Chronic lymphocytic leukemia (CLL): Full guide

What is CLL?

Chronic lymphocytic leukemia (CLL) is a cancer of lymphocytes. Lymphocytes are white blood cells that help fight infection. CLL starts in a kind of lymphocyte called a B cell. The cancer cells build up in the blood, bone marrow, lymph nodes, and spleen. Bone marrow is the soft, spongy tissue inside your bones where blood cells are made.

"Chronic" means it usually grows slowly. The CLL cells look grown-up, but they do not work the way healthy B cells do. Over time, they can crowd out healthy blood cells. This can lead to anemia (low red blood cells), low platelets, and a weaker immune system.

CLL is the most common leukemia in adults in the US. Most people are in their late 60s or 70s when they are diagnosed. It is a bit more common in men. Having a parent, brother, or sister with CLL raises the chance a little.

Many people have no symptoms at all. CLL is often found by chance, when a routine blood test shows a high white blood cell count. Others notice swollen lymph nodes, tiredness, night sweats, or more infections than usual. CLL usually cannot be cured with standard treatment. But it is very treatable, and many people never need treatment or go years before they do. With newer treatments, most people live for many years, and many live a normal or near-normal life span.

Types and related conditions

CLL and a few related conditions are really the same disease seen in different places or at different amounts. Your care team will tell you which one fits you.

CLL can also be grouped by how active it is. Early CLL that is not causing problems is watched. Active CLL that is causing problems is treated. Rarely, CLL changes into a faster-growing lymphoma.

Chronic lymphocytic leukemia (CLL)

The CLL cells are mainly in the blood and bone marrow. A blood test shows at least 5,000 of these abnormal B cells in each small drop (microliter) of blood.

Small lymphocytic lymphoma (SLL)

The same cancer cells as CLL, but they are mostly in the lymph nodes, with fewer in the blood. It is treated the same way as CLL.

Monoclonal B-cell lymphocytosis (MBL)

A small number of CLL-like cells in the blood, below the level needed to call it CLL, with no swollen nodes or other signs. It is not cancer. It does not need treatment, but you may have a blood count about once a year. Only a small number of people with MBL (about 1 in 100 each year, or fewer) go on to need CLL treatment.

Early, symptom-free CLL

Most people are diagnosed at this point. Blood counts are mostly normal and there are no troubling symptoms. The usual plan is careful watching, not treatment.

Active CLL

CLL that is causing problems, such as low blood counts, large or painful lymph nodes, a big spleen, or symptoms like fevers and soaking night sweats. This is when treatment usually starts.

Richter transformation

Rarely, CLL changes into a fast-growing lymphoma, most often diffuse large B-cell lymphoma. Signs can include a lymph node that grows quickly, new fevers, or weight loss. It needs a biopsy and prompt treatment.

Prolymphocytic changes

Some people have larger, younger-looking cells called prolymphocytes. Your report may mention them. A high number can mean the disease may act faster.

Tests you may have

CLL can usually be diagnosed with blood tests alone. Some tests are done at diagnosis, and some are repeated right before treatment starts, because the results can change over time.

During watch and wait, you will mostly have a blood count and a physical exam every few months. Most people do not need scans or a bone marrow biopsy.

Complete blood count (CBC)

Measures your white cells, red cells, and platelets. A high lymphocyte count is often the first clue. Your CBC is the main test used to follow CLL over time.

Flow cytometry of the blood

A lab test that looks at markers on the surface of your blood cells. It shows whether the extra lymphocytes are CLL cells. This test confirms the diagnosis.

Physical exam

Your doctor feels your neck, armpits, groin, and belly to check lymph nodes, spleen, and liver. This is part of staging.

FISH test

A lab test on blood cells that looks for missing or extra pieces of chromosomes, such as del(17p), del(11q), trisomy 12, and del(13q). It helps show how CLL may behave and which treatment will work best.

IGHV mutation test

Checks a gene in the CLL cells. The result does not change over time, so it is done once. It helps predict how CLL may act and guides some treatment choices.

TP53 gene test

Looks for changes (mutations) in the TP53 gene. It is usually done with FISH before each new treatment, because TP53 changes can show up later.

Other blood tests

These may include kidney and liver tests, LDH, beta-2 microglobulin, antibody levels (immunoglobulins), and a test for hemolysis, which is when red blood cells break down too early.

Hepatitis B and other infection tests

Some CLL treatments can wake up an old hepatitis B infection. You will be tested before starting. If you have had hepatitis B, you may take a medicine to protect your liver.

Bone marrow biopsy

Not needed for most people. It may be done if your blood counts are low and the reason is not clear. A needle takes a small sample from the back of the hip bone after numbing medicine.

Imaging scans

CT or PET scans are not needed for everyone. They may be done before some treatments, to check large lymph nodes, or if Richter transformation is a concern.

Heart check

Before some BTK inhibitor pills, your care team may check your blood pressure, heart rhythm (ECG), or heart history, because these drugs can affect the heart.

Stages and when to treat

CLL is staged with simple tests: a blood count and a physical exam. In the US, doctors mostly use the Rai system. In Europe, the Binet system is more common. Both look at whether lymph nodes, spleen, or liver are swollen, and whether red blood cells or platelets are low.

