EHA 2026: Triplet therapy improves progression-free survival in relapsed/refractory CLL patients
Adding pirtobrutinib to standard therapy significantly extends progression-free survival in patients with relapsed/refractory chronic lymphocytic leukemia.
Researchers at Dana-Farber Cancer Institute (MA, USA) have reported positive findings on the use of a fixed-duration triplet therapy regimen for patients with relapsed/refractory chronic lymphocytic leukemia (CLL). Led by Matthew Davids (Boston, Massachusetts) and presented at the European Hematology Association 2026 Congress (June 11–14, Stockholm, Sweden), the BRUIN CLL-322 trial (NCT04965493), sponsored by Eli Lily, demonstrated that adding pirtobrutinib to standard venetoclax-rituximab therapy significantly improves progression-free survival (PFS) while maintaining a favorable safety profile.
Chronic lymphocytic leukemia is a blood cancer affecting white blood cells that impacts thousands of patients worldwide, with many experiencing disease relapse after initial treatment. Patients typically receive covalent Bruton tyrosine kinase (BTK) inhibitors such as ibrutinib, acalabrutinib or zanubrutinib as first-line therapy. Standard second-line treatment combines venetoclax, a BCL-2 inhibitor, with rituximab, an anti-CD20 immunotherapy. This doublet regimen has been the standard of care for approximately 8 years, though questions have emerged about its effectiveness in patients who have progressed after modern BTK inhibitor therapy. The BRUIN CLL-322 trial offers new hope, showing that adding a third targeted agent could improve outcomes for this challenging disease.
This randomized Phase III study enrolled 639 patients with relapsed/refractory CLL, the majority of whom had previously received a covalent BTK inhibitor. Patients were randomized to receive either triplet therapy (pirtobrutinib, venetoclax and rituximab) or standard doublet therapy for approximately 2 years. The results were compelling: at 2 years, 86.9% of patients receiving triplet therapy remained alive without disease progression compared to 71.8% receiving the doublet, representing a 45% reduction in the risk of disease worsening or death. Additionally, undetectable minimal residual disease (MRD) rates at the end of treatment were substantially higher with the triplet therapy at 86% versus 61% with the doublet.
“When pirtobrutinib is added to the standard venetoclax-rituximab regimen, we see a substantial improvement in progression-free survival, even better than we hypothesized,” explained Davids. “That speaks to the power of the triplet-based therapy over the doublet and supports consideration of the triplet as a new standard of care option for relapsed/refractory CLL.”
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The trial outcomes demonstrate consistent benefits across multiple high-risk patient subgroups, including those with prior BTK inhibitor exposure, resistance to these agents and TP53 aberrations. Notably, the addition of pirtobrutinib resulted in minimal additional side effects. “Pirtobrutinib is one of the best tolerated targeted drugs we use in CLL,” noted Davids. “Patients are getting this added progression-free survival benefit without much added toxicity, suggesting that this triplet therapy can benefit a wide range of patients, including older patients with other medical comorbidities.”
These findings represent the first randomized Phase III data for a BTK inhibitor as part of fixed-duration therapy in relapsed/refractory CLL. Pirtobrutinib, a non-covalent BTK inhibitor, received full FDA approval in 2025 as single-agent therapy for patients with relapsed/refractory CLL.
The time-limited nature of the triplet therapy offers advantages over continuous therapy approaches, including reduced treatment burden and potential for future retreatment strategies. While longer follow-up is needed to evaluate overall survival, the BRUIN CLL-322 trial establishes a new benchmark for treating relapsed/refractory CLL in the era of targeted therapies.