New phase 3 data from the BRUIN CLL-322 trial suggest that fixed-duration PVR may represent a new treatment option for patients with relapsed/refractory CLL or SLL, particularly following prior covalent BTK inhibitor exposure
“This may mark the beginning of a new era of fixed-duration combination therapy in relapsed CLL”
touchHEMATOLOGY coverage from EHA 2026
Abstract LB5001: Davids M, Eyre TA, Woyach J, et al. FIXED-DURATION PIRTOBRUTINIB PLUS VENETOCLAX–RITUXIMAB VERSUS VENETOCLAX–RITUXIMAB FOR PATIENTS WITH PREVIOUSLY TREATED CLL/SLL: A PHASE 3, RANDOMIZED TRIAL (BRUIN CLL-322). Presented at: EHA 2026, Stockholm, Sweden. June 11–14th, 2026.
Presented at the late-breaking session at the European Hematology Association (EHA) 2026 Congress, the BRUIN CLL-322 (NCT04965493) compared pirtobrutinib plus venetoclax–rituximab (PVR) against standard venetoclax–rituximab (VR) in 639 patients with relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The triplet demonstrated a statistically significant improvement in investigator-reviewed progression-free survival (PFS), with a hazard ratio of 0.547 (95% CI, 0.400–0.748; P=0.0001). At 24 months, PFS was 86.9% with PVR versus 71.8% with VR. Notably, the benefit was maintained across key high-risk subgroups, including patients previously treated with covalent BTK inhibitors and those with del(17p)/TP53 mutation. Peripheral blood undetectable MRD4 rates at end of treatment were also significantly higher with PVR (86% vs 61%; P<0.0001), with a broadly similar safety profile.
BRUIN CLL-322 marks an important step in the evolution of fixed-duration targeted therapy in relapsed CLL. Beyond improving PFS, the combination’s deeper MRD responses and manageable toxicity profile support a broader shift toward time-limited combination strategies. While longer follow-up will be needed to determine the durability of these responses and the impact on overall survival, the data establish a strong rationale for integrating noncovalent BTK inhibition earlier in the relapsed treatment pathway.
Following his late-breaking presentation, Dr Matthew Davids (Chief of the Division of Lymphoma, Dana-Farber Cancer Institute and Associate Professor of Medicine, Harvard Medical School, Boston, MA, USA) discussed the broader implications of the findings.
Do these data change how we should think about treatment sequencing in relapsed CLL?
Yes, I think they do. This raises the interesting possibility of a fixed-duration therapy that includes both a BTK inhibitor and a BCL2 inhibitor in the relapsed setting. Previously, we would typically choose either a continuous BTK inhibitor approach or a time-limited venetoclax-based regimen with a CD20 antibody. This is the first time in the relapsed setting that we have phase 3 data supporting the combination of BTK and BCL2 inhibition together with rituximab. We found this to be a very potent regimen that induces deep responses and promising progression-free survival at this interim analysis.
The PVR arm achieved substantially higher undetectable MRD rates. How do you see MRD evolving as a treatment goal in relapsed CLL?
In the frontline setting, there is already a lot of focus on MRD as a strategy to achieve deep remissions that we hope will be long-lasting. In the relapsed setting, we also have strong data from the MURANO study showing that achieving undetectable MRD can improve both progression-free and overall survival. Now we are taking that to the next level by combining a noncovalent BTK inhibitor with venetoclax. In BRUIN CLL-322, we are seeing very deep levels of undetectable MRD, even down to 10^-6 using highly sensitive assays. We only have relatively short-term follow-up, but based on these MRD data, we think this may translate into durable progression-free survival.
Were there any safety findings or practical management considerations clinicians should pay particular attention to?
A couple of things stand out. Pirtobrutinib is generally a very well-tolerated BTK inhibitor, and in this study we did not see an increased risk of atrial fibrillation, which is reassuring from a cardiovascular standpoint. We did see slightly higher rates of neutropenia and infections in the pirtobrutinib-containing arm, but the differences were not substantial compared with standard therapy. Another important feature was the study design: the first three cycles consisted of pirtobrutinib plus rituximab as a debulking strategy before starting venetoclax. This was intended to reduce tumor lysis syndrome risk, and that’s exactly what we observed, with lower TLS rates in the PVR arm.
Is this the beginning of a broader shift away from continuous therapy paradigms in relapsed CLL?
I think the field has already been moving in that direction. When BTK inhibitors were first developed, continuous therapy was the standard paradigm. But now in the frontline setting, we have very strong data supporting time-limited BTK-BCL2 combinations. These are the first randomized data in the relapsed setting showing that this approach can also work. We will need longer follow-up to understand the full implications, but I do think these findings will inspire additional studies in relapsed CLL. Time-limited therapy offers a number of advantages, including reducing long-term toxicity, allowing patients time off treatment, and lowering treatment costs.
What is the key clinical takeaway for practicing hematologists?
The study clearly demonstrates that PVR is superior with respect to progression-free survival compared with VR, without adding much toxicity. We believe this establishes a new standard of care for relapsed/refractory CLL.
This content has been developed independently by Touch Medical Media for touchHEMATOLOGY. Views expressed are the speaker’s own and do not necessarily reflect the views of Touch Medical Media. This article was created by the editorial team utilizing AI as an editorial tool (ChatGPT 5.5 [Large language model]. https://chat.openai.com/chat.) The content was developed and edited by human editors. No funding was received in the publication of this article.
Cite: BRUIN CLL-322 positions fixed-duration pirtobrutinib triplet as potential new standard in relapsed CLL. touchHEMATOLOGY. 1st July 2026.
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