Chronic lymphocytic leukemia (CLL) is a slow-growing cancer of the immune system. Because it’s slow-growing, many people with CLL won’t need to start treatment for many years after their diagnosis.

Once the cancer begins to grow, there are many available treatment options that can help people achieve remission. This means people can experience long periods of time when there’s no sign of cancer in their bodies.

The exact treatment option that you’ll receive depends on a variety of factors. This includes:

  • whether your CLL is symptomatic
  • the stage of the CLL, based on results of blood tests and a physical exam
  • your age
  • your overall health

While there’s no cure for CLL yet, breakthroughs in the field are on the horizon.

Doctors typically stage CLL using a system called the Rai system. Low risk CLL describes people who fall in “stage 0” under the Rai system.

In stage 0, the lymph nodes, spleen, and liver are not enlarged. Red blood cell and platelet counts are also near normal.

If you have low risk CLL, your doctor (usually a hematologist or oncologist) will likely advise you to “watch and wait” for symptoms. This approach is also called active surveillance.

Someone with low risk CLL may not need further treatment for many years. Some people will never need treatment. You’ll still need to see a doctor for regular checkups and lab tests.

Intermediate risk CLL describes people with stage 1 to stage 2 CLL, according to the Rai system. People with stage 1 or 2 CLL have enlarged lymph nodes and potentially an enlarged spleen and liver but close to normal red blood cell and platelet counts.

High risk CLL describes patients with stage 3 or stage 4 cancer. This means you may have an enlarged spleen, liver, or lymph nodes. Low red blood cell counts are also common. In the highest stage, platelet counts may be low as well.

If you have intermediate or high risk CLL, your doctor will likely recommend that you start treatment right away.

Chemotherapy and immunotherapy

In the past, the standard treatment for CLL included a combination of chemotherapy and immunotherapy agents, such as:

  • a combination of fludarabine and cyclophosphamide (FC)
  • FC plus an antibody immunotherapy known as rituximab (Rituxan) for people younger than 65
  • bendamustine (Treanda) plus rituximab for people older than 65
  • chemotherapy in combination with other immunotherapies, such as alemtuzumab (Campath), obinutuzumab (Gazyva), and ofatumumab (Arzerra). These options may be used if the first round of treatment doesn’t work.

Targeted therapies

Over the last few years, a better understanding of the biology of CLL has led to a number of more targeted therapies. These drugs are called targeted therapies because they’re directed at specific proteins that help CLL cells grow.

Examples of targeted drugs for CLL include:

  • zanubrutinib (Brukinsa): Approved by the Food and Drug Administration (FDA) in 2023, zanubrutinib targets the enzyme known as Bruton’s tyrosine kinase (BTK), which is crucial for CLL cell survival.
  • ibrutinib (Imbruvica): This targets BTK with less precision than zanubrutinib.
  • venetoclax (Venclexta): This used in combination with obinutuzumab (Gazyva), targets the BCL2 protein, a protein seen in CLL.
  • idelalisib (Zydelig): This blocks the kinase protein known as PI3K and is used for relapsed CLL.
  • duvelisib (Copiktra): This also targets PI3K but is typically used only after other treatments fail.
  • acalabrutinib (Calquence): This is another BTK inhibitor approved in late 2019 for treating CLL.

Monoclonal antibody therapies

Monoclonal antibody therapies are a type of treatment in which proteins are made in a laboratory and designed to target certain antigens. They help jolt your immune system into attacking the cancer cells.

There are several monoclonal antibody treatments approved for treating CLL by targeting the antigens CD20 and CD52:

  • rituximab (Rituxan): targets CD20, often used with chemotherapy or targeted therapy as part of the initial treatment or in the second-line treatment
  • obinutuzumab (Gazyva): targets CD20, used with venetoclax (Venclexta) or chlorambucil (Leukeran) for patients with previously untreated CLL
  • ofatumumab (Arzerra): targets CD20, usually used in patients whose disease has not responded to prior treatments and is given in combination with chlorambucil (Leukeran) or FC
  • alemtuzumab (Campath): targets CD52

Blood transfusions

You may need to receive intravenous (IV) blood transfusions to increase blood cell counts.

Radiation

Radiation therapy uses high-energy particles or waves to help kill cancer cells and shrink painful, enlarged lymph nodes. Radiation therapy is rarely used in CLL treatment.

Stem cell and bone marrow transplants

Your doctor may recommend a stem cell transplant if your cancer doesn’t respond to other treatments. A stem cell transplant allows you to receive higher doses of chemotherapy to kill more cancer cells.

Higher doses of chemotherapy can cause damage to your bone marrow. To replace these cells, you’ll need to receive additional stem cells or bone marrow from a healthy donor.

A large number of approaches are under investigation to treat people with CLL. Some have been recently approved by the FDA.

Drug combinations

In May 2019, the FDA approved venetoclax (Venclexta) in combination with obinutuzumab (Gazyva) to treat people with previously untreated CLL as a chemotherapy-free option.

In April 2020, the FDA approved a combination therapy of rituximab (Rituxan) and ibrutinib (Imbruvica) for adult patients with chronic CLL.

These combinations make it more likely that people may be able to do without chemotherapy altogether in the future. Nonchemotherapy treatment regimens are essential for those who can’t tolerate harsh chemotherapy-related side effects.

CAR T-cell therapy

One of the most promising future treatment options for CLL is CAR T-cell therapy. CAR T-cell therapy, which stands for chimeric antigen receptor T-cell therapy, uses a person’s own immune system cells to fight cancer.

The procedure involves extracting and altering a person’s immune cells to better recognize and destroy cancer cells. The cells are then put back into the body to multiply and fight off the cancer.

CAR T-cell therapy research is still ongoing. In September 2023, researchers reported a possible “universal” CAR T-cell treatment that may be effective in all types of blood cancers.

CAR T-cell therapies are promising, but they do carry risks. One risk is a condition called cytokine release syndrome. This is an inflammatory response caused by the infused CAR T-cells. Some people can experience severe reactions that may lead to death if not quickly treated.

Other drugs under investigation

Some other targeted drugs currently being evaluated in clinical trials for CLL include:

  • entospletinib (GS-9973)
  • tirabrutinib (ONO-4059 or GS-4059)
  • cirmtuzumab (UC-961)
  • ublituximab (TG-1101)
  • pembrolizumab (Keytruda)
  • nivolumab (Opdivo)

Once clinical trials are completed, some of these drugs may be approved for treating CLL. Talk with a doctor about joining a clinical trial, especially if current treatment options aren’t working for you.

Clinical trials evaluate the efficacy of new drugs as well as combinations of already approved drugs. These new treatments may work better for you than the ones currently available. Hundreds of clinical trials are ongoing for CLL.

Many people who receive a diagnosis of CLL won’t actually need to start treatment right away. Once the disease starts to progress, you have many treatment options available.

There’s also a wide range of clinical trials to choose from that are investigating new treatments and combination therapies.