Pirtobrutinib added to venetoclax-rituximab slows relapse in treated CLL

Adding the newer targeted drug pirtobrutinib to a fixed course of venetoclax and rituximab reduced the chance that previously treated chronic lymphocytic leukaemia progressed: in the phase 3 BRUIN CLL-322 trial, 24-month progression-free survival was 87% with the three-drug regimen against 72% with venetoclax-rituximab alone [s1]. The hazard ratio for progression or death was 0.547 (95% confidence interval, 0.400 to 0.748; p=0.0001), and the benefit held in the patients who had already been treated with an older drug of pirtobrutinib's class [s1].

Chronic lymphocytic leukaemia (CLL), and its closely related form small lymphocytic lymphoma, is a slow-growing cancer of B cells. Two drug classes dominate its treatment: covalent Bruton tyrosine kinase (BTK) inhibitors such as ibrutinib, which bind the enzyme permanently, and the BCL2 inhibitor venetoclax, which lowers a cancer cell's resistance to its own death signals. For patients whose disease returns after a covalent BTK inhibitor, a fixed course of venetoclax plus the antibody rituximab is a standard next step — attractive because it stops after a set time rather than continuing indefinitely [s1].

Pirtobrutinib is a non-covalent BTK inhibitor: it binds the same enzyme reversibly, which lets it work even when the mutations that defeat the covalent drugs are present. It was already approved as a continuous, open-ended therapy after a covalent BTK inhibitor [s1]. BRUIN CLL-322 asked a different question — whether folding pirtobrutinib into the time-limited venetoclax-rituximab backbone would deepen the response without turning treatment back into an indefinite commitment.

What they did

The open-label trial enrolled patients at 152 community and academic sites across 22 countries [s1]. Between October 2021 and October 2024, 784 patients were screened and 639 randomly assigned 1:1: 321 to pirtobrutinib plus venetoclax-rituximab and 318 to venetoclax-rituximab alone [s1]. Both groups took oral venetoclax for 25 cycles and intravenous rituximab for six; the three-drug group added oral pirtobrutinib for 28 cycles, starting with a three-cycle pirtobrutinib-rituximab lead-in before venetoclax began [s1]. Patients who had previously received a non-covalent BTK inhibitor or any BCL2 inhibitor were excluded, so the comparison was clean [s1].

The enrolled group was typical of relapsed CLL: median age 68.0 years, 69% male, a median of two previous lines of therapy, and 510 of 639 patients (80%) with prior exposure to a covalent BTK inhibitor — of whom 362 (71%) had stopped that drug because their disease was progressing [s1]. The primary endpoint at this prespecified interim analysis was progression-free survival judged by a masked independent review committee, with a data cutoff of 2 February 2026 [s1]. The trial is registered as NCT04965493 and is ongoing but no longer recruiting [s2].

What it showed

At a median follow-up of 27.3 months, the three-drug regimen cut the rate of progression or death roughly in half: hazard ratio 0.547 (95% confidence interval, 0.400 to 0.748; p=0.0001) [s1]. The 24-month progression-free survival rate was 87% (95% confidence interval, 82.3 to 90.4) with pirtobrutinib added, versus 72% (65.7 to 77.0) without [s1]. Median progression-free survival had not been reached in the pirtobrutinib group; in the comparison group it was 39.7 months [s1]. The advantage was consistent across prespecified subgroups, including the large majority who had already had a covalent BTK inhibitor [s1] — the group for whom the next option matters most.

The trial's authors describe this as the first randomised phase 3 evidence pitting a novel fixed-duration regimen against the venetoclax-rituximab standard in relapsed or refractory CLL [s1]. That framing is worth keeping in view: progression-free survival measures time without the disease worsening, not length of life, and at 27 months of follow-up the overall-survival picture is not yet mature.

The cost side

Adding a third drug did not, on these data, add much toxicity. Grade 3-or-higher treatment-emergent adverse events occurred in 79% of the pirtobrutinib group and 73% of the comparison group [s1]. The most common event of any grade in both arms was diarrhoea, at 34% and 35% respectively [s1]. Two numbers cut the other way: severe tumour lysis syndrome — a dangerous flood of contents from dying cancer cells that venetoclax can trigger — was less common with pirtobrutinib added (1% versus 4%), and treatment-related deaths were fewer (one versus four) [s1]. Atrial fibrillation, a signature side-effect of the older covalent BTK inhibitors, was uncommon in both groups (3% each) [s1]. Discontinuation for a related side-effect was identical at 5% [s1].

What to watch

BRUIN CLL-322 was funded by Eli Lilly and Company, which makes pirtobrutinib [s1]. The result strengthens the case for a time-limited three-drug course in relapsed CLL, but three questions remain open: whether the progression-free gain will translate into longer survival, how the regimen compares with simply continuing pirtobrutinib on its own, and how durable remissions prove to be once treatment stops. The appeal of a fixed-duration approach — like the fixed-duration venetoclax combinations tested in acute leukaemia and the newer BCL2 inhibitors moving through lymphoma — is that patients can stop and live untreated. Whether that promise holds for this combination will take longer follow-up than this interim analysis provides [s1].

Sources

• [s1] 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. 9 July 2026. doi:10.1016/S0140-6736(26)01204-3.
• [s2] ClinicalTrials.gov. A Study of Pirtobrutinib (LOXO-305) Plus Venetoclax and Rituximab Versus Venetoclax and Rituximab in Patients With CLL/SLL (BRUIN CLL-322, NCT04965493). U.S. National Library of Medicine.