Where a Newer Drug Like Jaypirca Fits In the Treatment Sequence for CLL Care

One advantage of being treated in the southern California region is access to specialists who have plenty of experience with new and evolving treatment approaches. Dr. Kevin Kelly, a hematologist at the University of Southern California, tells SurvivorNet that the treatment approach for CLL has largely evolved from chemotherapy given intravenously (through an IV) to easier-to-manage targeted treatments.

“We transitioned over very much to targeted therapy, oral agents, which patients can take at home,” Dr. Kelly explains, adding that opting for a drug taken orally allows patients to maintain more of a sense of normalcy.

“I like to stick to oral agents as much as possible,” Dr. Kelly says, because a pill lets people keep living their lives, whether that means traveling or spending time with grandkids, instead of coming into the hospital for infusions.

The Targeted Therapy Evoluation

Two classes of drugs drove this shift: BTK inhibitors and BCL-2 inhibitors such as venetoclax. Both target specific pathways that CLL cells depend on to survive, instead of broadly attacking all fast-dividing cells the way chemotherapy does (which is a big reason chemo is so hard on the body).

BTK inhibitors work by blocking Bruton’s tyrosine kinase, an enzyme that sits inside a signaling pathway CLL cells rely on to grow. Shut that pathway down, and the disease is often well controlled.

BTK inhibitors — including ibrutinib, acalabrutinib, and zanubrutinib — bind permanently to the BTK enzyme. They remain widely used and highly effective.

More recently, a different kind arrived: a non-covalent, or reversible, BTK inhibitor, sometimes called a third-generation BTK inhibitor. The first one approved for CLL is pirtobrutinib (Jaypirca).

Because it attaches to BTK in a reversible way, it can keep working even after the disease has stopped responding to an earlier BTK inhibitor.

Where Does Jaypirca Fit In?

“We usually use [Jaypirca] after patients have progressed on the first-generation or second-generation BTK inhibitor,” Dr. Kelly explains. “It works very well for the mutations that occur after acalabrutinib, for instance.”

Over time on a covalent BTK inhibitor, some people’s cancer develops small changes (called resistance mutations) that let it keep growing despite the medication. Fortunately, doctors can now test for these.

“We can test for mutations in the BTK gene, and there’s certain mutations that could be present that could help us predict what might be the next best line of therapy,” Dr. Kelly explains. When those resistance changes appear, he says, a third-generation BTK inhibitor “can fit around those resistant mutations” and bring the disease back under control.

Pirtobrutinib (Jaypirca) may also be used for patients who cannot tolerate their current BTK inhibitor.

“If they have excess bruising, excess bleeding, intolerability for one reason or another, switching to [Jaypirca] can offer a different side effect profile, and patients often are able to tolerate [Jaypirca] when they couldn’t tolerate earlier generation BTK inhibitors,” Dr. Kelly says.

Pirtobrutinib’s approval has expanded over the past few years:

• In 2023, the FDA granted accelerated approval for adults with CLL who had already had at least two prior lines of therapy, including a covalent BTK inhibitor and a BCL-2 inhibitor.
• In 2025, based on the Phase 3 BRUIN CLL-321 trial, the FDA converted that to full approval and broadened it to adults with relapsed (returned) or refractory (no longer responding) CLL who had previously received a covalent BTK inhibitor — so it no longer requires two full prior lines of treatment.

It’s also currently being studied in people who haven’t had any CLL treatment yet, though it isn’t FDA-approved as a first treatment.

Side Effects to Know About

BTK inhibitors have been associated with a range of side effects, with the risk of infections being the most common and most serious.

“General side effects that we have are bleeding, bruising, and skin rash,” Dr. Kelly adds.

Potential side effects to watch for with this class include:

• A higher chance of infections
• Low blood counts (which routine blood tests can catch)
• Occasional irregular heartbeats
• Liver problems
• Other cancers such as skin cancers (less frequent)

Reporting anything new or unusual early gives your care team the best chance to find good ways to manage side effects.

Questions To Ask Your Doctor

• Am I a candidate for pirtobrutinib, and why might it be the right choice for me at this point?
• Where does it fit compared with my other options right now?
• What side effects should I watch for, and which ones should I report right away?
• How will we know whether it’s working, and how soon?
• Could it interact with my other medications, supplements, or over-the-counter drugs?

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