Chronic lymphocytic leukaemia (CLL) is a type of blood cancer that occurs due to monoclonal proliferation of B-lymphocytes.

CLL is the most common form of leukemia found in adults in Western countries. It occurs most frequently in older adults and is exceedingly rare in children. It accounted for 1% of all new cancer cases in the UK annually. The causes of CLL are largely unknown and it is not associated with any environmental or external factors. It usually develops very slowly and most patients do not have any symptoms in the early stages of the disease.

The exact cause of most cases of CLL is not known.

The main aetiological factors are:

• Genetic
  • In CLL, the most common genetic change is the deletion in chromosome 13, but other chromosomes such as 11 and 17 can also be affected.
• Family history
  • There is an inherited genetic susceptibility for CLL, with a 6- to 9-fold increased risk for first degree relatives of CLL patients.
• Immunity
  • People with low immunity due to HIV or AIDS are three times more likely than the general population to develop leukaemia.

CLL is characterized by the clonal expansion of CD5+, CD23+ B cells and coupled with low levels of surface immunoglobulins. This oncogenic transformation of monoclonal B cells leads to the accumulation of lymphocytes in the bone marrow and then spreads to the lymph nodes and other lymphoid tissues.

Main pathophysiology of CLL are:

• Deletion of chromosomes
  • CLL cells commonly harbour deletion at 13q, which occurs in more than 50% of patients. Other abnormal karyotypes observed in CLL are deletions at 11q and 17p chromosomes. In approximately 1 in 10 of untreated CLL patients, deletion of 17p disrupts the TP53 tumor suppressor gene and it has been associated with rapid progression, short remission, and decreased overall survival.
• Hypogammaglobulinaemia and haematopoiesis
  • As CLL progresses, abnormal differentiation of blood cells results in anaemia, neutropenia, thrombocytopenia, and decreased immunoglobulin production. Patients have increased susceptibility to autoimmune hemolytic anaemias and autoimmune thrombocytopenia.
• Transformation of CLL to aggressive forms
  • CLL can evolve into B-cell pro-lymphocytic leukaemia and transform to a higher grade non-Hodgkin lymphoma. About 2 to 10% of CLL cases develop into diffuse large B-cell lymphoma (called Richter's transformation).

CLL has variable presentations and more than 50% cases are often diagnosed coincidentally following routine blood tests. Early in the course of the disease, CLL often has little effect on a person’s well-being. Some people with CLL may not have any symptoms. It is important to know that not everyone will experience the same symptoms.

Patients may present with symmetrically enlarged lymph nodes in the neck, armpits or groin which is seen in more than 80% of patients at the time of diagnosis. In addition to localized or generalized lymphadenopathy, it can also manifest as hepatomegaly and/or splenomegaly, which results in abdominal discomfort.

Due to anemia tiredness can be a presenting symptom, sometimes increasing to extreme fatigue. Recurrent infections may occur as a result of low immunoglobulin levels and decreased neutrophil counts. Bleeding or bruising may also occur due to thrombocytopenia.

The onset of the classic “B symptoms” is a sign that the CLL may be active. The symptoms include:

• Frequent, severe night sweats
• Unexplained weight loss >10% of body weight in the previous 6 months
• High fever in the absence of any infections (>38°C)

The diagnosis of CLL is usually evident from the results of blood cell counts and an examination of blood cells.

British Society for Haematolgy (BSH) advises to do a full blood count, reticulocyte count, direct antiglobulin test (DAT), immunophenotype, routine biochemistry and serum immunoglobulins in asymptomatic stage A patients.

FBC is one of the key tests and is usually the first step. A person with CLL will have absolute lymphocytosis, with more than 5000 B-lymphocytes/µL.

Microscopic examination of the peripheral blood smear is indicated to confirm lymphocytosis. This abnormal lymphocytes are small but slightly larger than normal lymphocytes and show scant cytoplasm and round to slightly irregular nuclei containing clumped chromatin. A characteristic morphologic feature is the presence of smudge cells which are artefacts from lymphocytes damaged during the slide preparation because of the fragile nature of these cells.

A FBC and peripheral blood smear alone will not be enough to confirm a diagnosis and more specialist blood tests including immunophenotyping will also be needed. Immunophenotyping of lymphocytes is the most valuable test for the confirmation of CLL. This test is especially important if the number of lymphocytes in the blood is only slightly elevated. It shows the characteristic clonal B lymphocytes expressing CD5 and CD23 antigens.

Cytogenetic testing using fluorescent in situ hybridisation (FISH) is not usually performed, but trisomy 12 or 14q+ or translocation 11:14 are the most usual findings.