Stage alone does not decide when to start treatment. Many people in early stages never need treatment for years. Doctors usually start treatment when CLL is causing problems. These include low red cells or platelets because of CLL, large or painful lymph nodes or spleen, lymphocyte counts that double quickly, or symptoms like fevers, soaking night sweats, weight loss, or extreme tiredness.

Starting treatment early, before CLL causes problems, has not helped people live longer in studies. That is why "watch and wait" (also called active monitoring) is the standard for early CLL. It is a real plan, not doing nothing. Doctors may also use a score called CLL-IPI, which combines several test results, to estimate how CLL may act.

Rai stage 0 (low risk)

A high lymphocyte count only. Lymph nodes, spleen, and liver are normal size, and red cells and platelets are normal.

Rai stage I and II (intermediate risk)

A high lymphocyte count plus swollen lymph nodes (stage I), or a swollen spleen or liver (stage II). Red cells and platelets are still normal.

Rai stage III and IV (high risk)

A high lymphocyte count plus anemia (stage III) or low platelets (stage IV) caused by CLL. Treatment is often needed.

Binet stage A

Fewer than 3 areas with swollen lymph nodes or organs, and normal red cells and platelets.

Binet stage B

3 or more areas with swollen lymph nodes or organs, and normal red cells and platelets.

Binet stage C

Anemia or low platelets, no matter how many areas are swollen.

Low counts from the immune system

Sometimes the immune system attacks red cells or platelets. This is called autoimmune hemolytic anemia or immune thrombocytopenia. It is treated differently, often with steroids first, and does not always mean the CLL itself needs treatment.

Gene tests and risk features

Gene tests on your CLL cells help predict how fast CLL may grow and, most importantly, which treatments will work best. Ask your care team for your results and what they mean for you.

FISH and TP53 testing are usually repeated before each new treatment, because CLL can pick up new changes over time. The IGHV result stays the same, so it only needs to be done once.

del(17p) or TP53 mutation

A missing piece of chromosome 17 or a change in the TP53 gene. This is the most important high-risk feature. Chemotherapy works poorly against it. Targeted drugs such as BTK inhibitors and venetoclax work much better and are preferred.

IGHV unmutated

The CLL cells have an unmutated IGHV gene. CLL tends to grow faster and come back sooner after chemotherapy. Targeted drugs still work well.

IGHV mutated

The CLL cells have a mutated IGHV gene. CLL tends to grow more slowly. This is a more favorable feature.

del(13q)

A missing piece of chromosome 13. When it is the only change, it is linked to slower-growing CLL.

Trisomy 12

An extra copy of chromosome 12. It is usually an intermediate-risk feature.

del(11q)

A missing piece of chromosome 11. It is often linked to large lymph nodes and faster growth. Targeted treatments work well against it.

Complex karyotype

Many chromosome changes at once (often 3 or more). It may mean CLL is more likely to come back sooner. Ask your care team if this applies to you.

Beta-2 microglobulin

A blood test that can be higher when there is more CLL in the body. It is one part of the CLL-IPI score.

Undetectable MRD

MRD means measurable residual disease, tiny amounts of CLL found only with very sensitive tests. Undetectable MRD after fixed-length treatment is linked to longer time before CLL comes back.

Main treatments

Most people with CLL now get targeted treatment instead of chemotherapy. There are two main approaches. One is a pill taken every day for as long as it keeps working (continuous treatment). The other is a combination given for a set time, often about 1 year, and then stopped (fixed-duration treatment). Both work very well. The best choice depends on your gene test results, other health problems, other medicines, and what matters most to you.

Treatment is usually not started until CLL is active. When treatment does start, the goal is to control CLL for as long as possible with good quality of life. Many people get years of control from their first treatment.

Watch and wait (active monitoring)

For early CLL with no problems, you see your care team every few months for a blood count and exam. Treatment starts only if CLL becomes active. Many people stay in this phase for years.

BTK inhibitor pills (continuous)

These pills block a protein called BTK that CLL cells need to grow. Examples are acalabrutinib, zanubrutinib, and ibrutinib. They are taken every day, usually for years, as long as they keep working and side effects are okay. Acalabrutinib and zanubrutinib tend to cause fewer heart problems than ibrutinib. Acalabrutinib is sometimes given with obinutuzumab. They work well for people with del(17p) or TP53 changes.

Venetoclax plus obinutuzumab (fixed duration)

Venetoclax is a pill that blocks a protein called BCL2, which helps CLL cells stay alive. Obinutuzumab is an antibody given by IV that targets a marker called CD20 on CLL cells. Together they are given for about 12 months, then stopped. Venetoclax is started at a low dose and raised over 5 weeks to lower the risk of tumor lysis syndrome.

BTK inhibitor plus venetoclax (fixed duration)

Some people get a BTK inhibitor and venetoclax together for a set time, then stop. Combinations such as acalabrutinib with venetoclax, or ibrutinib with venetoclax, are approved or used in some places. Ask your care team if one is available and fits you.

