Jaypirca: A Promising Therapy Against Chronic Lymphocytic Leukemia

Fresh off an expanded FDA approval, pirtobrutinib (Jaypirca) is making headlines at the 2025 American Society of Hematology (ASH) Annual Meeting in Orlando. The BRUIN trial shows the drug cuts the risk of disease progression or death by 46% in relapsed or refractory chronic lymphocytic leukemia (CLL), with an overall response rate of 81% and a median progression-free survival of 18 months.

Dr. Michael Randall, assistant clinical professor in hematology, blood and marrow transplant, and cellular therapy at the University of California, San Francisco, described the trial results as highly encouraging.

“So in the final analysis of the BRUIN trial, which was presented at this ASH meeting, they reported that the median overall response rate with pirtobrutinib was 81% in patients with relapsed and refractory CLL. The median progression-free survival was about 18 months,” Dr. Randall explained.

“And so these data confirm what we had previously known about pirtobrutinib, which is that it’s highly effective among patients with relapsed, refractory CLL.”

The BRUIN CLL-321 Trial: A Closer Look

Several experts explained to SurvivorNet that this research is noteworthy because it is the first randomized trial exclusively focused on people with CLL/SLL who have already been treated with a covalent BTK inhibitor. Many of these patients had also been treated with venetoclax or other therapies, indicating that the trial population often had aggressive or hard-to-treat disease.

Trial Design and Participants

The trial included 238 patients who had either CLL or SLL. On average, the patients had received three prior lines of therapy, and all had at least one prior covalent BTK inhibitor (such as ibrutinib, acalabrutinib, or zanubrutinib). About half had also received an inhibitor of BCL-2 called venetoclax.

Patients were assigned to receive either one daily dose of Jaypirca or a physician’s choice between idelalisib plus rituximab (IdelaR) or bendamustine plus rituximab (BR).

Researchers aimed to assess progression-free survival (PFS), or how long patients lived without their disease getting worse.

They also looked at overall response rate, duration of response, event-free survival (EFS), overall survival, time to next treatment (TTNT), safety, and patient-reported outcomes.

Major Findings

• Progression-Free Survival (PFS): Jaypirca lowered the chance of disease progression or death by 46% compared to the control group (idelalisib plus rituximab or bendamustine plus rituximab)
  • Patients on pirtobrutinib had a median PFS of 14.0 months, compared to 8.7 months in the control group.
  • Hazard Ratio, 0.54; 95% CI, 0.39 to 0.75]; P= .0002.

• Overall Survivor: An updated analysis of OS, conducted with a median follow-up of 19.8 months, showed an HR of 1.09 (95% CI, 0.68-1.75). Interpretation of this endpoint is limited by the high crossover rate; of the 119 patients randomized to the control arm, 50 (42%) eventually crossed over to receive pirtobrutinib.

• Event-Free Survival (EFS): Jaypirca cut the risk of an event (progression, death, or major toxicity-related discontinuation) by 61%. This indicates that Jaypirca’s benefits extend beyond disease control and into how well patients can tolerate the therapy.
• Time to Next Treatment (TTNT): One particularly encouraging finding was that Jaypirca extended the median time to the next therapy (or death) from 10.9 months in the control group to about 23.9 months in the Jaypirca group. Many consider TTNT to be an especially meaningful endpoint because it reflects how long patients can go before needing another change in therapy.
• Safety and Tolerability: Jaypirca was associated with fewer grade 3 or higher adverse events and fewer treatment discontinuations due to side effects compared to idelalisib plus rituximab or bendamustine plus rituximab. When experts adjusted for the duration of therapy (i.e., taking into account how long patients stayed on treatment), Jaypirca had an overall lower rate of side effects.

Taken together, the results confirm that Jaypirca is highly effective in delaying disease progression, postponing the need for additional therapies, and preserving quality of life for patients whose CLL or SLL has stopped responding to other BTK inhibitors.

“I think these data are what supported the traditional approval. So the initial approval in 2023 required that patients had received two prior lines of therapy before Pirtobrutinib could be prescribed. The new approval requires patients to have received a covalent PTK inhibitor previously, but I think it doesn’t require the two prior lines of therapy,” Dr. Randall said.

“It can be, it’s approved now in the second line, provided patients have received a covalent PTK inhibitor previously.”

What Does This Mean For Patients?

“So, in general, patients with CLL have long durations of response to initial therapy, whether that be BTK inhibitor-based therapy or BCL2 inhibitor-based therapy. But the real unmet need in CLL is among patients who are so-called double refractory. [That means patients who have progressed on both a BTK inhibitor and a BCL2 inhibitor],” Dr. Randall told SurvivorNet.

“For those patients, we have relatively few options, one of which is the non-covalent BTK inhibitor, Pirtobrutinib”.

Indications for  Pirtobrutinib

These are the two FDA-approved indications for Jaypirca:

• Adult patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) who have previously been treated with a covalent BTK inhibitor.
• Adult patients with relapsed or refractory (R/R) mantle cell lymphoma (MCL) after at least two lines of systemic therapy, including a BTK inhibitor. This indication is approved under accelerated approval based on the response rate. Continued approval for this indication may be contingent upon verification and description of clinical trial benefit in a confirmatory trial.