The Role of BTK Inhibitors in CLL
- BTK inhibitors have transformed the treatment of chronic lymphocytic leukemia (CLL). These targeted medications block a protein called Bruton’s tyrosine kinase (BTK), which helps CLL cells survive and grow.
- For many people, BTK inhibitors control CLL for years. They are taken as pills and, in most cases, are continued for as long as they are working and side effects remain manageable.
- When CLL progresses while a patient is taking a BTK inhibitor such as acalabrutinib, zanubrutinib, or ibrutinib, doctors often consider either switching to a different class of therapy, such as venetoclax, or using a different type of BTK inhibitor called pirtobrutinib.
- Pirtobrutinib is a newer type of BTK inhibitor called a non-covalent BTK inhibitor. It binds to the BTK protein in a different way which allows it to continue working even when CLL cells develop some of the genetic changes, like the common C481 mutation, that make earlier BTK inhibitors ineffective.
Drugs such as ibrutinib, acalabrutinib, and zanubrutinib have helped many people live longer with good quality of life and have largely replaced chemotherapy.
Read MoreWhen BTK Inhibitors Stop Working
While these medications are very effective, CLL is a chronic disease. Over time, the leukemia can change, and the treatment may stop working. This is called disease progression or treatment resistance.
Some patients also need to stop a BTK inhibitor because of side effects, such as heart rhythm problems, bleeding or high blood pressure.
When a BTK inhibitor is no longer the right treatment, it does not mean that effective options have run out. Instead, your doctor will consider why the medication was stopped and what treatments you have already received.
Venetoclax
One option is a regimen using venetoclax, a targeted therapy that works differently by blocking a protein called BCL-2.
Because it attacks CLL cells through a different pathway, venetoclax can be very effective after a BTK inhibitor and remains an important treatment option for many patients.
Pirtobrutinib
Another option is pirtobrutinib which is a newer type of BTK inhibitor called a non-covalent BTK inhibitor. Unlike earlier BTK inhibitors, which attach permanently to a specific part of the BTK protein, pirtobrutinib binds in a different way. This allows it to continue working even when CLL cells develop some of the genetic changes, including the common C481 mutation, that make earlier BTK inhibitors ineffective.
Pirtobrutinib is taken as a once-daily oral pill and has shown encouraging results in patients whose CLL has progressed after treatment with a previous BTK inhibitor. Many patients experience another period of disease control, including some whose leukemia has become resistant to earlier BTK inhibitors.
In clinical studies, pirtobrutinib has also been generally well tolerated.
“Pirtobrutinib, the non-covalent BTK inhibitor, has more or less a similar adverse effect profile with covalent BTK inhibitors, but it appears to be better tolerated,” Dr. Pongas says. “So, it has less risk for arrhythmias and hypertension when compared with first generation covalent BTK inhibitors [like] ibrutinib.”
Making Treatment Decisions
For patients whose CLL progresses while taking a covalent BTK inhibitor such as acalabrutinib, zanubrutinib, or ibrutinib, doctors often consider either switching to a different class of therapy, such as venetoclax, or using pirtobrutinib, depending on the patient’s previous treatments, overall health, and treatment goals.
If a BTK inhibitor was stopped because of side effects rather than resistance, switching to another BTK inhibitor may also be appropriate for some patients.
For patients whose CLL has progressed after both a BTK inhibitor and venetoclax, additional options are available, including CAR T-cell therapy, and clinical trials. Your doctor will help determine which approach is most appropriate based on your individual situation.
The key takeaway is that there are now more effective treatments for CLL than ever before. Even if one therapy stops working, several additional options are available.
By understanding why a treatment is no longer effective, and selecting the next therapy based on your individual situation, your healthcare team can continue to tailor treatment to help control the disease while maintaining your quality of life.
Questions To Ask Your Doctor
- How will I be monitored while taking a BTK inhibitor?
- What are the benefits of trying a newer BTK inhibitor like pirtobrutinib?
- What are the risks?
- What can I do to help with side effects?
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