Phase 3 BRUIN CLL-322 Trial Supports Fixed-Duration Pirtobrutinib Regimen as Potential New Standard in Relapsed/Refractory CLL

According to emerging data from the phase 3 BRUIN CLL-322 trial (NCT04965493) presented during the Late-Breaking Oral Session at the European Hematology Association (EHA) 2026 Congress, fixed-duration pirtobrutinib (Jaypirca; Eli Lilly and Company) combined with venetoclax (Venclexta, AbbVie Inc) and rituximab (Rituxan, Genentech) significantly improved progression-free survival (PFS) in comparison with venetoclax and rituximab alone in patients with previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).¹

The addition of pirtobrutinib reduced the risk of disease progression or death by 45% compared with venetoclax and rituximab (HR, 0.547; 95% CI, 0.400-0.748; P=.0001).¹ PFS rates were 86.9% at 24 months in patients treated with pirtobrutinib, venetoclax, and rituximab (PVR) in comparison with 71.8% in those receiving venetoclax and rituximab (VR).¹ The researchers of the trial noted that these findings represent the first randomized phase 3 evidence supporting the incorporation of a BTK inhibitor into a fixed-duration regimen for relapsed or refractory CLL, potentially establishing a new standard of care for this patient population.¹˒²

Advancing Fixed-Duration Treatment Strategies in CLL

The introduction of targeted therapies, particularly Bruton tyrosine kinase (BTK) inhibitors and BCL2 inhibitors, has caused the treatment landscape for CLL to shift dramatically over the past decade.³ Although these agents have improved outcomes and reduced reliance on chemotherapy, treatment sequencing following progression on covalent BTK inhibitors remains a major clinical challenge.¹˒³

Venetoclax plus rituximab is currently a standard fixed-duration treatment option for patients with relapsed or refractory disease.¹ However, prospective data evaluating treatment strategies following exposure to covalent BTK inhibitors are limited despite these therapies now being widely used in the frontline setting.¹

Pirtobrutinib is a highly selective noncovalent BTK inhibitor designed to maintain activity in the presence of resistance mechanisms that can emerge during treatment with covalent BTK inhibitors.⁴ Previous studies have demonstrated clinical activity in both BTK inhibitor–naïve and BTK inhibitor–exposed patients, leading to regulatory approvals in relapsed or refractory CLL/SLL.²˒⁴

The BRUIN CLL-322 trial was designed to determine whether the combination of pirtobrutinib with venetoclax and rituximab could deepen responses and improve long-term outcomes through simultaneous inhibition of BTK and BCL2 signaling pathways.¹

BRUIN CLL-322 Trial Design

In the international phase 3 study, researchers randomly assigned 639 patients with relapsed or refractory CLL/SLL to receive either fixed-duration PVR (n = 321) or standard VR (n = 318).¹ Patients with prior exposure to noncovalent BTK inhibitors or BCL2 inhibitors were excluded.¹

Both groups received venetoclax for 25 cycles and rituximab for 6 cycles.¹ Patients assigned to the investigational arm additionally received fixed-duration pirtobrutinib for 28 cycles, including a 3-cycle pirtobrutinib-rituximab lead-in period before venetoclax initiation.¹

The primary end point was independent review committee–assessed PFS according to International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 criteria.¹ Secondary end points included investigator-assessed PFS, overall survival (OS), time to next treatment (TTNT), overall response rate, and safety.¹

The median age was 68 years, and patients had received a median of 2 prior lines of therapy.¹ Notably, 79.8% of patients had prior exposure to a covalent BTK inhibitor, and 71.0% of those patients had discontinued treatment because of progressive disease.¹

Pirtobrutinib Combination Demonstrates Superior Disease Control

At a median follow-up of 27.3 months, PVR demonstrated statistically significant superiority over VR for the primary end point of PFS.¹ The benefit was observed across all major prespecified patient subgroups, including patients with prior covalent BTK inhibitor exposure, those who discontinued prior BTK inhibitor therapy because of disease progression, and patients harboring high-risk del(17p) or TP53 abnormalities.¹

