When Treatment Stops Working, There are Options
- Targeted treatments known as covalent BTK inhibitors (ibrutinib, acalabrutinib, and zanubrutinib) are often given as a first-line (first) treatment for chronic lymphocytic leukemia (CLL). Though they are effective, CLL does sometimes become resistant to the drugs.
- When CLL progresses, there are still treatment options available. A new development is the non-covalent BTK inhibitor pirtobrutinib (Jaypirca), which is designed to overcome resistance mutations.
- “We have options for blocking BTK now that are unaffected by the resistance we see in prior versions,” Dr. Cole Sterling, an oncologist who specializes in hematologic malignancies at Johns Hopkins Medicine, tells SurvivorNet.
- The CLL treatment landscape continues to evolve rapidly, with clinical trials exploring next‑generation BTK inhibitors, CAR T-cell therapy, bispecific antibodies, and novel combinations.
When it comes to CLL, treatment options have developed a great deal in the past decade or so, Dr. Cole Sterling, an oncologist who specializes in hematologic malignancies at Johns Hopkins Medicine in Baltimore, tells SurvivorNet.
Read MoreWhen BTK Inhibitors Stop Working
For more than a decade, Bruton tyrosine kinase (BTK) inhibitors, a type of targeted therapy, have been a cornerstone of CLL treatment. The first widely used BTK inhibitor, ibrutinib, is further classified as a covalent BTK inhibitor — a drug that binds irreversibly to a specific site on the BTK protein (the C481 residue). This binding blocks signals that help CLL cells survive. Dr. Sterling notes that while these drugs are highly effective, resistance can still develop.“These covalent BTK inhibitors bind at a particular location … but we’ve found that many patients do eventually develop resistance to them,” he explains.
Most resistance to covalent BTK inhibitors is driven by mutations in the BTK gene — especially BTK C481S, which prevents the drug from binding effectively, according to research published in the “Journal of Clinical Oncology.”
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Second‑generation covalent BTK inhibitors — acalabrutinib and zanubrutinib — were developed to be more selective for BTK, and head-to-head trials against ibrutinib have shown lower rates of cardiac side effects like atrial fibrillation.
Dr. Sterling adds that acalabrutinib and zanubrutinib are “very effective and associated with less toxicity, but they can’t always overcome these particular mutations that lead to resistance.”
Non‑Covalent BTK Inhibitors: A New Option
To address covalent BTK inhibitor resistance, researchers developed non‑covalent (reversible) BTK inhibitors, which bind to BTK without relying on the C481 site. The most advanced of these is pirtobrutinib (brand name Jaypirca).
“Pirtobrutinib allows for effective targeting of BTK that doesn’t depend on that particular site that is mutated … we have options for blocking BTK now that are unaffected by the resistance we see in prior versions,” Dr. Sterling explains.
Pirtobrutinib has demonstrated strong activity in patients who previously progressed on covalent BTK inhibitors, according to ressearch published in the “New England Journal of Medicine.”
In that study, pirtobrutinib produced:
- Response rates of ~73% in CLL/SLL patients previously treated with a covalent BTK inhibitor
- Durable responses, including in heavily pretreated patients
- A favorable safety profile
This makes pirtobrutinib one of the most important newer tools for patients whose CLL has stopped responding to earlier BTK inhibitors. However, Dr. Sterling emphasizes that the oncology community is still learning how best to sequence pirtobrutinib.
“We’re all still figuring out how and when would be the best time to use pirtobrutinib,” Dr. Sterling says. “In patients who have failed or progressed beyond covalent BTK inhibitors… pirtobrutinib is one of the best options we have at this time.”
The Future of CLL Treatment
As of the FDA’s most recent label update (December 2025), pirtobrutinib is approved only for relapsed or refractory CLL/SLL in patients previously treated with a covalent BTK inhibitor. It does not yet have FDA approval as a front-line (first) treatment.
However, this may change as phase 3 data from the BRUIN CLL-313 and BRUIN CLL-314 trials, reported in late 2025, showed pirtobrutinib significantly outperformed both chemoimmunotherapy and the covalent BTK inhibitor ibrutinib in treatment-naive patients, and regulatory submissions for frontline label expansion are underway.
Clinical trials are also ongoing to determine whether pirtobrutinib may eventually play a role earlier in treatment.
Overall, traditional chemotherapy has largely been replaced by targeted agents such as BTK inhibitors and BCL‑2 inhibitors (venetoclax) in CLL care.
The pipeline is growing as clinical trials are continuing to explore:
- Next‑generation BTK inhibitors
- Novel combinations (e.g., BTK inhibitor + venetoclax)
- CAR T-cell therapy
- Bispecific antibodies
“Based on the current [investigations] underway, I have no doubt that a decade from now we’ll be in a much, much better place,” Dr. Sterling said.
Questions To Ask Your Doctor
- What options are available if my treatment stops working?
- Can I make adjustments to my treatment plan if side effects become too difficult?
- Is there anything I can do to reduce the risk of side effects?
- Are there any clinical trials I should consider joining?
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