Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma (CLL/SLL)

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) have essentially the same cellular, immunophenotypic, and biological features and are considered different clinical forms of the same disease.

The distinction is based mainly on where the abnormal B cells are found:

• CLL: Abnormal B cells are found primarily in the blood and bone marrow and may also involve the lymph nodes, spleen, and other tissues.

• SLL: Abnormal B cells are found mainly in the lymph nodes or other lymphoid tissues, with relatively few abnormal cells in the blood.

CLL/SLL usually progresses slowly. Many people have no symptoms when they are diagnosed, and the disease may be discovered during a routine blood test or physical exam.

A diagnosis of CLL/SLL does not always mean that treatment needs to start right away. People without indications for treatment are often monitored regularly.

The exact cause of CLL/SLL is not known. The disease develops through a series of genetic and molecular changes in B lymphocytes that allow abnormal cells to survive longer than they normally would and gradually build up in the blood, bone marrow, lymph nodes, and other tissues.

Factors that may be associated with an increased risk include:

• Age: CLL/SLL is most common in older adults.

• Family history: Having a close relative with CLL/SLL or certain other blood cancers may increase the risk.

• Sex: CLL is more common in men than in women.

• Certain environmental or occupational exposures: Some exposures may be associated with an increased risk, although their role is still being studied.

Having one or more risk factors does not mean that someone will develop CLL/SLL, and many people diagnosed with the disease have no known risk factors.

Many people with CLL/SLL have no symptoms in the early stages. When symptoms do occur, they may include:

• Painless swelling of lymph nodes in the neck, armpits, or groin

• Ongoing fatigue or weakness

• Unexplained fever

• Drenching night sweats

• Unexplained weight loss

• Frequent or persistent infections

• Easy bruising or bleeding

• Abdominal fullness or discomfort caused by an enlarged spleen

• Feeling full after eating only a small amount

• Shortness of breath

Some patients may also develop anemia, a low platelet count, or other blood cell abnormalities if normal blood cell production is affected.

These symptoms can also be caused by other conditions. Testing is needed to determine whether they are related to CLL/SLL.

Diagnosis of CLL/SLL may involve blood tests, flow cytometry, tissue pathology, and genetic and molecular testing. Because CLL and SLL differ mainly in where the abnormal B cells are found, the diagnostic approach may differ between the two.

Blood Tests

A complete blood count (CBC) measures white blood cells, lymphocytes, red blood cells, and platelets.

When CLL is suspected, the healthcare team evaluates the number and persistence of abnormal B cells in the blood and looks for abnormalities such as anemia or a low platelet count.

Flow Cytometry and Immunophenotyping

Flow cytometry examines specific markers on the surface of abnormal B cells and is an important test for diagnosing CLL.

CLL/SLL has a characteristic immunophenotype. These findings can help confirm the diagnosis and distinguish CLL/SLL from other B-cell lymphomas.

Tissue Biopsy

For patients suspected of having SLL—particularly those with enlarged lymph nodes but without enough abnormal B cells in the blood to meet the criteria for CLL—a biopsy of an affected lymph node or other tissue is usually needed.

Pathology and immunohistochemistry can help confirm SLL and distinguish it from other types of lymphoma.

Genetic and Molecular Testing

Genetic and molecular testing plays an important role in assessing CLL/SLL and selecting treatment.Common tests include:

• FISH: Can identify chromosomal abnormalities such as del(17p), del(11q), trisomy 12, and del(13q).

• TP53 testing: TP53 abnormalities are important for assessing disease risk and selecting treatment.

• IGHV mutation status: Provides important information about the biology and prognosis of the disease.

In particular, findings such as TP53 abnormalities and del(17p) can directly influence treatment decisions, so these results are often evaluated when treatment is being considered.

Bone Marrow Tests

Bone marrow testing is not required for every patient when CLL/SLL is diagnosed.

A bone marrow aspiration and/or biopsy may be performed in selected cases to evaluate bone marrow involvement, investigate the cause of low blood cell counts, or provide additional information needed for treatment.

Treatment for CLL/SLL depends on whether there are indications for treatment, the characteristics of the disease, genetic and molecular test results, age, overall health, and previous treatments.

Not everyone with CLL/SLL needs treatment right away. For people without indications for treatment, starting therapy early generally does not provide a clear benefit, so regular monitoring may be recommended.

With the development of targeted therapies, treatment for CLL/SLL has changed significantly, and many patients can now receive targeted therapy–based treatment.

Active Surveillance (Watch and Wait)

For people without symptoms or other indications for treatment, regular monitoring may be recommended instead of starting treatment immediately.

Follow-up usually includes a review of symptoms, physical exams, and blood tests. The healthcare team monitors changes in lymphocyte counts, lymph nodes and spleen size, other blood cell counts, and the development of new symptoms.

If the disease remains stable, monitoring can continue. Treatment can be started if the disease progresses or other indications for treatment develop.

Targeted Therapy

Targeted therapy is now one of the most important approaches to treating CLL/SLL. Major types of targeted therapy include:

• BTK inhibitors: These drugs interfere with signaling pathways that CLL/SLL cells use to grow and survive.

• BCL-2 inhibitors: These drugs block the BCL-2 protein and help trigger the death of lymphoma cells.

These medications may be used alone or combined with treatments such as anti-CD20 monoclonal antibodies.

The choice of treatment depends on factors such as TP53/del(17p) and IGHV status, overall health, other medical conditions, and previous treatments.

Anti-CD20 Monoclonal Antibodies

CLL/SLL cells typically express CD20. Anti-CD20 monoclonal antibodies, such as obinutuzumab or rituximab, can help the immune system recognize and attack abnormal B cells.

These medications are often combined with other treatments depending on the individual situation.

Chemotherapy and Chemoimmunotherapy

Chemotherapy and chemoimmunotherapy were widely used for CLL/SLL in the past.

With the development of BTK inhibitors, BCL-2 inhibitors, and other targeted therapies, traditional chemotherapy is no longer the main first-line approach for many patients.

Chemotherapy or chemoimmunotherapy may still be considered in selected situations.

Relapsed or Refractory CLL/SLL

Some patients may experience disease progression after treatment or may not respond adequately to previous therapy.

Treatment for relapsed or refractory CLL/SLL depends on previous medications, duration of response, resistance patterns, biological features such as TP53 status, and overall health.

New targeted therapies, immunotherapies, and cellular therapies continue to expand treatment options for relapsed or refractory disease.

CAR T-Cell Therapy

For selected patients with CLL/SLL that remains relapsed or refractory after multiple treatments, CAR T-cell therapy may be an option.

CAR T-cell therapy involves collecting a patient’s own T cells and modifying them in a laboratory so they can recognize a specific target on cancer cells. The modified cells are then expanded and infused back into the patient.

Whether CAR T-cell therapy is appropriate depends on previous treatments, disease status, age, overall health, and treatment eligibility.

Hematopoietic Stem Cell Transplantation (HSCT)

With the development of targeted therapies and other newer treatments, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is no longer a routine treatment for most people with CLL/SLL.

For a small number of patients with high-risk disease that remains difficult to control after multiple treatments, allogeneic HSCT may be considered.

The decision depends on disease risk, response to previous treatments, age, overall health, and donor availability.

Clinical Trials

Treatment for CLL/SLL continues to evolve. Clinical trials are studying new targeted therapies, immunotherapies, cellular therapies, and treatment combinations.

Clinical trials may be available for both newly diagnosed and relapsed or refractory CLL/SLL.