Smart Patients Get Smart Care™

The World’s Leading Authority for Chronic Lymphocytic Leukemia Patients

Managing Side Effects of Oral Targeted Therapies in CLL

In science and medicine, information is constantly changing and may become out-of-date as new data emerge. All articles and interviews are informational only, should never be considered medical advice, and should never be acted on without review with your health care team.

Essentially all medications have side effects, minor and major, common and rare. Nearly all side effects can be managed if they are recognized early and treated appropriately.

This is not a substitute for the advice of your healthcare provider (HCP) but rather a guide as to what is common, what to watch for, and when to get help. It’s usually best to be over-cautious.

Many different medications are used to treat CLL. We will restrict this discussion to the approved oral target therapies that are taken at home.

Ibrutinib, Acalabrutinib, and Zanubrutinib (BTK Inhibitors)
Bruising and clinically relevant bleeding

Bruising is very frequent but is not considered a precursor of major bleeding, nor should bruising lead to holding therapy. Major bleeding is rare but does occur in 2-4% of patients.

Ensure your HCP knows you are on ibrutinib, acalabrutinib, or zanubrutinib before starting anti-platelet or anti-coagulant therapy (blood thinners).

Generally, any BTK inhibitor should be held before any invasive surgery and even some dental procedures. Discuss any planned procedure ahead of time with your healthcare team.

Atrial Fibrillation (AF)

AF is an irregular heart rhythm that occurs in as many as 1 of 10 patients. You might notice a fast or irregular heartbeat. Let your doctor know. Stopping ibrutinib may not resolve the AF. AF should be managed by your healthcare team quite similarly to any patient who is not on ibrutinib, with the added caution of avoiding medications that shouldn’t be taken with ibrutinib. AF is less common with acalabrutinib and zanubrutinib.


1 out of 4 patients will develop hypertension. It should be treated the same as any other patient. Hypertension is less common with acalabrutinib.


Headaches are common with acalabrutinib during the start of therapy and usually resolve over time. Often acetaminophen or even a simple cup of coffee can ease headache pain.


It is usually mild and goes away on its own or with a change in diet and over-the-counter anti-diarrheal medications (loperamide or Imodium). Talk to your HCP if it persists for> 3 days.


Rashes often recover spontaneously without any specific treatment. An itchy rash may require topical corticosteroid therapy and oral antihistamines.

Nail Changes

Brittle fingernails or splitting of the nails developed in 2/3 of patients, usually at about 6 months after starting, which is consistent with the growth time of nails. Oral biotin and clear strengthening nail polish may help.

Muscle and Joint Pains

Achy sore muscles and joints usually get better with time and may respond to acetaminophen. If severe or persistent, the dose must sometimes be reduced or the medication held.

Idelalisib and Duvelisib (PI3K inhibitors)

Mild diarrhea is common in the first 8 weeks of starting and can often be managed with antidiarrheal agents (loperamide or Imodium). If it is more severe or if it persists > 2-3 days, then the PI3K inhibitor should be stopped, and your doctor should be consulted about more aggressive work-up and management.

Diarrhea that begins later than 2 months after starting treatment, often around 7 months, can be much more serious, especially if there is any blood or mucus in the stool. It needs immediate medical attention. Treatment usually means holding the medication and steroids to calm the gut. This may necessitate hospital admission. Call your HCP promptly with “late onset” diarrhea.

Pneumonia and pneumonitis

Cough, shortness of breath, and fever that progresses over weeks need to be promptly assessed. There are a few different possible causes, including common and rare infections and inflammation of the lungs. Antibiotics or steroids may be needed.


Discuss any rash with your healthcare team. Sometimes the medication needs to be stopped (held).

Abnormal Liver Function Tests

This is usually an asymptomatic elevation of liver enzymes that suggests some inflammation. Your HCP will monitor this. It usually responds to holding the medication.

Low Neutrophil Count (Neutropenia)

This is usually an asymptomatic drop in neutrophils, a type of white blood cell that needs to be monitored and medication held until the count recovers.


PI3K inhibitors are associated with a higher risk of some serious infections.

Tumor Lysis Syndrome

Although tumor lysis syndrome is the most serious early side effect of venetoclax, where it kills the cancer cells too fast for the kidney to handle, with the standard slow ramp-up dosing and with careful monitoring, it is rarely a problem these days.

Diarrhea and/or Nausea

About half of the patients will get some GI issues that can usually be handled by a change in diet and medications, both over the counter or by prescription, to help with the symptoms.

Low Blood Counts

Some patients will see their neutrophils (a type of white blood cell) and/or platelets fall. While this is usually not clinically significant, it does need to be monitored, and occasionally therapy will need to be modified.

All Meds

All medications may cause fatigue that is sometimes hard to differentiate from the fatigue caused by the CLL itself. Please see our handout on fatigue and talk to your doctor.

There are many other potential side effects that are less common but still may need medical attention. Please don’t ignore them and quickly consult your healthcare team.