-free survival with PVR was seen across subgroups of patients, including patients with deletion 17p / TP53 mutation and patients who had previously progressed on a covalent BTKi.
- More patients in the PVR group (86%) had undetectable measurable residual disease in the blood (uMRD) at the end of treatment than in the VR group (61%).
- The overall rate of side effects was similar between both treatment groups, with about 75% having a significant adverse event.
- Rates of abnormal heart rhythm, high blood pressure, and hemorrhage were low.
- Severely low neutrophils occurred in 50% of patients in the PVR group and 44% of patients in the VR group.
- Approximately 5% of patients in each group discontinued treatment due to intolerable side effects.
Conclusions:
Venetoclax-rituximab is still an effective treatment for relapsed / refractory CLL but adding pirtobrutinib improved efficacy without any major changes in side effects. Adding pirtobrutinib to venetoclax-rituximab improved progression-free survival and uMRD rates, and the incidence of side effects was similar for the two treatment groups. This three-drug fixed-duration combination therapy is particularly promising for patients who have relapsed on a covalent BTKi. An alternative approved treatment is continuous single-drug pirtobrutinib, which had a higher risk of progression after 2 years in the CLL-321 trial than this three-drug regimen, but a lower rate of significant side effects (58%).
Links and Resources:
You can read the actual EHA abstract here: Fixed-Duration Pirtobrutinib plus Venetoclax–Rituximab Versus Venetoclax–Rituximab for Patients with Previously Treated CLL / SLL: A Phase 3, Randomized Trial (BRUIN CLL-322)
Take care of yourself first.
Ann Liu, PhD
