Chronic lymphocytic leukemia (CLL)

Last updated date: 09-Jun-2023

Originally Written in English

Chronic lymphocytic leukemia


Chronic lymphocytic leukemia (CLL) is a blood and bone marrow malignancy. CLL affects white blood cells known as lymphocytes. It takes a long time to develop. It is the most prevalent adult leukemia in Western nations, accounting for 25 to 30 percent of all leukemias in the US. There are several varieties of leukemia, and the therapy you require is determined by which type you have.


What is Leukemia?


Leukemia is a kind of cancer that begins in the bone marrow's blood-forming cells. When one of these cells transforms and becomes a leukemia cell, it no longer develops properly and expands uncontrollably. It often divides to produce new cells at a quicker rate than usual. Cells with leukemia do not die when they should. This permits them to proliferate in the bone marrow and crowd out regular cells.

Leukemia cells eventually exit the bone marrow and enter the circulation. This raises the concentration of white blood cells in the blood. Once in the circulation, leukemia cells can move to other organs, where they can interfere with the proper functioning of other cells in the body.

Leukemia is distinct from other cancers that begin in organs such as the lungs, colon, or breast and subsequently travel to the bone marrow. Cancers that begin elsewhere and spread to the bone marrow are not considered leukemia. Knowing the specific kind of leukemia allows doctors to better estimate each patient's prognosis and choose the appropriate treatment.


What is Chronic lymphocytic leukemia (CLL)?

 Chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is a slow-growing malignancy that primarily affects developing B-lymphocytes. B lymphocytes (also known as B-cells) are white blood cells with particular functions. Under normal circumstances, they create immunoglobulins (also known as antibodies), which help defend our bodies from infection and disease. Lymphocytes in persons with CLL undergo a malignant (cancerous) transformation and become leukemic cells.

It is critical to note that for many people, CLL remains stable for months or years with little, if any, influence on their lifestyle or overall health. Around 30-50 percent of persons diagnosed with CLL never need treatment and can live for many years despite their diagnosis.

For others, leukemic cells grow uncontrollably, survive longer than expected, and amass in the bone marrow, circulation, lymph nodes (glands), spleen, liver, and other organs. Because these cells are aberrant, they are unable to act normally. An overabundance of lymphocytes crowds the bone marrow over time, interfering with normal blood cell formation.

CLL often begins and progresses gradually over months and years. When most patients are first diagnosed, they have no symptoms of their condition. People in these situations frequently require no therapy for an extended period of time, except from regular check-ups with their doctor to closely monitor their health. Others may require treatment immediately after being diagnosed.


What is a Chronic Leukemia?

Cells in chronic leukemia can partially mature (and more are like normal white blood cells). although not quite. These cells may appear to be normal, but they are not. They do not fight infections as well as regular white blood cells. Leukemia cells outlive normal cells and multiply, driving out normal cells in the bone marrow. Chronic leukemias can take a long time to manifest difficulties, and most individuals can live with them for many years. However, chronic leukemias are more difficult to treat than acute leukemias.


What is a Lymphocytic leukemia?

Depending on which bone marrow cells the malignancy begins in, leukemia is classified as myeloid or lymphocytic.

Lymphocytic leukemias (also known as lymphoid or lymphoblastic leukemias) begin in lymphocyte precursor cells. Lymphomas are malignancies that begin in those cells as well. The primary distinction between lymphocytic leukemias and lymphomas is that cancer cells in leukemia are mostly found in bone marrow and blood, whereas cancer cells in lymphoma are found in lymph nodes and other organs.



CLL accounts for 25 to 30% of all leukemias in the United States. According to the American Cancer Society, in 2020 there will be around 21,040 new CLL cases and roughly 4,060 fatalities. CLL is responsible for 191,000 cases and 61,000 deaths worldwide each year. CLL can strike persons as early as 30 years old. However, it is primarily found in persons above the age of 70. CLL is relatively uncommon in children.

