In chronic lymphocytic leukemia (CLL), Bruton tyrosine kinase (BTK) inhibitors are given continuously until progression or intolerance, and venetoclax-based combinations stop after a defined period. Pirtobrutinib, a highly selective non-covalent BTK inhibitor, has shown activity after covalent BTK inhibition, has been used as continuous treatment and recently received expanded frontline approval. Combined with venetoclax-rituximab (VR), it allows non-covalent BTK inhibition within a time-limited regimen.
Evidence for fixed-duration combinations in relapsed CLL has lagged behind the frontline setting. VR remains an established fixed-duration option, but the pivotal MURANO trial largely enrolled patients before covalent BTK inhibitors became routine earlier in the course. Prospective data for VR after covalent BTK inhibitor exposure are limited.
BRUIN CLL-322 provides the first randomized phase III evidence for a fixed-duration, BTK inhibitor-containing regimen in relapsed or refractory CLL, and the first phase III comparison of a novel regimen against a fixed-duration venetoclax-containing control in this setting.
BRUIN CLL-322 Studied a Contemporary Relapsed CLL Population
BRUIN CLL-322 was an open-label, randomized phase III trial conducted across 152 centers in 22 countries. Investigators randomized 639 patients with previously treated CLL/SLL to PVR (n=321) or VR alone (n=318). Previous venetoclax, another BCL2 inhibitor, or a non-covalent BTK inhibitor was not permitted. The primary endpoint was progression-free survival assessed by a masked independent review committee.
Median age was 68 years and patients had received a median of two previous lines of therapy. Seventy-one percent of those previously treated with a covalent BTK inhibitor had stopped it because of disease progression. High-risk biology was common: ~40% had TP53 mutation and/or del(17p).
PVR included pirtobrutinib 200 mg daily for 28 cycles, six cycles of rituximab, and 25 cycles of venetoclax. Patients received three cycles of pirtobrutinib-rituximab before venetoclax was introduced. The VR group received the established venetoclax ramp-up followed by rituximab.
Pirtobrutinib Addition Produced a Clear PFS Benefit
At a median follow-up of 27.3 months, PVR reduced the risk of progression or death by 45.3% compared with VR (HR 0.547). Median PFS had not been reached with PVR and was 39.7 months with VR. At 24 months, 86.9% of patients receiving PVR remained progression-free compared with 71.8% receiving VR.
Overall response rates were similar: 88.5% with PVR and 83.3% with VR. Complete response or complete response with incomplete marrow recovery occurred in 32% and 23%, respectively. Time to next treatment also favored PVR (HR 0.498; nominal secondary analysis). Overall survival remains immature: the interim HR was 0.891, with median overall survival not reached in either group.
PFS Benefit Held in Patients Previously Treated With a Covalent BTKi
Among the 510 patients previously exposed to a covalent BTK inhibitor, median PFS was not reached with PVR compared with 36.2 months with VR (HR 0.509). In the 362 patients who had discontinued their previous covalent BTK inhibitor because of progression, median PFS was 43.3 vs 33.2 months (HR 0.444).
Pirtobrutinib binds BTK non-covalently and can retain activity after failure of covalent inhibitors. Combined with venetoclax, it targets two survival pathways: B-cell receptor signaling through BTK and BCL2-mediated apoptotic resistance. Rituximab adds CD20-directed immune clearance.
High-Risk CLL Also Benefited
Patients with TP53 mutation and/or del(17p) had a particularly large numerical separation: 24-month PFS was 87.2% with PVR and 55.6% with VR (HR 0.372). Benefit was also observed across prespecified subgroups including unmutated IGHV and complex karyotype.
The trial was powered for the overall comparison, with wide confidence intervals in several smaller subsets, and the authors caution against comparing subgroups given limited event numbers.
Complex karyotype was present in 26% of the PVR group and 37% of the VR group. Eight patients in the PVR group and 16 in the VR group developed investigator-reported Richter transformation. Central histologic confirmation was not required, and complex karyotype itself is associated with transformation risk, so a treatment effect on Richter transformation can’t be established from these data.
