Chronic Lymphocytic Leukemia

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Understanding chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults and has been the focus of headlines over the past few years because of enormous progress in its treatment.

In 2015, the American Society of Clinical Oncology recognized these developments as its Cancer Advance of the Year. Four targeted drugs had been approved, giving patients with CLL treatments that were more effective and produced fewer side effects than older therapies.

Those improvements introduced meaningful options for older patients who could not have withstood the harsher regimens of the past. They also made it more possible to treat CLL long term as a chronic condition.

But what exactly is CLL? What are the warning signs, and who should be on the lookout for them?


CLL originates in the bone marrow where cells form blood. This causes blood cells to produce B lymphocytes, a type of white blood cell, that are not normal, healthy or able to effectively fight infection. These leukemia cells may look basically normal under a microscope, but they may reproduce too rapidly, survive longer than normal cells and crowd out healthy white blood cells. CLL cells may also grow in the lymph nodes and the spleen. Eventually, the cancerous cells may spill into the bloodstream and reach a threshold that defines the patient as having CLL, though it may be years before any symptoms arise.

Each year, about 21,000 people receive a diagnosis of CLL and about 4,500 die from the disease. The average risk of developing CLL is about 1 in 175.

Scientists are not certain what causes the disease but have identified some risk factors. People over 50 have a higher likelihood of developing CLL as do those who have had significant exposure to the herbicide Agent Orange. People with a family history of the disease among first-degree relatives are also at higher risk, as are men in general and people of either sex in North America and Europe compared with those in Asia.

However, screening for the disease is not recommended because most cases are sporadic, or random, without any clear risk factor. Also, most patients receive diagnoses of early-to intermediate-stage CLL and can be treated with a watch-and-wait strategy.


Among people with CLL, 80% have no symptoms at diagnosis. Typically, the disease is found when a blood test ordered for an unrelated health condition or a routine checkup reveals a high number of lymphocytes. In CLL, the overall white blood cell count can be elevated, too.

It doesn’t happen often, but patients sometimes detect CLL themselves. They might notice enlarged lymph nodes, which feel like lumps, typically in the neck or above the collarbone, or in the armpits or groin. As the disease progresses, other symptoms may emerge: fatigue, weight loss, chills, unexplained fever, night sweats and bleeding or bruising easily, as well as an enlarged spleen or liver that causes gastrointestinal symptoms and increased risk of infections. Those symptoms warrant a visit to a doctor. Any lymph node that reaches a width of two fingers or more should be evaluated if it persists. An enlarged node may accompany a cold or the flu, so it’s reasonable to wait until the illness resolves to see if the node shrinks to its normal size.


Unlike most leukemias, CLL does not require a bone marrow aspiration for diagnosis; rather, a doctor can check for the disease via blood tests. CT scans are also usually not needed at time of diagnosis.

Doctors can easily determine how advanced the disease is by using a staging system based on the presence of any enlarged lymph nodes in addition to lymphocytes; an enlarged liver or spleen; low hemoglobin, also known as anemia; or a low count of platelets, blood cells that help form clots to stop bleeding.

That assessment doesn’t reveal everything doctors need to know, however. About 30% of patients will never need treatment for their CLL; to differentiate, doctors conduct prognostic tests on circulating leukemia cells in the blood. Chromosome analysis and other blood tests can suggest the likelihood of disease progression in the near future, because certain chromosome abnormalities in CLL cells are known to be favorable for slow-moving disease and some for the opposite.

Genetic tests might be used to look for a mutated immunoglobulin gene, present in half of patients with CLL, which indicates that the disease will progress more slowly. Testing for mutations of TP53 is recommended before any treatment because it can help determine which therapies are the most appropriate.


Treatment for CLL typically includes single drugs or combinations of medications. The many possible options include oral targeted drugs (kinase inhibitors and BCL-2 blockers) and chemoimmunotherapy, in which an intra- venous monoclonal antibody is given with chemotherapy. Experimental drugs or novel combinations of new and old drugs, given in clinical trials, or “off label,” may be a good option.

People who have experienced disease progression while taking other lines of therapy might consider a stem cell transplant.

In some very rare circumstances, the spleen or lymph nodes become so enlarged that treatment with radiation or surgery might be warranted.

All drugs can have side effects, and each drug in each class has a different side effect profile.

BTK (Bruton’s tyrosine kinase) inhibitors are oral targeted therapies that have revolutionized the care of CLL. Their side effects may include low white blood cell counts, increased risk of infection, bleeding, musculoskeletal pain, hypertension, mouth sores, nausea, rash and headaches. PI3K inhibitors may cause diarrhea, liver inflammation, colitis, lung inflammation and infections, rash and low white blood cell counts. When first started, BCL-2 blockers can cause tumor lysis syndrome by killing the cancer so quickly that the body can’t cope, and this can later cause low blood counts, pneumonia and other infections. Monoclonal antibodies can cause reactions at the time of the infusions, plus diarrhea, nausea, constipation, fatigue, shortness of breath, increased risk of new or reactivated infections such as hepatitis B, and a drop in blood counts. Chemotherapy for CLL may be associated with bone marrow, nerve, heart or bladder damage, low blood counts, hair loss, nausea and increased risk of second cancers.


Even in the early stage of disease, patients with CLL have diminished immune systems. It’s important for them to alert their care team if they believe they’re getting an infection, even if it’s just a cold. Patients with CLL have a high rate of hospitalization and even death with COVID-19 infections and should follow all the guidelines to minimize their risk. Vaccinations should be reviewed and updated, but patients should receive no live vaccines. Also, age- and gender-appropriate cancer screening is recommended as patients are at higher risk of a second cancer, especially skin cancers.

With attention to these kinds of details and the new therapies available for advanced CLL, it is now possible for some with the disease to achieve an average life span. In fact, new treatments and better understanding of the biology of the disease are improving outcomes for nearly all patients with CLL, regardless of their age or risk factors.


Those who want more help understanding CLL, navigating treatment decisions or finding a doctor, support group or clinical trial can contact the CLL Society (

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