Chronic Lymphocytic Leukemia – Risk Factors, Symptoms, Staging, Treatment


chronic lymphocytic leukemia


Chronic Lymphocytic Leukemia is the most common leukemia in the US and western hemisphere accounting for about one-quarter of all leukemia cases. The overall incidence and mortality rate of CLL has been slightly declining during the last decade.

Chronic Lymphocytic Leukemia more commonly affects older age individuals with highest incidence observed in individuals aged between 65 to 74 years. The incidence rate of CLL is slightly higher in males than in females.

The blood is a connective tissue consisting of a liquid extracellular matrix (the plasma) and suspended formed elements (comprising blood cells and cell fragments). The 3 main components of formed elements include red blood cells (RBCs), white blood cells (WBCs) and platelets.

The WBCs are further divided into various subtypes based on their appearance under the microscope (with the application of different staining): neutrophils, basophils, eosinophils, monocytes, and lymphocytes (T-cells, B-cells, and natural killer cells). Each type of blood cell has a distinct function and is produced from pluripotent stem cell in the red bone marrow by a process called hemopoiesis.

CLL is a disorder in which abnormal B lymphocytes (leukemia cells in CLL look like mature B lymphocytes) start dividing without control. The abnormal B lymphocytes slowly get crowded in the red bone marrow and peripheral blood causing a reduction in the number of normal RBCs, WBCs, and platelets.

The CLL cells can spread to different organs like liver, spleen, and lymph nodes. Pathologically, CLL is defined as the presence of >/=5 x 10^9/L malignant monoclonal B cells in the blood. CLL cells express the B-cell markers CD19, CD20, CD21, CD23; and T-cell marker CD5.

Differential Diagnosis of Chronic Lymphocytic Leukemia (CLL)

Differential Diagnosis of CLL

Small lymphocytic lymphoma (SLL)

A disorder closely related to CLL, which is characterized by the presence of malignant monoclonal B-cells mainly in the lymphoid tissue (lymph nodes and spleen) and bone marrow but <5 x 10^9/L malignant cells are present in the blood (as opposed to CLL).

Monoclonal B-cell lymphocytosis (MBL)

A precursor to CLL, which is characterized by the presence of <5 x 10^9/L of abnormal monoclonal B cells in blood but in the absence of palpable lymph node(s), or other clinical features of a lymphoproliferative disorder. About 1% to 2% of patients with MBL progress to CLL, each year.

Prolymphocytic leukemia (PLL)

An aggressive type of lymphocytic leukemia, which is characterized by the presence of an abnormally high number of prolymphocytes, splenomegaly, and minimal involvement of lymph nodes. It can be either B-cell or T-cell type. It tends to grow and spread faster than CLL.

Large granular lymphocyte (LGL) leukemia

A rare T-cell or natural killer (NK)-cell lymphoproliferative disorder, which is characterized by the presence of an abnormally high number of larger than normal lymphocytes in the blood, cytopenia (neutropenia, anemia, and thrombocytopenia), and serological abnormalities (rheumatoid factor, antinuclear antibody, hypergammaglobulinemia, and high beta2- microglobulin). LGL leukemia cells can have features of either T -cells or of (NK)-cells, with NK-cells phenotype tends to be more aggressive.

Hairy cell leukemia (HCL)

A rare chronic B-cell lymphoproliferative disorder, which is characterized by the presence of an abnormally high number of hairy cells (twice as large as normal lymphocytes that have irregular cytoplasmic projections when viewed under the microscope), cytopenia, and splenomegaly. Recently it was found that patients with HCL have mutation in the BRAF (V600E) gene. The HCL tends to progress slowly and have a favorable outcome when treated with the modern therapeutic agents. The HCL represents about 2% of all adult leukemias.

Risk Factors for Chronic Lymphocytic Leukemia (CLL)

Risk Factors for CLL

Several epidemiological studies have revealed a few risk factors that can predispose CLL. Following is the list of such risk factors:

Industrial/Occupational/Accidental exposure 

An exposure to carcinogens like Agent Orange (an herbicide used during the Vietnam War); other pesticides, benzene and petroleum products has been indicated to increase the risk of CLL.

Family History

Individual with a history of CLL in close relatives are considered to be at increased risk of developing CLL.


CLL is more common among old age individuals and is very rare in individuals with age less than 20 years. Thus, CLL is considered as an exclusive adult disease.


CLL is more common in males than females (2:1).


