CLL Treatment: What Side Effects Can I Expect From BTK Inhibitors?

“The covalent BTK inhibitors as a class — acalabrutinib (Calquence) and zanubrutinib (Brukinsa) are the two most common ones used nowadays — do have side effects of their own,” Dr. Hilal tells SurvivorNet. Covalent BTK inhibitors work by permanently attaching to the BTK protein, blocking a key signal that CLL cells need to survive and grow.

Rare But Serious Heart-Related Side Effects

Before beginning treatment, Dr. Hilal discusses the uncommon but potentially serious risks associated with BTK inhibitors.

“We worry about cardiovascular toxicities. They’re rare, but they’re real and they happen,” he explains.

These can include:

• Atrial fibrillation (an irregular heartbeat)
• High blood pressure (hypertension)
  • Blood pressure monitoring is mandatory for patients using BTK Inhibitors
• Other abnormal heart rhythms (arrhythmias)
• Rare bleeding complications, including spontaneous hemorrhage

Although these complications can occur, Dr. Hilal emphasizes that they are uncommon.

“I warn patients about them, but it’s rare that we encounter them,” he says.

Patients with pre-existing heart disease or other cardiovascular conditions may have a higher risk of developing these complications, making it especially important to review your medical history with your healthcare team before starting treatment.

More Common Side Effects Are Usually Mild

Far more often, patients experience side effects that, while uncomfortable, are not considered dangerous.

Dr. Hilal says the most common include:

• Headaches
• Joint aches
• Muscle aches
• Bruising
• Changes in blood counts

These symptoms are generally manageable and often improve with supportive care or adjustments to treatment.

Combination Therapy Can Affect Blood Counts

Some patients receive a BTK inhibitor together with venetoclax, another targeted therapy commonly used to treat CLL. When these drugs are combined, doctors pay particularly close attention to blood counts.

“If you add the venetoclax onto the mix, then you’re seeing cytopenia, so blood counts start going down from bone marrow suppression,” Dr. Hilal explains.

Cytopenias occur when the bone marrow produces fewer blood cells than normal, which can increase the risk of infection, anemia, or bleeding depending on which blood cells are affected.

Because of this, your healthcare team will monitor your blood work regularly throughout treatment.

Managing Side Effects

Experiencing side effects does not necessarily mean a treatment has failed or must be discontinued.

Instead, doctors have several strategies to help patients stay on therapy while minimizing toxicity.

“A lot of times it’s dose reductions. Sometimes you hold the medicine, give it a few days or a week, let that side effect or toxicity resolve, restart it back,” Dr. Hilal says.

In some cases, restarting the medication at the same dose works well. Other times, lowering the dose may be necessary. If low blood counts are caused primarily by venetoclax, that medication may be adjusted instead of the BTK inhibitor.

“I don’t think everybody does it exactly the same way, but there are things you can do before you give up on the medicine,” Dr. Hilal explains.

Only in rare cases do side effects become severe enough to require permanently stopping treatment.

“Once you reduce the doses to the maximum you are able to, and patients still have toxicities, you might find yourself in a situation where you have to discontinue early. That is extremely rare, but there are ways around it. Usually most of these side effects resolve when the treatment is either dose reduced or even discontinued.”

What to Expect When Starting Treatment

One advantage of BTK inhibitors is that they are relatively simple to begin. Unlike some cancer therapies, they require little monitoring when first started.

“It’s very easy to initiate. There’s very little monitoring involved in the beginning and we give it time to work,” Dr. Hilal says.

BTK inhibitors are taken continuously as oral medications. While many patients notice improvement early, the treatment continues working over time.

“It’s continuous oral therapy and we get maximum response months down the road,” Dr. Hilal says. “You start seeing a response in the beginning, but it keeps working very slowly over many months.”

Patients receiving a BTK inhibitor together with venetoclax often experience faster responses.

“If you’re doing it in combination with venetoclax, the responses are much faster… you see a much more rapid, faster drop in white count, a lot more shrinkage of the lymph nodes,” he adds.

What Patients Should Remember

Although BTK inhibitors can cause side effects, most are manageable and do not prevent patients from benefiting from treatment. Knowing which symptoms are common, understanding the rare but serious risks, and maintaining regular communication with your healthcare team can help ensure side effects are addressed early.

For patients experiencing new symptoms — particularly heart palpitations, chest pain, unusual bleeding, severe bruising, fever, or signs of infection — it’s important to contact your healthcare provider promptly rather than waiting until your next scheduled appointment. Early intervention can often prevent side effects from becoming more serious while helping patients stay on these highly effective therapies.

Questions To Ask Your Doctor

• What side effects are most common with the BTK inhibitor I’m taking?
• If I experience headaches, muscle aches, or joint pain, what can I do to manage them?
• Which side effects are considered serious and require me to call your office right away?
• Am I at higher risk for heart-related side effects because of my medical history?
• Will you monitor my blood pressure or heart rhythm while I’m taking this medication?

Learn more about SurvivorNet's rigorous medical review process.