Clinical Summary: 

• Design/Population: The phase 3 BRUIN CLL-322 trial compared fixed-duration pirtobrutinib plus venetoclax and rituximab with venetoclax and rituximab in patients with relapsed or refractory chronic lymphocytic leukemia, including a large proportion previously treated with covalent BTK inhibitors.
• Key Outcomes: Pirtobrutinib plus venetoclax and rituximab significantly improved progression-free survival, delayed time to next treatment, and increased rates of undetectable MRD, with a comparable safety profile.
• Clinical Relevance: These findings support fixed-duration pirtobrutinib plus venetoclax and rituximab as a potential new standard-of-care option, including those previously treated with covalent BTK inhibitors.

Results from the phase 3 BRUIN CLL-322 trial demonstrated that pirtobrutinib plus venetoclax and rituximab significantly improved outcomes compared with venetoclax and rituximab in patients with relapsed/refractory chronic lymphocytic leukemia (CLL).

These results were presented by Matthew Davids, MD, Dana-Farber Cancer Institute, Boston, Massachusetts, at the 2026 European Hematology Association (EHA) Congress in Stockholm, Sweden.

In this study, 639 patients with relapsed or refractory CLL and no prior exposure to noncovalent BTK inhibitors or BCL2 inhibitors were randomized 1:1 to receive either pirtobrutinib plus venetoclax and rituximab (n = 321) or venetoclax plus rituximab (n = 318), stratified by del(17p) status and prior covalent BTK inhibitor exposure. Patients in the pirtobrutinib arm received a 3-cycle lead-in of pirtobrutinib plus rituximab before venetoclax initiation.

The primary end point was progression-free survival (PFS) as assessed by an independent review committee. Key secondary end points included investigator-assessed PFS, overall survival (OS), time to next treatment, overall response rate (ORR), and safety.

At a median follow-up of 27.3 months, median PFS was not estimable in the pirtobrutinib plus venetoclax and rituximab arm and was 39.7 months in the venetoclax plus rituximab arm (hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.40-0.75; P = .0001). The 24-month PFS rates were 86.9% and 71.8%, respectively. The PFS benefit was consistent across prespecified subgroups, including patients with prior covalent BTK inhibitor exposure and those with del(17p) or TP53-mutated disease.

Median investigator-assessed PFS was not estimable in the pirtobrutinib plus venetoclax and rituximab arm and 44 months in the venetoclax plus rituximab arm. ORRs were 88.5% and 83.3%, respectively. Time to next treatment also favored pirtobrutinib plus venetoclax and rituximab (HR, 0.50; 95% CI, 0.35-0.70). OS data were immature at the time of analysis.

Among patients with evaluable peripheral blood samples, undetectable MRD at a sensitivity threshold of 10^-4 was achieved in 86% of patients receiving pirtobrutinib plus venetoclax and rituximab compared with 61% of patients receiving venetoclax plus rituximab (P < .0001).

Any-grade adverse events were reported in 99.7% of patients in the pirtobrutinib plus venetoclax and rituximab arm and 98.1% of patients in the venetoclax plus rituximab arm. Rates of atrial fibrillation or flutter (3.5% vs 2.6%), hypertension (12.0% vs 7.4%), and hemorrhage (14.2% vs 10.6%) were low in both treatment groups. Grade ≥3 adverse events occurred in 78.8% and 73.0% of patients, respectively, and most commonly included neutropenia (50.3% vs 43.7%), including febrile neutropenia (2.2% vs 3.5%). Grade ≥3 tumor lysis syndrome occurred in 0.9% and 3.9% of patients, respectively. Treatment-related adverse events led to treatment discontinuation in 5.4% and 5.1% of patients, respectively. 

“BRUIN CLL-322 provides the first randomized phase 3 data for any BTKi as part of a fixed-duration regimen in [relapsed or refractory] CLL, including in pts previously treated with cBTKi, and establishes fixed-duration [pirtobrutinib plus venetoclax and rituximab] as a potential new [standard of care],” concluded Dr Davids. 

Source: 

Davids M, Eyre TA, Woyach J, et al. Fixed-duration pirtobrutinib plus venetoclax-rituximab versus venetoclax-rituximab for patients with previously treated CLL/SLL: A phase 3 randomized trial (BRUIN CLL-322). Presented at EHA Congress. June 11 - June 14, 2026. Stockholm, Sweden. Abstract EHA-7224.