It is well known that the incidence rises dramatically with age. Male populations have a somewhat greater incidence of CLL than female populations. Women, however, have a more aggressive type of the disease than males, according to research.

CLL prevalence varies by geographic area and race. CLL is more frequent in people in the Western world. It is significantly higher among Caucasians than among Asian Pacific Islanders or African-Americans. CLL is more common in Western countries than in the United States, although it is uncommon in Asian countries. CLL is frequent among Jews of Eastern European ancestry. It is more frequent in non-Hispanic whites and is rare in Asians.

CLL is said to have a hereditary foundation and to occur in families (familial CLL). When compared to the father, the second-generation offspring is roughly 20 years younger upon diagnosis. CLL patients' first-degree relatives (siblings, children, or parents) are twice as likely to get the disease.


Chronic Lymphocytic leukemia Causes

The specific cause of CLL is uncertain. CLL is most likely caused by genetic reasons rather than environmental influences. However, there are only a few identified risk factors for CLL, such as occupational exposure to specific chemicals, radiation exposure, and cigarette users. Farmers working near rubber manufacturing plants and laborers exposed to benzene and strong solvents have been linked to an elevated incidence of CLL. These links, however, have yet to be confirmed. There is no reported increase in the incidence of CLL in atomic explosion survivors. However, the risk of other forms of leukemia has increased.

CLL incidence has grown in the uranium mining community, which is exposed to both ionizing and non-ionizing radiation. Tobacco and cigarette smokers have a much higher risk of CLL than non-tobacco users. 


Chronic Lymphocytic Leukemia Symptoms

Chronic Lymphocytic Leukemia Symptoms

When a routine CBC reveals aberrant lymphocytosis, which leads to CLL diagnosis, patients with CLL are frequently asymptomatic. Approximately 5 to 10% of CLL patients have B symptoms such as:

  • Fever of > 100.5 degrees F for > 2 weeks with no evidence of infection,
  • Unintentional weight loss >/= 10% of body weight over the last 6 months
  • Drenching night sweats with no evidence of infection
  • Extreme fatigue; and 
  • Early satiety. 

Physical examination reveals that 50 to 90 percent of CLL patients have localized/generalized lymphadenopathy. The most prevalent locations are the lymph nodes in the cervical, supraclavicular, and axillary regions. The nodes are solid, non-tender, spherical, and freely movable when palpated. Splenomegaly is the second most frequent lymphoid organ enlargement, occurring in 25 to 55 percent of cases. It is painless to palpate on a non-tender, smooth, hard surface. Hepatomegaly occurs in 15% to 25% of patients. The liver is somewhat enlarged and may be felt 2-6 cm below the right costal border. The liver is solid and non-tender to the touch, with a smooth surface.

Skin malignancies are a reasonably common CLL complication, hence skin inspection is an important aspect of the physical evaluation. Skin is the most often implicated non-lymphoid tissue in CLL patients. Leukemia cutis (skin lesions) usually affects the face and appears as papules, macules, plaques, ulcers, blisters, or nodules. A skin biopsy can assist confirm a CLL diagnosis. Secondary cutaneous lesions may develop as a result of hemorrhage, vasculitis, or infection. Exaggerated reactions to bug bites have also been documented in patients.

Splenomegaly and hypercellular bone marrow are caused by neoplastic B cell infiltration of the spleen and bone marrow. Splenomegaly causes greater sequestration of RBCs and platelets, which causes anemia and thrombocytopenia by lowering RBCs and platelets. Anemia patients experience exhaustion and loss of breath; thrombocytopenia patients readily bleed/bruise, and petechiae can be visible on physical examination. A lack of functioning B cells reduces the body's ability to create antibodies for immunological responses, resulting in hypogammaglobinemia and an increased risk of infection.