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MRD Responses Were Deeper With PVR, but Data Were Limited
Among patients with evaluable end-of-treatment samples, undetectable measurable residual disease in peripheral blood at <10⁻⁴ was achieved in 86% with PVR compared with 61% with VR. The separation persisted at greater assay depth: 74% vs 50% at 10⁻⁵ and 52% vs 35% at 10⁻⁶.
Only 234 of 639 patients, 37% of the intention-to-treat population, had evaluable end-of-treatment samples. With all randomized patients as the denominator, the <10⁻⁴ rates were 32% and 22%. MRD was exploratory, peripheral-blood based, and lacked serial early kinetics and bone marrow assessment.
The Pirtobrutinib Lead-In Reduced Tumor Lysis Risk
The three-cycle pirtobrutinib-rituximab lead-in debulked disease before venetoclax initiation. Among evaluable patients initially classified as high risk for tumor lysis syndrome , 78% were downgraded before starting venetoclax. Among those initially at medium risk, 61% moved into the low-risk category. Grade ≥3 TLS occurred in 1% with PVR compared with 4% with VR.
Venetoclax ramp-up can require intensive laboratory monitoring, prophylaxis, and hospitalization in patients with substantial disease burden. Debulking beforehand could reduce those needs, but the trial didn’t measure resource use.
Adding Pirtobrutinib Did Increase Some Toxicities
The overall frequency of grade ≥3 treatment-emergent adverse events was 79% with PVR and 73% with VR. Treatment-related discontinuation of the regimen was identical at 5% in each group, so the added toxicity did not cause more discontinuations.
Any-grade infections occurred in 79% with PVR and 72% with VR, grade ≥3 infections occurred in 34% vs 23%. Grade ≥3 neutropenia events occurred in 50% and 44%, and grade ≥3 pneumonia in 11% and 7%, respectively. That matters in an older population receiving three drugs.
BTK inhibitor-associated cardiovascular toxicity was comparatively limited. Atrial fibrillation or flutter occurred in 3% of both groups. Hemorrhage occurred in 14% with PVR and 11% with VR. One treatment-related death occurred with PVR and four with VR.
Treatment Duration and the PFS Benefit
PVR had a longer overall treatment period because venetoclax began in cycle 4, after the pirtobrutinib-rituximab lead-in. Both groups received the same venetoclax duration (25 cycles) and six cycles of rituximab.
PFS was measured from randomization, so the added pirtobrutinib treatment time counts in the comparison from the start. A substantial proportion of PFS events in the VR group occurred before 24 months, before total treatment duration meaningfully diverged between the groups.
What Happens After Progression on Fixed-Duration PVR?
A fixed-duration regimen allows a treatment-free interval, but it is not yet known whether pirtobrutinib, venetoclax, or the combination can be reused when CLL progresses. The authors plan a translational analysis of resistance mechanisms at progression to clarify how fixed-duration exposure affects sensitivity to either pathway.
They cite indirect support from CAPTIVATE, where acquired BTK and BCL2 mutations were not detected in patients progressing after fixed-duration ibrutinib-venetoclax. The concern becomes more pressing if PVR moves earlier in relapsed disease, since later treatment choices depend partly on the resistance biology.
How Does Frontline Pirtobrutinib Approval Influence the Interpretation of BRUIN CLL-322?
In October 2026, the FDA expanded pirtobrutinib approval to previously untreated CLL/SLL without known 17p deletion, following BRUIN CLL-313, which compared continuous pirtobrutinib with bendamustine–rituximab. The trial did not establish its relative efficacy against contemporary frontline targeted therapies.
This approval raises a sequencing consideration for BRUIN CLL-322. Patients previously treated with non-covalent BTK inhibitors or BCL2 inhibitors were excluded, leaving the efficacy of the fixed-duration triplet after frontline pirtobrutinib or venetoclax unknown.
The findings remain most directly applicable to venetoclax-naive patients previously treated with covalent BTK inhibitors. Whether prior pirtobrutinib exposure, especially progression on treatment, affects subsequent response to a pirtobrutinib-containing combination requires prospective evaluation.
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Reference
- Davids, M. S., Eyre, T. A., Woyach, J. A., et al. (2026). 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. The Lancet, 408(10553), 453–470. PubMed
- U.S. Food and Drug Administration. (2026, October 2). FDA approves pirtobrutinib for previously untreated chronic lymphocytic leukemia or small lymphocytic lymphoma. FDA.