CLL is more common in Caucasians than Asians.

Signs and Symptoms of Chronic Lymphocytic Leukemia (CLL)

leukemia symptoms

Following are some common signs and symptoms of CLL:

  • Unexplained weight loss
  • Loss of appetite
  • Fever and night sweats
  • Fatigue and weakness attributable to anemia, or other anemia-related symptoms like shortness of breath and dizziness
  • Recurrent infections (e.g. pneumonia) due to dysfunctional WBCs
  • Increased bleeding tendency, bruising, frequent or severe nosebleeds, and bleeding gums due to low platelet count (thrombocytopenia)
  • Swollen lymph nodes
  • Enlargement of the spleen or liver

Chronic Lymphocytic Leukemia (CLL) Investigations for Diagnosis and Staging

CLL Investigations for Diagnosis and Staging

If a person is suspected to have CLL, some investigations are required to confirm the diagnosis of the disease. Further, these investigations can help in determining the extent of disease and help in selecting an appropriate treatment approach.

Following are some commonly used diagnostic tools for CLL:

Blood Tests

Blood Tests

Blood tests provide very important information that provides direction to the diagnostic workup of CLL. Following are the commonly employed blood tests for the diagnosis of the CLL:

Complete Blood Cells Count (CBC): This test provides information on the level of RBCs, WBCs, and platelets. In most cases of CLL, low level of RBCs and platelets and high level of WBCs is observed. A higher level of WBCs is observed due to the presence of monoclonal B-lymphocytes which look like WBCs but cannot perform functions of WBCs.

Blood Smear: In this test, a drop of a blood sample is spread on a glass slide and this is observed under a microscope. This test helps in detecting changes in the distribution or appearance of various blood cells. Ruptured lymphocytes or “smudge” cells are usually observed in case of CLL, reflecting the fragility of CLL cells.

Flow cytometry: In this technique, the blood sample is first treated with some fluorescent antibodies that get attached to certain specific proteins (antigens) on the surface of cells. The treated sample is then analyzed using a laser beam and a detector attached to a computer.

This test can establish the diagnosis of CLL through detection of different types of cells (with specific cell surface proteins) in the blood sample along with the quantification of each type of cells. Presence of CD19, CD20, CD5, CD23, and CD10 cell surface proteins is usually detected in CLL by this technique. Restricted expression of either kappa or lambda immunoglobulin light chain on the cell surface membrane establishes the clonality of B-cells.

Fluorescent in situ hybridization (FISH): In this technique, fluorescent RNA probes are used, which bind to a specific portion of a chromosome in the sample cells. Then, the sample can be examined under a microscope to determine the presence of certain chromosomal abnormalities like translocation, addition, or deletion.

This technique is very sensitive, fast, and accurate. This technique is preferably used for detecting common genetic abnormalities in CLL cells, for example, del(13q), del(11q), del(17p), trisomy 12, and mutation in TP53 gene.

Polymerase chain reaction (PCR): This is a very sensitive diagnostic tool which can detect a very small number of leukemia cells with a specific genetic change, for example, Immunoglobulin heavy-chain variable (IGHV) region gene mutation.

This technique is generally used to diagnose minimum residual disease (MRD) in patients after treatment.

Bone Marrow Aspiration/Biopsy

Bone Marrow Aspiration

Bone marrow biopsy samples (are not absolutely required) may also be collected and analyzed to obtain information related to certain prognostic factors for CLL.

The biopsy sample is then tested in a laboratory and can provide very useful information about the CLL cells such as the pattern of spread (nodular versus interstitial pattern) or the severity of cancerous changes involved, and the presence of specific defective genes or proteins.


In this technique, a very thin portion of a sample is first attached to a microscope glass slide. The sample is then treated with a specific antibody which gets attached to a protein specific to certain types of cancer cells. Some reagents are then added to the treated sample that causes the bound antibody to changes its color.

The change in color of the antibody-protein complex can be observed under the microscope, which confirms the type of cancer cells. The determination of CD38, CD49d, and ZAP-70 expression can be achieved by this technique (or by flow cytometry), which provides prognostic information and guides appropriate treatment selection.

Imaging Tests

Utility of imaging tests is limited for the diagnosis of Chronic Lymphocytic Leukemia. However, these tests can be used to detect the involvement of different body parts by CLL. Alternatively, these tests are employed to assess accompanying problems like infection.