Fixed duration vs continuous: how to choose

Fixed-duration treatment gives a planned break with no CLL drugs, and fewer long-term side effects and costs. Continuous treatment avoids the IV infusions and the careful start-up needed for venetoclax, and it is often preferred for people with del(17p) or TP53 changes. Your care team will help you weigh these choices.

Chemoimmunotherapy

Older combinations like FCR (fludarabine, cyclophosphamide, and rituximab) or BR (bendamustine and rituximab) are used much less today. They may still be an option for a few younger, fit people with mutated IGHV and no TP53 changes, but targeted drugs are usually preferred.

Treatment if CLL comes back

If CLL returns or stops responding, there are many options. Your care team may switch to the other main drug type (for example, venetoclax after a BTK inhibitor), or repeat a fixed-duration treatment that worked well. Pirtobrutinib is a different kind of BTK inhibitor that can work after other BTK inhibitors stop working.

CAR-T cell therapy

Your own T cells (immune cells) are collected and changed in a lab to attack CLL cells. Lisocabtagene maraleucel (liso-cel) is approved for CLL that has come back after both a BTK inhibitor and venetoclax. It is given once, at a specialized center.

Allogeneic stem cell transplant

A transplant using stem cells from a donor. It is the only treatment that may cure CLL, but it has serious risks. It is used rarely, for younger, fit people whose CLL has stopped responding to other treatments.

Clinical trials

Many new drugs and combinations for CLL are being studied. A clinical trial may be an option at any point. Ask your care team.

Infections, side effects, and what helps

CLL weakens the immune system, even before any treatment. Infections are the most common serious problem for people with CLL. Treatment can lower your defenses further. Preventing and quickly treating infections is a big part of care.

Each CLL drug has its own side effects. Most can be managed, often by changing the dose or switching to another drug. Tell your care team about any new symptom, and check with them before starting any new medicine, supplement, or herbal product, because many interact with CLL pills.

Infections

Pneumonia, sinus infections, and shingles are more common. Get the flu shot every year and stay up to date on COVID, pneumonia, RSV, and the non-live shingles vaccine (Shingrix). Do not get live vaccines. Your care team may give medicines to prevent shingles or other infections during some treatments. Call right away for a fever.

Low antibody levels

Many people with CLL have low antibody (immunoglobulin) levels. If you keep getting serious infections, you may get IVIG, an infusion of antibodies from donors, every few weeks.

Bruising and bleeding with BTK inhibitors

Easy bruising and small bleeds are common. Tell your care team if you take a blood thinner, aspirin, or fish oil. These pills are often paused for a few days before and after surgery or dental work, so tell every doctor and dentist you take one.

Heart rhythm and blood pressure with BTK inhibitors

BTK inhibitors can cause an irregular heartbeat called atrial fibrillation and raise blood pressure. This is more common with ibrutinib. Check your blood pressure at home if you can, and report a racing or fluttering heartbeat, chest pain, or dizziness.

Headache, joint pain, and diarrhea

Headaches are common in the first weeks of acalabrutinib and often fade. Joint and muscle aches and diarrhea can happen with BTK inhibitors. These often get better with time or a dose change.

Tumor lysis syndrome (TLS) with venetoclax

When many CLL cells die quickly, they release salts that can harm the kidneys and heart. To prevent this, venetoclax starts at a low dose and goes up each week for 5 weeks. You will drink plenty of water, may take allopurinol, and get frequent blood tests. Some people stay in the hospital for the first doses.

Low white blood cells (neutropenia)

Venetoclax and obinutuzumab can lower white blood cells and raise infection risk. Your care team checks your counts and may pause treatment or give a shot to boost white cells.

Infusion reactions with obinutuzumab

Chills, fever, or shortness of breath can happen during the first infusion. You get medicines beforehand, and the first dose is given slowly over 2 days. Reactions are much less common later.

Food and drug interactions

Grapefruit, Seville oranges, and starfruit can raise levels of venetoclax and some BTK inhibitors. Some antibiotics, antifungals, and acid reducers also interact. Always check with your pharmacist.

Skin cancer and other cancers

People with CLL have a higher risk of skin cancer and some other cancers. Use sunscreen, cover up in the sun, and have a skin check every year.

Living with CLL

For most people, CLL is a long-term condition. You may spend years in watch and wait, then have treatment, then a long break or ongoing pills. Many people work, travel, and enjoy family life as usual.

Watch and wait can feel stressful. It is normal to worry while you are not on treatment. Remember that waiting is the proven best approach for early CLL, and your blood tests will catch changes. Write down your counts and questions to bring to each visit.

Protect yourself from infection every day. Wash your hands often, avoid people who are sick, and keep up with vaccines. Vaccines may work less well in CLL, especially during treatment, so family members should also get vaccinated. Call your care team right away for a fever, even if you feel okay otherwise.

Take care of your whole health. Stay active, eat well, keep up with heart and cancer screenings, and see a dermatologist once a year. Support is available for you and your caregivers. Groups like the CLL Society and Blood Cancer United (formerly the Leukemia and Lymphoma Society) offer free education and help.