Lilly’s Jaypirca cuts risk of disease progression or death by 45% when paired with a time-limited venetoclax regimen in previously treated CLL/SLL

Eli Lilly and Company has shared results from the Phase 3 BRUIN CLL-322 trial, which examined Jaypirca (pirtobrutinib), a non-covalent Bruton tyrosine kinase inhibitor, combined with venetoclax and rituximab against venetoclax and rituximab alone in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma. The trial achieved its primary endpoint, measured through independent review committee assessment of progression-free survival, with the addition of pirtobrutinib to a two year venetoclax and rituximab regimen lowering the risk of disease progression or death by 45%.

These findings are set to be presented during a late-breaking oral session at the 2026 European Hematology Association Annual Meeting in Stockholm, Sweden, and will also feature within the meeting’s press programme.

“These results from BRUIN CLL-322 show that the addition of pirtobrutinib as part of a time-limited regimen further enhanced an already effective treatment and extended the duration of remission for patients with previously treated CLL. Importantly, the study provides the first robust evidence for such an approach in patients who received a prior BTK inhibitor,” said Matthew S. Davids, M.D., M.M.Sc., Chief of the Division of Lymphoma at Dana-Farber Cancer Institute, lead author on the study. “Time-limited regimens are an important option in CLL care and provide patients with meaningful treatment-free intervals. In the context of the modern CLL treatment landscape, where many patients may only receive two lines of therapy, these results speak to the potential benefits that improving second-line therapy can have. Our study has the potential to establish a new standard of care in this population.”

The trial brought together 639 patients with relapsed or refractory disease, four out of five of whom had previously been exposed to a covalent BTK inhibitor. Participants were split evenly between two arms, one receiving pirtobrutinib alongside venetoclax and rituximab, the other receiving venetoclax and rituximab on its own. Those assigned to the combination arm began with three cycles of pirtobrutinib and the initial three cycles of rituximab before venetoclax was added to the regimen. Based on a data cutoff in early February 2026 and a median follow up exceeding two years, the trial demonstrated a significant improvement in progression-free survival with the three drug combination compared to the two drug regimen. Median progression-free survival had not yet been reached in the combination arm, while the comparator arm reached a median of just under 40 months. This advantage held consistently across predefined subgroups, including those previously exposed to covalent BTK inhibitors, those who had stopped a prior covalent BTK inhibitor due to disease progression, and those carrying high-risk genetic features such as unmutated IGHV, TP53 mutations, 17p deletion, or complex karyotype. Looking specifically at second-line patients whose disease had progressed following an initial covalent BTK inhibitor, median progression-free survival again was not reached in the combination arm, compared to roughly 28 months in the comparator arm, with two-year progression-free survival rates of 88% versus 52% respectively, a benefit that held steady regardless of which covalent BTK inhibitor patients had previously received.

Overall survival, tracked as a key secondary endpoint, remained too early to draw firm conclusions from at this stage, with final analysis of overall survival superiority planned for a later date. Time to next treatment, another secondary endpoint, consistently favored the pirtobrutinib combination.

Safety data from BRUIN CLL-322 aligned with what is already known about each medicine individually, with minimal additional toxicity introduced by adding pirtobrutinib to venetoclax and rituximab. Rates of grade 3 or higher adverse events were broadly comparable between the combination and control arms, at 78.8% and 73.0% respectively. Low rates of atrial fibrillation or flutter, hypertension, and hemorrhage of any grade were observed in both arms, though all ran somewhat higher in the combination group. Among adverse events of particular clinical interest at grade 3 or above, neutropenia occurred more frequently in the combination arm, while tumor lysis syndrome was less common there than in the control arm. Discontinuation rates linked to treatment-related adverse events were similar between the two groups. Notably, adding pirtobrutinib to the regimen allowed many patients to be reclassified to a lower tumor lysis risk category, with the majority of high-risk and medium-risk patients downgraded accordingly.

“These remarkable findings support the potential addition of two years of Jaypirca to a time-limited venetoclax-based regimen in relapsed or refractory CLL,” said Jacob Van Naarden, Executive Vice President and President of Lilly Oncology. “BRUIN CLL-322 enrolled a mostly covalent BTK inhibitor-pretreated population, ensuring that these results have applicability to the modern CLL treatment landscape where covalent BTK inhibitor use is now common. Additionally, these data further strengthen the unique body of evidence for Jaypirca across the CLL continuum, from monotherapy to combination therapy and across multiple settings where CLL patients need effective treatment.”

Lilly intends to submit the BRUIN CLL-322 findings to regulatory authorities worldwide as part of an effort to broaden Jaypirca’s approved label.

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CLL/SLL, Eli Lilly, jaypirca, Lilly's Jaypirca (pirtobrutinib)