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

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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.

Following are certain lymphoproliferative disorders that may look similar to CLL and required to be differentiated from CLL:

  1. 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).

  2. 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.

  3. 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.

  4. 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.

  5. 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.

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RISK FACTORS

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 to certain carcinogens: 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.
  • Age: 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.
  • Gender: CLL is more common in males than females (2:1).
  • Ethnicity: CLL is more common in Caucasians than Asians.

Signs and 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 Diagnosis

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:

  1. 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.

  2. Bone Marrow Aspiration/Biopsy: 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.

    Immunohistochemistry: 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.

  3. 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: 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: 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.

Apart from establishing the diagnosis of Chronic Lymphocytic Leukemia, investigational tests play an important role in assessing the response to treatment. Following are various terms used to indicate the different responses to treatment:

  • 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 STAGERISK GROUPDESCRIPTION
0LowLymphocytosis (>/=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
IIntermediateLymphocytosis with enlarged lymph node(s)
IIIntermediateLymphocytosis with splenomegaly and/or hepatomegaly
IIIHighLymphocytosis with hemoglobin <11.0 g/dL or hematocrit <33%
IVHighLymphocytosis with platelets <100,000/microliter
BINET STAGEDESCRIPTION
AHemoglobin >/=10 g/dL, Platelets >/=100,000/mm^3 and <3 enlarged nodal areas
BHemoglobin >/=10 g/dL, Platelets >/=100,000/mm^3 and >/=3 enlarged nodal areas
CHemoglobin <10 g/dL and/or Platelets <100,000/mm^3

PROGNOSTIC FACTORS

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

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.

Functional/Risk GroupTreatment
CLL without del(17p) or TP53 mutationChemoimmunotherapy (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 mutationTargeted therapy is considered the preferred treatment for both elderly and young patients with or without any significant comorbidities.

Chronic Lymphocytic Leukemia Treatment Options

  1. Chemotherapy: 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 due to its effect on normal body cells apart from cancerous cells.

  2. Corticosteroids: 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.

  3. 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.

  4. Targeted Therapy: Targeted drugs are designed to target a specific gene or protein characteristic of the CLL cells. Examples of targeted drugs for CLL include Ibrutinib that targets Bruton’s tyrosine kinase (Btk) and Idelalisib that targets phosphoinositide-3 kinase (PI3K) delta in leukemia cells. These drugs are generally used as the first-line treatment for CLL with the presence of certain adverse prognostic factor(s).

  5. Stem Cell Transplant (SCT): SCT can be considered for the treatment of CLL in some patients with poor prognostic factors who are the good candidate for the same (younger patients in good health). Allogenic SCT is mainly used for the treatment of CLL:

    Allogeneic SCT: In this technique, healthy stem cells to be administered to the patient after high dose chemotherapy are obtained from another person known as the donor. It is very important that donor is a close blood relative (preferably a sibling) so that donor’s HLA type closely match with the patient’s.

    The allogenic SCT helps in removing any remaining leukemia cells (due to graft versus leukemia effect). However, allogeneic SCT is riskier due to the graft-versus-host disease in which the new immune cells originated from donor’s cells attack the host cells.

  6. Radiation Therapy: Radiation therapy (or radiotherapy) uses high-energy x-rays or other high-energy radiations which are directed to the affected area to kill cancerous cells. Radiotherapy is not generally used for the treatment of CLL. However, an external beam radiation therapy can sometimes be employed (along with main treatment): for enlarged spleen pressing on other organs; with high dose chemotherapy before stem cell transplant (SCT); and to reduce bone pain in bones invaded by leukemia cells.

  7. Supportive Care: Supportive care is an integral part of CLL treatment. This can be used to relieve certain symptoms arising from the disease itself or certain problems associated with CLL treatment.

    Examples of supportive care in CLL include immunoglobulins, antibiotics, and antiviral drugs (for treating infections that usually occur in patients with CLL or those caused due to side-effect of certain drugs used for the treatment of CLL); vaccine (for prophylaxis against certain infections); transfusion with blood products, etc.

It is very important to assess the benefits of each treatment option versus the possible risks and side effects before making a treatment decision. Sometimes patient’s choice and health condition are also important to make a treatment choice.

Following are the goals of treating Chronic lymphocytic leukemia:

  • Prolongation of life.
  • Reduction of symptoms.
  • Improvement in quality of life.
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