Computed tomography (CT) scan

CT Scan

In this technique, detailed cross-sectional images of body organs are generated using x-rays. It can be utilized for scanning neck, chest, abdomen and pelvis for the diagnosis of any abnormal lymph node or involvement of liver, spleen, or other structures.

Magnetic resonance imaging (MRI) scan

MRI Scan

This technique provides detailed images of internal body structures using radio waves, strong magnetic field, and gadolinium-based contrast material (which is used via intravenous injection to improve the clarity of the MRI images).

It can be utilized for scanning neck, chest, abdomen and pelvis for the diagnosis of any abnormal lymph node or involvement of liver, spleen, or other structures. It is considered very sensitive to detect the involvement of CNS the patients with neurological symptoms.

Response Assessment in Chronic Lymphocytic Leukemia (CLL)

Complete response (CR)

A CR means meeting following criteria : peripheral blood lymphocyte counts <4 x 10^9/L; absence of lymphadenopathy (that is, palpable nodes must be </=1.5 cm in diameter); absence of splenomegaly or hepatomegaly; absence of constitutional symptoms (that is, weight loss, significant fatigue, fevers, night sweats); and normalization of blood counts without growth factor support (that is, neutrophils >1.5 x 10^9/L, platelets >100 x 10^9/L, hemoglobin >11 g/dL).

Confirmation of CR requires bone marrow evaluation with aspirate and core biopsy, demonstrating <30% lymphocytes, with no B lymphoid nodules.

Partial response (PR)

PR means meeting at least 2 of the following criteria for at least 2 months: at least 50% reductions in – peripheral blood lymphocyte counts (from baseline), lymphadenopathy (based on the sum of the products of multiple affected nodes), hepatomegaly, and/or splenomegaly. In addition, at least 1 of the blood counts should be normalized or increase by >/=50% from baseline, for at least 2 months duration.

Progressive Disease

Progressive disease means any of the following: at least 50% increase from baseline in – lymphocyte counts, lymphadenopathy, hepatomegaly, or splenomegaly; appearance of any new lesions; or occurrence of cytopenia attributable to disease (that is, >/=50% decrease from baseline in platelet count, >2 g/dL decrease from baseline in hemoglobin levels).

Stable disease

Patients who do not have a progressive disease but do not meet the criteria for a CR or PR are considered to have stable disease.

Refractory Disease

A failure to achieve a response or having disease progression within 6 months of the last treatment is termed as the refractory disease.

Disease Relapse

An evidence of disease progression after a period of 6 months or more following an initial CR or PR is known as disease relapse.

Minimal Residual Disease (MRD)

When leukemia cells are undetectable with conventional diagnostic technique after treatment but leukemia cells are detectable with a more sensitive technique such as PCR, it is known as MRD. Patients with MRD after treatment are more likely to have disease relapse.

Chronic Lymphocytic Leukemia Staging

The staging system is used to describe the severity of Chronic Lymphocytic Leukemia based on various clinical parameters such as lymphocytosis; involvement of lymph nodes; enlargement of the spleen and/or liver; hemoglobin level; and platelets count. Staging helps to determine the disease prognosis, and thus, to select an appropriate treatment strategy.

“Rai” and “Binet” are the two most commonly used staging system for CLL by the medical community. The Rai system is mostly used in the US and the Binet system is mainly used in Europe. The Rai system assigns 5 stages (from 0 to IV) to the disease while the Binet system assigns 3 stages (A, B, and C) to the disease.

Following table describes the characteristics of CLL according to different stages and different systems:

Rai Staging

0 Low Lymphocytosis (>/=5*10^9/L leukemia cells in the blood and >40% leukemia cells in the bone marrow); no enlargement of the lymph nodes, spleen, or liver; RBCs and platelet counts are near normal
I Intermediate Lymphocytosis with enlarged lymph node(s)
II Intermediate Lymphocytosis with splenomegaly and/or hepatomegaly
III High Lymphocytosis with hemoglobin <11.0 g/dL or hematocrit <33%
IV High Lymphocytosis with platelets <100,000/microliter

Binet Staging

A Hemoglobin >/=10 g/dL, Platelets >/=100,000/mm^3 and <3 enlarged nodal areas
B Hemoglobin >/=10 g/dL, Platelets >/=100,000/mm^3 and >/=3 enlarged nodal areas
C Hemoglobin <10 g/dL and/or Platelets <100,000/mm^3

