Treatment of chronic lymphocytic leukemia by risk group

Treatment options for people with chronic lymphocytic leukemia (CLL) vary greatly, depending on their age, the disease risk group, and the reason for treating (like the symptoms the leukemia is causing). While many people live a long time with CLL, in general it is very difficult to cure, and early treatment hasn't been shown to help people live longer. Because of this and because treatment can cause side effects, doctors often advise waiting until the disease is progressing or symptoms appear before starting treatment.

The risk group, based on the Rai staging system (see the section called "How is chronic lymphocytic leukemia staged?"), is one factor when looking at treatment options. A person's age, general health, and other prognostic factors are important as well. Newer lab tests that look at chromosome changes and molecular markers may also offer important information about a patient's outlook. For example, people whose CLL cells have chromosome 17 or chromosome 11 deletions or high levels of ZAP-70 and CD38 are more likely to have faster growing forms of CLL and may need to be treated more aggressively.

Low-risk CLL

People in this group are often diagnosed based on a high lymphocyte count in the blood but otherwise have normal blood counts and do not have enlarged lymph nodes or organs. The prognosis (outlook) for people in this group is often very good, with long survival expected.

Most people can be observed with careful and frequent follow-up exams. Treatment is considered if there are signs that the leukemia is progressing or if a person develops bothersome symptoms. When needed, initial treatment is usually chemotherapy (chemo), which is described in the next section.

Intermediate- and high-risk CLL

Some patients with intermediate-risk CLL (stages I and II) may not have any symptoms and might not need treatment right away. They can often be watched for signs of disease progression and the start of new symptoms. Patients with high-risk CLL (stages III and IV) are more likely to need immediate treatment.

When treatment is needed there are many options. What treatment is used will depend upon factors like the patient's health, possible side effects, the reason that treatment is needed, and any need for a rapid response. Commonly used treatments include:

• FCR: fludarabine (Fludara), cyclophosphamide (Cytoxan), and rituximab (Rituxan)
• PCR: pentostatin (Nipent), cyclophosphamide, and rituximab
• FR: fludarabine and rituximab
• CVP: cyclophosphamide, vincristine, and prednisone (sometimes with rituximab)
• CHOP: cyclophosphamide, doxorubicin, vincristine (Oncovin), and prednisone
• Chlorambucil and prednisone
• Bendamustine (sometimes with rituximab)
• Alemtuzumab (Campath)
• Fludarabine (sometimes with rituximab)

Other drugs or combinations of drugs may also be also used.

If the only problem is an enlarged spleen or swollen lymph nodes in one region of the body, localized treatment with low-dose radiation therapy may be used. Splenectomy (surgery to remove the spleen) is another option if the enlarged spleen is causing symptoms.

Some people who have very high-risk disease may be best treated early with some type of stem cell transplant (SCT). Because it's still not clear how effective this treatment is for CLL, most stem cell transplants are done as part of a clinical trial. Younger people may be eligible for an autologous or allogeneic SCT. Some older people who may not be able to tolerate such transplants may still be eligible for a non-myeloablative transplant (mini-transplant).

Second-line treatment of CLL

If the initial treatment is no longer working or the disease comes back, another type of treatment may help. If the initial response to the treatment lasted a long time (usually at least a few years), the same treatment can often be used again. If the initial response wasn't long-lasting, using the same treatment again isn't as likely to be helpful. The options will depend on what the first-line treatment was and how well it worked, as well as the person's health.

Many of the drugs and combinations listed above may be options as second-line treatments. For many people who have already had fludarabine, alemtuzumab seems to be helpful as second-line treatment, but it carries an increased risk of infections. Other purine analog drugs, such as pentostatin or cladribine (2-CdA), may also be tried. Ofatumumab may be another option if other second-line treatments are no longer working.

Some people may have a good response to first-line treatment (such as fludarabine) but may still have some evidence of a small number of leukemia cells in the blood, bone marrow, or lymph nodes. This is known as minimal residual disease. CLL can't be cured, so doctors aren't sure if further treatment right away will be helpful. Some small studies have shown that alemtuzumab can sometimes help get rid of these remaining cells, but it's not yet clear if this improves survival.

Treating complications of CLL

CLL can cause serious problems with the blood and some of its components. It can also (rarely) transform into another, more aggressive type of cancer. Treating CLL itself may also lead to the development of another cancer.

Sometimes very high numbers of leukemia cells in the blood cause problems with normal circulation. Chemo may not lower the number of cells until a few days after the first dose, so before the chemo is given, some of the cells may be removed from the blood with a procedure called leukapheresis. This treatment lowers blood counts right away. The effect is only for a short time, but it may help until the chemo has a chance to work. Leukapheresis was discussed in more detail in the section called “Leukapheresis for chronic lymphocytic leukemia.”

People with CLL often have weakened immune systems and are at high risk for certain kinds of infections. Doctors may suggest vaccines to prevent some of these infections. Sometimes the drugs used to treat CLL may increase the risk of certain infections. Patients on these drugs are placed on antibiotics and anti-viral drugs to help lower the risk of these infections. Even if they aren’t on a drug linked to a high risk of infection, patients with CLL are watched closely for infection. Finding and treating infections early is an important part of follow-up for people with CLL, even in those who aren't getting treatment with chemotherapy.

People with CLL sometimes have low levels of the antibodies needed to fight infections. As a result, they may get frequent or severe infections with bacteria, such as pneumonia or sinus infections. This condition, called hypogammoglobulinemia, can be found by a blood test. It is treated by giving antibodies (called immunoglobulin) as an infusion into a vein (IV).

Sometimes CLL alters a patient's immune system in a way that causes it to attack his or her own red blood cells (called auto-immune hemolytic anemia) or blood platelets (immune-mediated thrombocytopenia). These conditions are treated with drugs that weaken the immune response. Steroids such as prednisone are often helpful, as are other drugs such as cyclosporine. Monoclonal antibodies like rituximab can also help in some cases.

One of the most serious complications of CLL is a change (transformation) of the leukemia to a high-grade or aggressive type of non-Hodgkin lymphoma called diffuse large cell lymphoma. This happens in about 5% of CLL cases, and is known as Richter syndrome. Treatment is often the same as it would be for lymphoma (see our document called Non-Hodgkin Lymphoma for more information), but these cases are often hard to treat.

Less often, CLL may transform to prolymphocytic leukemia. As with Richter syndrome, these cases can be hard to treat. Some studies have suggested that certain drugs such as cladribine (2-CdA) and alemtuzumab may be helpful.

In rare cases, patients with CLL may have their leukemia transform into acute lymphocytic leukemia (ALL). If this happens, treatment is likely to be similar to that used for patients with ALL (see our document called Leukemia: Acute Lymphocytic).

Acute myeloid leukemia (AML) is another rare complication in patients who have been treated for CLL. Drugs such as chlorambucil and cyclophosphamide can damage the DNA of blood-forming cells. These damaged cells may go on to become cancerous, leading to AML, which is very aggressive and often hard to treat (see our document called Leukemia: Acute Myeloid).