Pirtobrutinib could form a new standard of care for relapsed/refractory chronic lymphocytic leukaemia (CLL), phase 3 data presented at the European Haematology Association (EHA) congress suggest.

The interim trial results showed that adding the non-covalent BTK inhibitor to fixed-duration venetoclax-rituximab (VR) almost halved the risk of disease progression in patients who had undergone at least one prior line of therapy, with a 24-month progression-free survival (PFS) rate of nearly 90%.

The PFS benefit of pirtobrutinib-venetoclax-rituximab (PVR) over VR was also seen in patients who had only undergone treatment with a covalent BTK inhibitor (cBTKi) and had progressed, with minimal residual disease (MRD) rates also superior. 

“We believe that these results establish PVR as a potential new standard of care option for patients with previously treated CLL,”  said Dr Matthew Davids of the Dana-Farber Cancer Institute, Boston, when presenting the findings at EHA 2026 in Stockholm.

In the Phase 3 trial, 639 patients (median age 68 years) with relapsed/refractory CLL who had undergone at least one prior line of treatment (excluding non-covalent BTKis or venetoclax) were randomised to receive PVR (n=321) or VR (n=318).

Patients had undergone a median of two prior lines of therapy, with 80% having been exposed to a cBTKi.

After a median follow-up of 27 months, patients treated with PVR showed significantly longer PFS (assessed by an independent review committee) than those given VR (Not estimable vs 40 months, HR 0.547, p=0.0001) and higher 24-month PFS rate (87% vs 72%).

“I think the control arm is also very important here with VR, because this is the first time we’ve seen data in a post-covalent BTK inhibitor population and the PFS rate of 72% is notably lower than what was seen in a chemoimmunotherapy-treated population of MURANO, which was closer to 85%,” noted Dr Davids.

“That suggests that the patients in this population of this study were particularly high risk,” he added.

PVR significantly improved PFS in all subgroups, including patients who had undergone prior cBTKi exposure (HR 0.509) and those who had discontinued a cBTKi due to disease progression (HR 0.444).

Dr Davids highlighted that PVR resulted in a substantial improvement in PFS over VR (HR 0.323) in patients whose only prior line of therapy was a cBTKi, on which they progressed, noting that this is “a common population we see now in the clinic with CLL.”

Time to next treatment was also improved by PVR compared to VR (HR 0.498) and rates of peripheral blood undetectable MRD at the end of treatment were higher among evaluable samples (86% vs 61%, p<0.001).

Rates of any grade and grade 3 or higher adverse events were similar with PVR and VR (99.7% vs 98.1% and 78.8% vs 73.0%, respectively), with comparably low rates in both groups of any-grade atrial fibrillation/flutter (3.5% vs 2.6%), hypertension (12.0% vs 7.4%), and haemorrhage (14.2% vs 10.6%), and grade 3 or higher bleeding (2.8% vs 2.6%).

Grade 3 or higher treatment-emergent neutropenia was more common with PVR than VR (50.3% vs 43.7%), but tumour lysis syndrome was less common (0.9% vs 3.9%).

“Generally, PVR was well-tolerated, with the safety profile consistent with the individual agents and no new safety signals identified,” Dr Davids concluded.