Pirtobrutinib Combination Improves Relapsed CLL Outcomes

A new study presented at the 2026 European Hematology Association (EHA) Congress found that adding pirtobrutinib to venetoclax and rituximab helped more people with previously treated chronic lymphocytic leukemia (CLL) experience cancer control. The combination also led to deeper responses without causing many more side effects. 

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Researchers tested a new treatment combination

Venetoclax (Venclexta, AbbVie/Genentech) plus rituximab is a common fixed-duration treatment for people whose CLL has returned after earlier therapy.

Researchers wanted to learn whether adding the non-covalent BTK inhibitor pirtobrutinib (Jaypirca, Eli Lilly) could improve results. 

The study included 639 people with relapsed or refractory CLL or small lymphocytic lymphoma (SLL). Relapsed means the cancer returned after treatment. Refractory means the cancer did not respond to prior treatment. 

Most patients had already received a covalent BTK inhibitor before joining the study. 

Outcomes were improved with the triplet 

Patients were assigned to one of two groups. One group of 321 patients received a combination of pirtobrutinib, venetoclax, and rituximab. The second group of 318 patients received a combination of venetoclax and rituximab. 

Researchers measured progression-free survival (PFS). This is the length of time a person is alive without the cancer progressing. At 24 months, the PFS rate was:

• 86.9% of patients who received pirtobrutinib, venetoclax, and rituximab
• 71.8% of patients who received venetoclax and rituximab 

The benefit was seen in several patient groups. This included people whose prior covalent BTK inhibitor had stopped working. It also included people with higher-risk CLL genetic changes, like TP53 mutations/deletion 17p. 

"The benefits of the PVR regimen over the current standard of care VR were most pronounced in patients with TP53 aberration and those who had progressed on a prior covalent BTK inhibitor, and therefore the results of the study suggest that patients in those scenarios are the most likely to benefit from this new regimen," said Dr. Matthew Davids, Chief of the Division of Lymphoma at Dana-Farber Cancer Institute and presenter of the results in the Late-Breaking Abstract session at the EHA 2026 Congress.

More patients experienced undetectable MRD

Researchers also measured minimal residual disease (MRD). MRD refers to the small number of cancer cells that may remain after treatment. Undetectable MRD means cancer cells could not be found, or the number was below the test’s threshold. 

At the end of treatment:

• 86% of patients who received the three-treatment combination had undetectable MRD
• 61% of patients who received venetoclax and rituximab had undetectable MRD

These results suggest that adding pirtobrutinib helped more patients experience deeper responses. A deeper response may support patients to stay in remission longer. 

Side effects were similar

The most common serious side effect was neutropenia. Neutropenia is a low level of infection-fighting white blood cells.

Researchers also monitored:

• Tumor lysis syndrome, which can occur when cancer cells break down quickly
• Atrial fibrillation, an abnormal heart rhythm
• High blood pressure
• Bleeding/bruising

The rates of these side effects were generally similar between the two groups. Only about 5% of patients stopped therapy because of treatment-related side effects. 

"The pirtobrutinib only added a modest amount of increased side effects, with higher rates of infection, bruising, and high blood pressure being the most common ones. These side effects were generally straightforward to manage, and most patients in the study tolerated the PVR regimen well," said Dr. Matthew Davids.

Key takeaways 

The study showed that adding pirtobrutinib to venetoclax and rituximab helped more patients experience progression-free survival and undetectable MRD. The benefit was seen even in patients with high-risk CLL genetic features and those whose earlier covalent BTK inhibitor had stopped working.

Researchers concluded that this fixed-duration combination could become a new standard treatment option for people with relapsed or refractory CLL.

"Given the widespread availability of these individual drugs and the familiarity of oncologists with them, I believe that the data from the BRUIN CLL-322 study support the rapid incorporation of PVR into the treatment landscape as a new option for patients with R/R CLL," said Dr. Matthew Davids.  

 

 

Source: 

• FIXED-DURATION PIRTOBRUTINIB PLUS VENETOCLAX–RITUXIMAB VERSUS VENETOCLAX–RITUXIMAB FOR PATIENTS WITH PREVIOUSLY TREATED CLL/SLL: A PHASE 3, RANDOMIZED TRIAL (BRUIN CLL-322)