Typical Treatment of Chronic Lymphocytic Leukemia (CLL)

Treatment options for chronic lymphocytic leukemia (CLL) can vary based on factors such as whether the leukemia is causing symptoms or other problems, whether the leukemia cells have certain gene or chromosome changes, and a person's age and overall health.

Treatment for people diagnosed with small lymphocytic leukemia (SLL) is essentially the same as for people with CLL. This is because CLL and SLL are basically different versions of the same disease.

“Watch and wait” (observation) for CLL that’s not causing symptoms

Doctors often advise waiting to treat chronic lymphocytic leukemia (CLL) until the leukemia progresses or causes bothersome symptoms.

In the meantime, the CLL is monitored carefully without active treatment. This might be called the watch-and-wait approach, watchful waiting, active surveillance, or observation. This is a standard approach for most people with early-stage CLL who don’t have symptoms.

Why might doctors use the watch-and-wait approach?
Many people live a long time with CLL, but in general it is very hard to cure. Treating it right away, especially if it isn't causing problems, doesn’t seem to help people live longer.

Research studies have shown that no harm comes from the watch-and-wait approach when compared with immediate treatment for early-stage CLL. Some people might not develop symptoms for years, or even decades, and some might never need any treatment.

Because of this, and because treatment can cause side effects, “watch and wait” is a standard approach.

What can I expect if I’m under observation for early-stage CLL?
During this time, your blood counts will be watched closely, and you will get physical exams on a regular basis. If the CLL shows signs of progressing, active treatment (see below) could be started at that time.

It might be hard to understand how you could have leukemia that your doctors don’t want to treat right away. This can be stressful. However, you may find that your concerns about active surveillance lessen over time.

It can be helpful to talk with your health care team about your questions and concerns.
Managing your overall health during this time
Although many people live with CLL comfortably without active treatment, it can be helpful to use this time to improve your overall health.

This can include:

• Stopping smoking
• Keeping immunizations (vaccines) up to date

For more information on getting vaccines when you have CLL, see Supportive or Palliative Care for Chronic Lymphocytic Leukemia (CLL).

Initial treatment of CLL

If you need treatment for your CLL, several factors are important.

Your cancer care team will consider your age and overall health. They will also consider certain changes in your leukemia cells and how those changes could help predict your outlook (prognosis). This includes whether the leukemia cells have a deletion in chromosome 17, a TP53 gene mutation, or an unmutated version of the IGHV gene.

Common options for first-line treatment

There are many options for first-line treatment of CLL, including targeted drugs, chemotherapy, immunotherapy, and different combinations of these.

Some of the more common options include:

• A BTK inhibitor such as ibrutinib (Imbruvica), zanubrutinib (Brukinsa), or acalabrutinib (Calquence), either alone or with an anti-CD20 immunotherapy such as obinutuzumab (Gazyva) or rituximab (Rituxan, other brand names)
• Venetoclax (Venclexta) and ibrutinib
• Venetoclax with either rituximab or obinutuzumab
• High-dose methylprednisolone and either rituximab or obinutuzumab
• Obinutuzumab alone

For people whose CLL cells do not have a deletion in chromosome 17 or a TP53 gene mutation, another option might be chemoimmunotherapy, such as:

• Fludarabine, cyclophosphamide, and rituximab (FCR)
• Bendamustine and either rituximab or obinutuzumab
• Chlorambucil and obinutuzumab

Other drugs or combinations of drugs may also be used.

Radiation or surgery

Localized treatment with low-dose radiation therapy may be an option if the only problem caused by your CLL is an enlarged spleen or swollen lymph nodes in one part of your body.

Splenectomy (surgery to remove the spleen) is another option if your enlarged spleen is causing symptoms.

Stem cell transplant

It's not common, but some people who have very high-risk CLL may be referred for a stem cell transplant (SCT) early in treatment.

Second-line or later treatments for CLL

If the first treatment for CLL is no longer working, or if the leukemia comes back, another type of treatment often helps.

Weighing your available treatment options

The options for second-line (or later) treatment are generally the same as the options for first-line treatment (targeted drugs, immunotherapy, and possibly chemotherapy). But your available options will depend on what treatments you’ve had and how well they worked.

Other factors, like your overall health, might also affect your options.

Looking at how your CLL responded to the first treatment

If the response to your initial treatment lasted a long time (usually at least a few years), the same treatment might be used again. If the response to your initial treatment wasn't long-lasting, using the same treatment isn't as likely to be helpful.

Possible treatment options

Many of the same drugs and combinations listed above (as well as others) may be options as second-line treatments.

Targeted therapy drugs and monoclonal antibodies are commonly used, alone or in combination.

Chemo drugs might also be an option for some people.

Other types of treatments might be options as well. For example, some people who've already had treatment might benefit from a type of immunotherapy known as CAR T-cell therapy.

At some point, a stem cell transplant may be an option for some people, especially if they have a type of CLL that's harder to treat, such as if the cells have a chromosome 17 deletion or a TP53 gene mutation.

Clinical trials of newer treatments might also be a good option at some point, especially if many treatments have been tried.

Treating complications of CLL

People with CLL are at risk for certain complications, including low blood counts, infections, and an increased risk of some more aggressive types of cancer.

Treating the CLL itself might help with some of these complications, but you might need other types of treatments as well.

Low blood cell counts and infections

CLL can sometimes cause serious problems with low blood counts and infections. To learn more about this, see Supportive or Palliative Care for Chronic Lymphocytic Leukemia.

Leukapheresis for very high white blood cell counts

Although it's rare, some people with CLL have very high numbers of leukemia cells in their blood when they're first diagnosed, which causes problems with blood circulation.

This is called leukostasis, and it needs to be treated right away. Sometimes a procedure called leukapheresis might be used to remove the white blood cells, although this isn't used very often.

To learn more, see Supportive or Palliative Care for Chronic Lymphocytic Leukemia.

Other cancers

One of the most serious complications of CLL is a change (transformation) in the leukemia to a high-grade or aggressive type of non-Hodgkin lymphoma (NHL) called diffuse large B-cell lymphoma (DLBCL), or to Hodgkin lymphoma.

When this happens, it’s known as Richter transformation (or Richter syndrome). Treatment is often the same as it would be for that type of lymphoma. It might include a stem cell transplant, because these cancers are often hard to treat.

Less often, CLL may progress to prolymphocytic leukemia (PLL), which can be hard to treat. Some studies have suggested that certain drugs such as cladribine (2-CdA) and alemtuzumab may be helpful.

Rarely, CLL transforms (changes) into acute lymphocytic leukemia (ALL). If this happens, treatment is likely to be similar to that used for people with ALL.

Acute myeloid leukemia (AML) is another rare complication in people who have been treated for CLL, especially with chemotherapy. Drugs like chlorambucil and cyclophosphamide can damage the DNA of blood-forming cells. These damaged cells may go on to become cancer, leading to AML, which tends to be very aggressive and often hard to treat.