Jaypirca: A New Beacon of Hope in the Fight Against Chronic Lymphocytic Leukemia

“We found that our medicine, Jaypirca, improved the rate of progression-free survival or death by about 50% relative to the standard of care,” Dr. Hyman explained. “One of the great things about this medicine is: it’s very convenient. This is a pill the patients can take. It doesn’t require admission to the hospital or very specialized monitoring. So it’s a community friendly medicine.”

CLL is one of the most common types of leukemia in adults, often progressing slowly over time. In CLL, the body creates too many lymphocytes (a type of white blood cell), which can interfere with normal blood cell production and immune system function.

When CLL cells are mainly in the lymph nodes (rather than the bloodstream), doctors often refer to the disease as small lymphocytic lymphoma (SLL). Despite the slightly different naming, CLL and SLL are generally considered the same disease; the difference mainly depends on where the cancer cells show up in the body.

What is Pirtobrutinib and How Does It Work?

Pirtobrutinib (Jaypirca) is a type of targeted therapy called a non-covalent (reversible) Bruton’s tyrosine kinase (BTK) inhibitor. BTK is an enzyme that helps certain cancer cells grow and survive. Drugs that target BTK—often called BTK inhibitors—have transformed care for CLL and several other B-cell cancers.

“Jaypirca is the first BTK inhibitor that works by a different mechanism. We call it a non-covalent inhibitor,” Dr. Hyman explained.

“It interacts with cancer cells differently than the other approved BTK inhibitors … the reason that this matters for patients is that it has the ability to work after these other BTK inhibitors that patients are on for often a long period of time stop working. And that is really important because it offers the opportunity to extend the benefits of targeting BTK in patients with various lymphomas.”

Most BTK inhibitors in current use (sometimes called “first-generation” or “second-generation” BTK inhibitors) bind to BTK in a permanent (covalent) manner. Over time, some cancer cells may develop mutations that make these covalent agents less effective. Jaypirca, on the other hand, is designed to bind to BTK in a reversible way and can remain active even in the presence of these resistance mutations. It also shows high selectivity for BTK compared to many other enzymes, potentially reducing unwanted effects.

Key attributes to keep in mind about Jaypirca include:

• Reversible binding: The drug allows for consistent BTK coverage, even when there are changes (mutations) at certain sites in the BTK enzyme.
• High selectivity: Preclinical studies suggest that pirtobrutinib is approximately 300 times more selective for BTK than it is for most other kinases, which may help limit off-target effects.
• Oral administration: It is taken by mouth, making it more convenient than certain treatments that require intravenous infusions.

The BRUIN CLL-321 Trial: A Closer Look

Dr. Hyman explained 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.

“This is the first clinical trial, randomized clinical trial that we’ve completed with Jaypirca. And this is really actually a first for the field. Believe it or not, despite those medicines first being approved almost 10 years ago, or more than 10 years ago for this condition, there’s never been a randomized study exclusively in patients that have received those therapies,” he explained.

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.
• 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.

Potential Side Effects & Safety

Like any medication, Jaypirca comes with some risks. In clinical trials, the majority of side effects were manageable, and the rate of severe side effects was relatively low, especially compared to some other treatments. However, it’s important to be aware of what might happen and how to handle any issues that arise.

Some areas of concern include:

• Infections: Patients treated with BTK inhibitors, including Jaypirca, may be at increased risk of bacterial, viral, and fungal infections. Serious or life-threatening infections can happen. Preventive measures, such as vaccinations and possibly prophylactic medications, may be considered in patients at high risk.
• Bleeding (Hemorrhage): There is a potential risk of bleeding problems, including major hemorrhages. Patients on blood thinners or other medications that increase bleeding risk should have a thorough discussion with their doctor.
• Low Blood Counts (Cytopenias): Some patients may experience a drop in white blood cells (like neutrophils), red blood cells (leading to anemia), or platelets (leading to bleeding). Regular blood tests can help monitor these levels.
• Heart Rhythm Problems (Atrial Fibrillation or Arrhythmias): A small percentage of patients may experience irregular heartbeats. Frequent check-ups and open communication with healthcare providers about heart-related symptoms are vital.
• Second Primary Malignancies: Though uncommon, there is a possibility of developing other types of cancers (such as skin cancers). Patients should talk to their doctor about routine skin checks and any unusual findings.
• Liver Toxicity: Liver function tests (LFTs) are often monitored because severe liver problems can occur, though they are rare.

If you are currently receiving treatment or about to start Jaypirca, be sure to discuss the potential side effects and any signs to look out for. Promptly reporting any unusual symptoms to your medical team is crucial—they can help manage and ease many side effects, ensuring the safest possible journey through treatment.

Questions to Ask Your Doctor

If you or a loved one has CLL/SLL, know that you are not alone. Discuss all available treatment options, including newer targeted agents, with your healthcare team. They can help tailor a plan that balances efficacy, side effect management, and individual goals. Here are some questions to keep in mind during doctor visits:

• Am I eligible to receive Jaypirca?
• Why do you think Jaypirca is the right option for me at this point in my treatment?
• Is the safety and tolerability of Jaypirca acceptable for long-term use?
• What are the most common side effects, and how can we manage them?
• How often and for how long will I need to take Jaypirca?
• How do we track how well Jaypirca is working, and how soon might we see results?
• How might Jaypirca interact with my current medications, supplements, or any over-the-counter drugs?

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