CLL Diagnosis

CLL Diagnosis

A peripheral blood smear is the initial step in the diagnosis of CLL. The peripheral blood smear reveals an absolute lymphocyte count more than 5000/mcL as well as smudge cells, confirming CLL. Although >=5000/mcL B cells on peripheral smear are the diagnostic criteria for CLL, a considerable number of individuals present with an absolute lymphocyte count more than 100,000/mcL.

Peripheral blood flow cytometry may be used to do immunophenotypic study of peripheral circulating lymphocytes, which can assist validate the clonality of circulating B cells in CLL patients. Flow cytometry may be used to check for the conventional immunophenotypic indicators of CLL in both peripheral blood and bone marrow aspirate. To restate, low immunoglobulin levels are a hallmark of the CLL lymphocyte phenotype (most often IgM immunoglobulin and sometimes both IgM and IgD).

Although they are not required for diagnosis, bone marrow aspiration and biopsy are frequently performed as part of a diagnostic workup or prior to therapy. If the biopsy material contains more than 30% lymphocytes of all nucleated cells in a normocellular/hypercellular bone marrow aspirate, the diagnosis of CLL is confirmed. 

Histology of excisional lymph nodes shows extensive effacement of nodal architecture with some scattered remaining probable germinal centers. These lymph node infiltrates are mostly made up of tiny lymphocytes.

Spleen histology shows red and white pulp penetration, with white pulp involvement being more prominent than red pulp. A CT scan, from an imaging aspect, aids in determining the degree of lymphadenopathy and organ infiltration in the form of spleen and liver sizes.


CLL Stages

The following stages are used for chronic lymphocytic leukemia:

  • Stage 0

There are too many lymphocytes in the blood in stage 0 chronic lymphocytic leukemia, but there are no other indications or symptoms of leukemia. Chronic lymphocytic leukemia in stage 0 is slow-growing (slow-growing).

  • Stage I

There are too many lymphocytes in the blood and the lymph nodes are bigger than usual in stage I chronic lymphocytic leukemia.

  • Stage II

There are too many lymphocytes in the blood in stage II chronic lymphocytic leukemia, the liver or spleen is bigger than usual, and the lymph nodes may be larger than normal.

  • Stage III

There are too many lymphocytes in the blood and not enough red blood cells in stage III chronic lymphocytic leukemia. The lymph nodes, liver, or spleen may be enlarged.

  • Stage IV

There are too many lymphocytes in the blood and not enough platelets in stage IV chronic lymphocytic leukemia. The lymph nodes, liver, or spleen may be bigger than normal, or there may be an insufficient number of red blood cells.


Chronic lymphocytic leukemia Treatment  

Chronic lymphocytic leukemia Treatment

Patients with chronic lymphocytic leukemia might receive a variety of treatments (CLL). Some therapies are mainstream (already used), while others are being investigated in clinical studies. A treatment clinical trial is a research study designed to enhance current medicines or gather information on novel treatments for cancer patients.

When clinical studies demonstrate that a novel therapy outperforms the conventional treatment, the new treatment may be adopted as the standard treatment. Patients may choose to consider participating in a clinical study. Some clinical trials are only available to people who have not yet begun therapy.

Six types of treatment are used:

1. Watchful waiting

Watchful waiting is the practice of attentively watching a patient's status without intervening until signs or symptoms arise or change. This is also known as observation. Asymptomatic and symptomatic or progressing CLL are treated with watchful waiting.