Prognostic Factors of Chronic Lymphocytic Leukemia (CLL)

Many other factors have been identified in different clinical research studies, which can predict the outcome of Chronic Lymphocytic Leukemia. These factors are not included in the staging system but are taken into account before starting the treatment for CLL. Following are examples of such prognostic factors:

Adverse prognostic factors: Examples of adverse prognostic factors include

  • Cytogenetic abnormalities (deletions of parts of chromosomes 17 or 11, trisomy 12, mutation in TP53 gene, and >/=3 unrelated chromosomal abnormalities);
  • flow cytometry-based parameters (CD38, CD49d and ZAP-70); elevated level of serum beta-2 microglobulin;
  • Increased fraction of prolymphocytes;
  • short lymphocyte doubling time;
  • diffuse pattern of bone marrow involvement; and
  • advanced age.

    Favorable prognostic factors: Examples of favourable prognostic factors include a mutated gene for IGHV; deletion of part of chromosome 13; and nodular pattern of bone marrow involvement.

Treatment of Chronic Lymphocytic Leukemia (CLL)

The treatment of Chronic Lymphocytic Leukemia depends on many factors, including but not limited to, patient’s age, overall health or comorbidities, stage/risk group, immunophenotypic/cytogenetic abnormality involved, etc.

Decision for whether to treat the patient or to observe is taken on the basis of – disease related symptoms (fever, night sweats, weight loss, etc), threatened end organ function, progressive bulky disease, progressive anemia or thrombocytopenia, lymphocyte doubling time, etc. If none is present, patient may be observed closely, but the final decision is taken after clinical assessment of the patient by an oncologist.

CLL without del(17p) or TP53 mutation

Chemoimmunotherapy (chemotherapy plus monoclonal antibody) or targeted therapy is considered as the preferred treatment for both elderly and young patients with significant comorbidities.
In patients <65 years of age and without significant comorbidities, Chemoimmunotherapy is considered as the preferred treatment approach.

CLL with del(17p) or TP53 mutation

Targeted therapy is considered the preferred treatment for both elderly and young patients with or without any significant comorbidities.

Chemotherapy for Chronic Lymphocytic Leukemia (CLL)

chemotherapy for cancer treatment

Chemotherapy means treatment with anti-cancer drugs that kill or decrease the growth of rapidly-growing cancer cells. Purine analogs and alkylating agents are the most commonly used chemotherapeutic agents for the treatment of CLL.

Chemotherapy is generally employed in combination with immunotherapy (monoclonal antibodies) for the management of CLL. It may be associated with side effects like  nausea/vomitinghair lossfatigue, cytopenias, etc due to its effect on normal body cells apart from cancerous cells.



These are a category of drugs which are structurally similar to cortisone, a hormone produced by the adrenal cortex. Examples of corticosteroids include dexamethasone and prednisone that are generally employed in the treatment CLL. These may have their own side effects like hyperglycemia, weight gain, mood changes, weakness in bones etc.

Monoclonal Antibodies for Chronic Lymphocytic Leukemia 

Monoclonal Antibodies

Monoclonal antibodies are man-made antibodies which can be directed to certain protein characteristic of cancer cells. These drugs activate the immune system to act against the cancer cells. For the treatment of CLL, Obinutuzumab gets attached to the CD20 protein on CLL cells and helps immune cells to identify and destroy the leukemia cells. Rituximab and ofatumumab are other monoclonal antibodies are generally employed for the treatment of CLL.

Following monoclonal antibodies are used for the treatment of CLL:




Rituximab is a CD20 targeted monoclonal antibody that binds to and inactivates CD20, a protein expressed on the surface of B cells. It is approved as the first-line treatment for CLL in combination with chemotherapy. Since then, rituximab in combination with chemotherapy has become standard of care for the management of patients with CLL. It has also been approved for the treatment patients with relapsed or refractory disease in combination with targeted agents or chemotherapeutic agents. 



Obinutuzumab is a type II monoclonal antibody that works differently than rituximab for blocking CD20 receptor expressed on the surface of B-cells resulting in greater destruction of CLL cells. It is approved in combination with chemotherapy for the first-line treatment of patients with CLL. Also, it may be used as a single-agent treatment for selected patients who cannot tolerate chemotherapy in both first-line or second-line therapy.




