Hematology · Medical Literature
[Articles] Fixed-duration pirtobrutinib plus venetoclax–rituximab versus venetoclax–rituximab for patients with previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (BRUIN CLL-322): an open-label, multicentre, randomised, controlled, phase 3 trial
Abstract
In patients with previously treated chronic lymphocytic leukaemia, PVR showed significant improvement in progression-free survival compared with VR, with consistent results in patients who had previously received covalent BTK inhibitors and no new safety signals. To our knowledge, these results represent the first randomised phase 3 evidence comparing a novel fixed-duration regimen to the current standard of VR in relapsed or refractory chronic lymphocytic leukaemia, supporting PVR as a potential new standard of care.
Clinical relevance
In patients with previously treated relapsed or refractory CLL or SLL, does the addition of fixed-duration pirtobrutinib to venetoclax–rituximab (PVR) improve progression-free survival compared with venetoclax–rituximab (VR) alone, including in patients with prior covalent BTK inhibitor exposure? __SNAPSHOT__ {"studyDesign":"Open-label, multicentre, randomized, controlled, phase 3 trial (prespecified interim analysis; data cutoff February 2, 2026)","setting":"Global, multicentre (international); specific institution types not reported in available abstract","sampleSize":"n=639 (PVR: n=321; VR: n=318); randomized 1:1","population":"Adults with confirmed relapsed or refractory CLL or SLL requiring treatment per iwCLL 2018 criteria with at least 1 prior line of therapy; approximately 80% had prior covalent BTK inhibitor exposure; cBTKi-naïve enrollment capped at approximately 20%; prior noncovalent BTK inhibitor or BCL-2 inhibitor exposure was excluded. Median age 68 years (PVR) and 67 years (VR); majority male (~67–70%). High-risk features including del(17p), TP53 aberrations, unmutated IGHV, and complex karyotype were represented.","intervention":"Fixed-duration pirtobrutinib 200 mg orally once daily for 28 cycles with a 3-cycle pirtobrutinib–rituximab lead-in prior to venetoclax introduction, combined with venetoclax (labeled doses, 25 cycles) and rituximab (6 cycles); total treatment duration up to approximately 2 years","comparator":"Fixed-duration venetoclax (labeled doses, 25 cycles) plus rituximab (6 cycles) alone; total treatment duration up to approximately 2 years; no crossover permitted","primaryOutcome":"Progression-free survival (PFS) as assessed by a blinded independent review committee (IRC)","followUp":"Median follow-up 27.3 months at data cutoff (February 2, 2026)","fundingSource":"Industry (Eli Lilly and Company); regulatory submission planned for 2026"}
Key findings
The primary endpoint was met. PVR demonstrated a statistically significant and clinically meaningful improvement in IRC-assessed PFS over VR alone. The hazard ratio for progression or death was 0.547 (95% CI: 0.400–0.748; p=0.0001), representing a 45.3% reduction in the risk of progression or death. Median PFS was not reached in the PVR arm versus 39.7 months in the VR arm. The 24-month PFS rate was 86.9% with PVR versus 71.8% with VR, yielding an absolute difference of 15.1 percentage points (calculated). NNT to prevent one progression or death event at 24 months: approximately 7 (calculated from absolute risk difference of ~15.1%). PFS benefit was consistent across prespecified subgroups, with the most pronounced benefit in patients with prior covalent BTK inhibitor exposure, including those who discontinued due to disease progression, and in those with high-risk genomic features (TP53 aberrations, del[17p], unmutated IGHV, complex karyotype). Overall survival, a key secondary endpoint, was not mature at the time of this analysis but was trending in favor of PVR. Depth of response was superior with PVR: peripheral blood undetectable MRD (uMRD) at end of treatment was 86% (PVR) versus 61% (VR) in patients with evaluable samples. Safety: Grade ≥3 adverse events occurred in 78.8% (PVR) versus 73.0% (VR). Notable adverse events included hypertension (12.0% vs 7.4% grade ≥3), atrial fibrillation (3.5% vs 2.6%), and reduced grade ≥3 tumor lysis syndrome (1% vs 4%). Discontinuation rates due to treatment-related adverse events were similar between arms (approximately 5% each). No new safety signals were identified. Neutropenia predominated as the most common grade ≥3 hematologic toxicity in both arms.