2. Targeted therapy

Targeted therapy is a kind of cancer treatment in which medicines or other substances are used to locate and destroy specific cancer cells. Targeted treatments are less likely to kill normal cells than chemotherapy or radiation therapy. CLL is treated with many forms of targeted therapy:

  • Tyrosine kinase inhibitor (TKI) therapy: This medication inhibits the enzyme tyrosine kinase, which causes stem cells to divide and produce more white blood cells than the body requires. TKIs used to treat symptomatic or progressive, recurrent, or refractory CLL include ibrutinib, acalabrutinib, idelalisib, and duvelisib.
  • BCL2 inhibitor therapy: This medication inhibits BCL2, a protein identified on certain leukemia cells. This has the potential to destroy leukemia cells while also making them more responsive to other anticancer treatments. Venetoclax is a BCL2 inhibitor that is used to treat symptomatic or progressing, recurring, or refractory CLL.
  • Monoclonal antibody therapy: Monoclonal antibodies are immune system proteins that are created in the lab to treat a variety of disorders, including cancer. As a cancer therapy, these antibodies can bind to a specific target on cancer cells or other cells, which may aid in the growth of cancer cells. The antibodies can then attack the cancer cells, stop their development, or prevent their spread. Infusions of monoclonal antibodies are used. They can be employed alone or in combination to deliver medications, poisons, or radioactive material directly to cancer cells. Rituximab, ofatumumab, and obinutuzumab are used to treat symptomatic or progressing, recurrent, or refractory CLL alone or in conjunction with chemotherapy.


3. Chemotherapy

Chemotherapy is a cancer treatment that employs medications to halt the proliferation of cancer cells, either by killing them or preventing them from growing. Chemotherapy medications enter the circulation and can reach cancer cells throughout the body whether administered orally or injected into a vein or muscle (systemic chemotherapy). Combination chemotherapy is a cancer treatment that involves the use of more than one anticancer medication.


4. Radiation therapy

Radiation therapy is a cancer treatment that employs high-energy x-rays or other forms of radiation to either kill or prevent cancer cells from developing. External radiation treatment involves using a machine outside the body to direct radiation toward a cancerous part of the body, such as a collection of lymph nodes or the spleen. This therapy may be used to relieve discomfort caused by an enlarged spleen or lymph nodes.


5. Immunotherapy

Immunotherapy is a cancer treatment that employs the patient's immune system to combat the disease. Substances produced by the body or created in a laboratory are used to augment, enhance, or restore the body's natural anti-cancer defenses. This cancer treatment is classified as a biologic therapy.


6. Chemotherapy with bone marrow or peripheral stem cell transplant

Chemotherapy is used to eradicate cancer cells. Cancer therapy destroys healthy cells, including blood-forming cells. Treatments to replenish blood-forming cells include bone marrow or peripheral stem cell transplants. Stem cells (immature blood cells) are extracted from the patient's or donor's blood or bone marrow then frozen and kept. After the patient has finished chemotherapy, the stored stem cells are thawed and infused back into the patient. These reinfused stem cells develop into (and replenish) blood cells in the body.



The survival duration for CLL patients might range from 2 to >20 years, with a typical survival of 10 years. Patients with Rai stage 0-II may live for 5 to 20 years without therapy. Lymphocyte doubling time, defined as the number of months required to double the absolute lymphocyte count, is a prognostic indicator for CLL.

Untreated individuals with a lymphocyte doubling time of 12 months had a more aggressive manifestation of CLL. The prognosis of individuals with multiple chain lymphadenopathy, hepatosplenomegaly, anemia, and thrombocytopenia is poor.



Complications of CLL may include increased susceptibility to infections, particularly of the respiratory tract, progression to diffuse large B-cell lymphoma (Richter syndrome), an increased risk of other cancers (e.g., cancers of the skin, lungs, and GI tract), and immune system issues, in which the immune system attacks red blood cells or platelets, though this is uncommon.



Chronic lymphocytic leukemia (CLL) is a kind of leukemia that affects white blood cells known as lymphocytes. It takes a long time to develop. Swollen glands, weight loss, and infections that do not resolve are all symptoms of CLL. Many persons with CLL are asymptomatic. Typically, you begin by seeing your primary care physician, who may refer you to a specialist and arrange for tests. If you have CLL at an early stage, you may not require therapy right immediately. If you require treatment, you will receive chemotherapy.