Ofatumumab is a second generation, type I anti-CD20 monoclonal antibody with increased efficacy (compared to rituximab) in some patients who have not responded to rituximab. Similar to rituximab and obinutuzumab, it can be employed (in combination with chemotherapy) for the first-line treatment of patients with CLL, or as a single-agent treatment for the management of relapsed or refractory disease. It can also be used as the maintenance treatment for patients with relapsed or refractory CLL who achieved complete or partial response after at least two prior lines of therapy. 




Alemtuzumab is a monoclonal antibody that targets the CD52 antigen found on the surface of B-cells, T-cells, natural killer cells, eosinophils, dendritic cells, and macrophages. Alemtuzumab may be employed as a single agent or in combination with rituximab for the treatment of relapsed or refractory CLL with or without del(17p)/TP53 mutation. In combination with rituximab, it can be employed for the treatment of del(17p)/TP53 mutation-positive CLL in the first-line setting.

Targeted Therapy for Chronic Lymphocytic Leukemia (CLL)

Targeted drugs are designed to target a specific gene or protein characteristic of the CLL cells. 

Following targeted drugs are used for the treatment of CLL



Ibrutinib is an orally active, irreversible inhibitor of Bruton’s tyrosine kinase (BTK), an enzyme involved in the B-cell receptor (BCR) signaling that supports the B-cell survival and proliferation. Ibrutinib was initially approved for the treatment of patients with relapsed or refractory CLL, but it has now gained approval to be used in first-line settings, especially for patients with del(17p) or TP53 mutation.

Single-agent therapy with Ibrutinib is recommended to be employed for the treatment of patients with significant comorbidity, those who are frail (cannot tolerate chemotherapy), and for patients with age >/=65 years or younger with significant comorbidities. It is also recommended for the treatment of patients with the relapsed or refractory disease. It is now considered a standard treatment for patients with del(17p) or TP53 mutation-positive CLL both as first-line therapy or for the relapsed/refractory disease. Ibrutinib may cause an initial transient increase in absolute lymphocyte count that does not indicate a disease progression and may persist for several weeks. 




Acalabrutinib is a second-generation BTK inhibitor that has been approved for the treatment of patients with relapsed or refractory CLL regardless of age. Of note, acalabrutinib is not helpful in the treatment of ibrutinib-resistant CLL with BTK C481S mutations, one of the common reasons for the development of resistance against ibrutinib treatment. 


Idelalisib is an orally active, p110 delta (δ) isoform-selective inhibitor of phosphoinositide-3 kinase (PI3K), an enzyme involved in B-cell activation, proliferation, and survival. Idelalisib, in combination with rituximab, has been approved by US FDA for the treatment of patients with relapsed or refractory CLL. Idelalsib with  rituximab is also effective for the treatment of patients with adverse prognostic factors, like del(17p) or TP53 mutations, ZAP70, CD38 expression, unmutated IGHV, and elevated beta-2 microglobulin (>4 mg/L). Single-agent therapy with Idelalisib may be helpful for some patients with relapsed/refractory disease. 


Duvelisib is an orally active, selective inhibitor of PI3K3γ and PI3Kδ isoforms that suppress B-cell proliferation and promotes apoptosis in CLL cells. Single-agent therapy with Duvelisib is recommended for the patients with relapsed or refractory CLL.



Venetoclax is an orally active, selective inhibitor of B-cell leukemia/lymphoma-2 (BCL2) protein, a protein found to be involved in the B-cell apoptosis and cancer development. Venetoclax has been approved as a single-agent therapy or in combination with rituximab for the treatment of patients with relapsed or refractory CLL who have received prior treatment with ibrutinib or idelalisib. Tumor lysis syndrome (TLS), a syndrome caused by the mass destruction of leukemia cells that release their constituents in the blood leading to kidney failure, was observed in some patients treated with venetoclax. 

Immune Checkpoint Inhibitors

Immune Checkpoint Inhibitors like pembrolizumab and nivolumab have shown activity in patients with Richter’s transformation refractory to chemotherapy or targeted therapy.

Adoptive T-cell Therapy

Similarly, adoptive T-cell therapy, directed towards CD19-surface protein and/or other proteins expressed on the surface of CLL cells, have demonstrated exciting results in different clinical trials. Additionally, the genetically modified CART cells persist for many years that is advantageous to eradicate the minimum residual disease (MRD) in patients with high-risk features. Considering the potential clinical application of CART therapy for the treatment of leukemia it may soon be incorporated into clinical practice for the treatment of CLL.

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