Practice implications
BRUIN CLL-322 establishes that fixed-duration PVR is superior to the current standard of fixed-duration VR for PFS in previously treated CLL/SLL, providing the first randomized phase 3 evidence for a BTK inhibitor-containing fixed-duration regimen in the relapsed/refractory setting. The PFS advantage was durable (median not yet reached at ~27 months follow-up) and extended to the clinically critical subgroup of patients with prior covalent BTK inhibitor exposure — a population for whom prospective phase 3 data had previously been absent. The higher uMRD rates observed with PVR are mechanistically coherent and prognostically favorable, though uMRD serves as a secondary/exploratory endpoint and its direct link to OS improvement is not yet established in this trial. Overall survival data are immature, and whether the PFS benefit translates into an OS advantage requires longer follow-up. Patients who previously received a noncovalent BTK inhibitor or a BCL-2 inhibitor were excluded, limiting generalizability to those populations. The benefit of PVR in the frontline setting is unknown. The open-label design introduces potential for performance and detection bias in patient-reported and investigator-assessed endpoints, though the primary PFS endpoint was assessed by blinded IRC. Industry sponsorship (Eli Lilly) is a relevant consideration for interpretation. Only the full publication in The Lancet (July 2026) provides complete data tables, subgroup forest plots, and safety analyses; this summary is based on published abstract-level and congress-presented data and should be updated as the complete dataset is reviewed. __LIMITATIONS__ 1. Open-label design: blinding was not feasible but introduces potential bias in endpoints not adjudicated by the IRC. 2. OS immaturity: the key survival endpoint has not yet been reached; PFS improvement does not guarantee OS benefit, particularly in a population with multiple available subsequent therapies. 3. Generalizability: prior noncovalent BTKi or BCL-2 inhibitor exposure was an exclusion criterion, limiting applicability to patients treated with these increasingly used agents; cBTKi-naïve patients were intentionally capped at ~20%, so findings are most applicable to cBTKi-pretreated patients. 4. Industry sponsorship: the trial was funded and conducted under Eli Lilly oversight, which is a recognized source of potential publication and reporting bias. 5. MRD as surrogate: while uMRD rates were substantially higher with PVR, MRD serves as a surrogate and its OS-predictive value within this specific regimen is not yet validated. 6. Prespecified interim analysis: this is an interim, not final, efficacy analysis; results may shift with maturation. 7. Lack of crossover: no crossover was permitted, which is appropriate for PFS analysis but limits understanding of post-progression outcomes. 8. Triplet toxicity: although grade ≥3 AE rates were broadly similar, the absolute increase in hypertension and numerically higher grade ≥3 AE rate with PVR warrants attention in older or comorbid patients. 9. Frontline setting unanswered: applicability to patients without prior therapy or those receiving frontline venetoclax-based triplets is not established. __BOTTOM_LINE_CATEGORY__ potentially_practice_informing __BOTTOM_LINE__ Fixed-duration PVR (pirtobrutinib + venetoclax + rituximab) significantly reduced the risk of progression or death by 45% and improved 24-month PFS from 71.8% to 86.9% compared with standard VR in previously treated CLL/SLL, including patients with prior covalent BTK inhibitor exposure, with no new safety signals and a manageable toxicity profile. This represents the first phase 3 randomized evidence supporting a BTK inhibitor-containing fixed-duration regimen in the relapsed/refractory CLL setting, with overall survival data still pending. Clinicians should consider PVR as a potential new standard of care for second-line CLL, particularly for cBTKi-pretreated patients, while awaiting regulatory review and OS maturation.