Beyond improving PFS, PVR also delayed the need for subsequent therapy.¹ Time to next treatment favored the pirtobrutinib-containing regimen, reducing the risk of requiring additional treatment by approximately 50% compared with VR alone (HR, 0.498; 95% CI, 0.352-0.704).¹

Although overall survival data remain immature, early analyses favored PVR (HR, 0.891; 95% CI, 0.568-1.398).¹ Investigators also observed deeper responses with the triplet regimen. Among patients with evaluable samples, peripheral blood undetectable minimal residual disease at a sensitivity threshold of 10⁻⁴ was achieved in 86% of patients receiving PVR compared with 61% receiving VR (P < .0001).¹

These findings suggest that the addition of pirtobrutinib may not only prolong disease control but also increase the depth of remission achieved with fixed-duration treatment.¹

Safety Profile Remains Manageable

The safety findings were generally consistent with the established profiles of the individual agents and did not reveal unexpected toxicities.¹ Rates of any-grade adverse events were similar between treatment groups, occurring in 99.7% of patients receiving PVR and 98.1% of those receiving VR.¹ Grade 3 or higher adverse events occurred in 78.8% and 73.0% of patients, respectively.¹

Adverse events commonly associated with BTK inhibition remained relatively infrequent. Any-grade atrial fibrillation or flutter occurred in 3.5% of patients receiving PVR and 2.6% of those receiving VR, while hypertension occurred in 12.0% and 7.4% of patients, respectively.¹

Neutropenia represented the most common grade 3 or higher adverse event, occurring in 50.3% of patients receiving PVR and 43.7% of those receiving VR.¹ Rates of febrile neutropenia remained low in both treatment groups.¹

Tumor lysis syndrome crucially occurred less frequently in the PVR arm than in the VR arm (0.9% versus 3.9%).¹ Treatment discontinuations because of treatment-related adverse events were nearly identical between groups, occurring in 5.4% and 5.1% of patients, respectively.¹

The addition of pirtobrutinib to a fixed-duration venetoclax-rituximab backbone significantly improved PFS, delayed the need for subsequent therapy, and increased rates of undetectable minimal residual disease without meaningfully increasing treatment discontinuations.¹

If incorporated into future treatment guidelines, fixed-duration PVR could provide clinicians with a highly effective, finite-duration treatment strategy for patients with previously treated CLL/SLL, including those who have progressed following prior covalent BTK inhibitor therapy.¹˒²

References

1. Fixed-duration pirtobrutinib plus venetoclax-rituximab versus venetoclax-rituximab for patients with previously treated CLL/SLL: a phase 3, randomized trial (BRUIN CLL-322). https://library.ehaweb.org/eha/2026/eha-2026/4214968/faculty.presenters.fixed-duration.pirtobrutinib.plus.venetoclaxrituximab.html?f=c_id%3D4207880&utm_source=chatgpt.com Presented at the European Hematology Association 2026 Congress. Abstract LB5001.

2. Eli Lilly and Company. Lilly's Jaypirca (pirtobrutinib) significantly reduced risk of disease progression or death when added to a venetoclax time-limited regimen in patients with previously treated CLL/SLL. Published April 13, 2026. https://investor.lilly.com/news-releases/news-release-details/lillys-jaypirca-pirtobrutinib-significantly-reduced-risk-disease

3. National Cancer Institute. Chronic lymphocytic leukemia treatment (PDQ®)–Health Professional Version. Accessed June 18, 2026. https://www.cancer.gov/types/leukemia/hp/cll-treatment-pdq

4. Jaypirca (pirtobrutinib) prescribing information. Eli Lilly and Company. Accessed June 18, 2026. https://pi.lilly.com/us/jaypirca-uspi.pdf