Understanding Your Next Treatment Options
- Targeted therapies called Bruton’s tyrosine kinase (BTK) inhibitors have transformed chronic lymphocytic leukemia (CLL) treatment, helping many patients control their disease for years.
- Some CLL patients develop resistance to BTK inhibitors, meaning the cancer stops responding to treatment. Pirtobrutinib (Jaypirca) is a newer, non-covalent BTK inhibitor that can help some patients whose CLL progresses after treatment with a covalent BTK inhibitor.
- Dallas-based hematologist Dr. Yair Levy says most patients can respond to pirtobrutinib despite progression on an earlier BTK inhibitor, calling it “another lifeline” for patients with a high unmet need.
- Other options after BTK resistance include BCL-2 inhibitors, combination therapies and CAR T-cell therapy, depending on the patient and their previous treatments. New treatments are also being studied for people whose CLL becomes resistant to multiple targeted therapies, including BTK degraders and bispecific antibodies.
- Overall, advances in CLL treatment are helping people live longer and better than ever before. Many patients can control their disease for years while maintaining a good quality of life and continuing to live full, active lives.
The good news is that BTK resistance does not mean treatment options have run out. A newer type of BTK inhibitor, pirtobrutinib (Jaypirca), can provide another option for patients whose CLL progresses after treatment with an earlier-generation BTK inhibitor.
Read MoreWhat Does BTK Resistance Mean?
BTK inhibitors block part of the B-cell receptor signaling pathway, which CLL cells rely on for growth and survival.The covalent BTK inhibitors ibrutinib (Imbruvica), acalabrutinib (Calquence), and zanubrutinib (Brukinsa) bind irreversibly to BTK and can provide long-lasting disease control. Because they bind permanently to the protein, they are also known as irreversible BTK inhibitors. But eventually, some cancers develop resistance.
Pirtobrutinib, by contrast, is a non-covalent, or reversible, BTK inhibitor. Rather than binding permanently to BTK, it binds differently from covalent BTK inhibitors.
This is where pirtobrutinib can make a difference for patients whose CLL has progressed on a covalent BTK inhibitor. With pirtobrutinib, “we’ve seen that we can get most patients to respond to this non-covalent [BTK] inhibitor despite progression on the covalent,” says Dr. Levy.
Resistance is different from intolerance. A patient who stops a BTK inhibitor because of side effects may be able to switch to another drug in the same class. When the cancer itself becomes resistant, however, switching between covalent BTK inhibitors may not overcome the problem.
How Pirtobrutinib Can Help
Pirtobrutinib is a non-covalent, or reversible, BTK inhibitor that binds to BTK differently from covalent BTK inhibitors.
That difference allows pirtobrutinib to continue targeting the BTK pathway even when a patient’s CLL has progressed on a covalent BTK inhibitor.
What Other Treatments Are Available?
Pirtobrutinib is one of several options doctors may consider after BTK resistance. Treatment depends on a patient’s previous therapies, disease characteristics, overall health and why the previous treatment stopped working.
- BCL-2 inhibitors: These targeted drugs interfere with a protein that helps CLL cells survive and may be used alone or in combination with other therapies.
- Combination therapies: Researchers are studying combinations of pirtobrutinib with other targeted treatments. Dr. Levy points to data from the BRUIN CLL-322 study showing improved progression-free survival and deeper, longer-lasting responses when pirtobrutinib was added to venetoclax (Venclexta) and rituximab (Rituxan).
- CAR T-cell therapy: This cellular therapy is available for some patients with CLL and may produce durable responses in a subset of people with difficult-to-treat disease.
What If CLL Becomes Resistant to Multiple Treatments?
Some patients eventually become resistant to both BTK and BCL-2 inhibitors, creating an important unmet need.
“We need to continue to develop new therapies for these patients,” says Dr. Levy, noting that treatment options are continuing to expand for people whose disease becomes resistant to multiple targeted therapies.
Researchers are studying new approaches, including BTK degraders, which target the BTK protein, as well as bispecific antibodies and other immune-based therapies.
These emerging treatments could provide additional options for patients whose disease no longer responds to currently available targeted therapies.
Questions to Ask Your Doctor
- Has my CLL become resistant to my BTK inhibitor, or am I experiencing intolerance?
- Would pirtobrutinib be appropriate for me?
- What are the benefits and risks of switching to a non-covalent BTK inhibitor?
- Should I consider a BCL-2 inhibitor or another targeted therapy?
- Would a combination treatment be an option?
- Could CAR T-cell therapy be appropriate at some point?
- What treatment would you recommend if my disease becomes resistant to multiple targeted therapies?
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