BSH recommends to detect deletion of TP53 gene before treatment and it should be performed on all patients prior to each line of therapy. This is a tumour suppressor gene and its deletion is associated with adverse prognostic features predicting poorer treatment responses and survival in CLL.

Additional investigations which could be done include:

• Bone marrow aspiration and biopsy
  • According to BSH, bone marrow examination is not essential for the diagnosis, but should be performed prior to therapy and to define complete response after treatment.
• Direct antiglobulin test (coombs test)
  • It should be done in all anaemic patients and before commencing therapy to identify autoimmune-related haemolytic anaemias.
• Imaging
  • CT scan of the chest, abdomen or pelvis may show obstructive uropathy or airway obstruction from lymph node compression on organs or internal structures.

Haematologic disorders that may resemble CLL in their clinical presentation, behavior, and microscopic appearance include mantle cell lymphoma, marginal zone lymphoma, B cell pro-lymphocytic leukemia, and lymphoplasmacytic lymphoma.

• Mantle cell lymphoma
  • It is a type of non-Hodgkin's lymphoma which is very similar to CLL, but more aggressive. Mantle cell lymphoma expresses CD5 but not CD23 antigen, which is expressed in CLL.

• Marginal zone lymphoma
  • It has a similar presentation and immunophenotype as CLL, but typically has a bright surface immunoglobulin and CD20, and bone marrow examination often reveals lymphocytes with notched nuclei.

• B-cell pro-lymphocytic leukemia
  • It is a very rare and typically aggressive malignancy and has similar clinical features as CLL. Circulating cells are greater than 55% pro-lymphocytes that are often CD5 negative.

• Lymphoplasmacytic lymphoma
  • CLL and lymphoplasmacytic lymphoma are lymphoproliferative disorders with similar presentation. However, the later can also manifest as hyperviscosity syndrome associated with macroglobulinemia, where the clinical picture varies.

It is generally accepted that CLL is not yet curable, but it is very treatable and it is usually possible to control the disease.

Staging for CLL helps the clinician to both assess how the disease is expected to progress over time and also to develop a treatment plan. The Binet staging system is commonly used in the UK for CLL staging and it has 3 stages.

Stage A: Hb at least 10 g/dL, platelets at least 100 x 109/L, and fewer than three lymph node areas involved.
Stage B: Hb and platelet levels as in stage A and three or more lymph node areas involved.
Stage C: Hb <10 g/dL, platelets <100 x 109/L, or both.

In each stage, a group of lymph nodes means lymph nodes in one area of the body, for example, in the neck, underarms or groin. Each area counts as one group even if the nodes on both sides of the body are swollen.

In the earlier stage of the CLL, many people have no symptoms. The standard treatment of patients with the early disease is a watch and wait strategy. In this case, blood cell counts and clinical examinations should be performed regularly to determine whether the disease is stable or beginning to progress.

Chemotherapy should only be given to patients with active, symptomatic disease. The main indication of treatment are:

• Evidence of progressive marrow failure
• Massive or progressive or symptomatic splenomegaly
• Massive or progressive or symptomatic lymphadenopathy
• Progressive lymphocytosis with an increase of more than 50% over a 2‐month period
• Lymphocyte doubling time of less than 6 months
• Autoimmune anaemia or thrombocytopenia not responding to prednisolone
• One or more of the following CLL‐related symptoms or signs such as
  • Night sweats
  • High fever
  • Extreme fatigue
  • Unintentional weight loss >10%

In CLL, molecular assessment prior to treatment is a very essential step. However, measurement of prognostic biomarkers is not currently recommended for patients with early CLL in whom there is no clinical indication for treatment. If required, tests for TP53 disruption (either deletion of chromosome 17p or mutation in the TP53 gene) should be performed on all patients.

The National Institute for Health and Care Excellence (NICE) recommends Fludarabine, cyclophosphamide and rituximab (FCR) as the initial therapy for previously untreated patients without TP53 disruption.


Chemotherapy with bendamustine is advised by NICE as an option for the first-line treatment of CLL (Binet stage B or C) in patients for whom FCR chemotherapy is not appropriate.

For adults with FCR or bendamustine-based therapy unsuitable, NICE recommends obinutuzumab in combination with chlorambucil as an option.

Patients with TP53 deletion/mutation have a poor prognosis even after first line FCR combined chemotherapy. In such cases, chemo agents like ibrutinib can be used.

Alemtuzumab is a monoclonal antibody which has also been shown to be effective in TP53 mutations.

Complications from CLL are also a main cause of death in such patients which is independent of age and comorbidities at the time of diagnosis.
Auto‐immune cytopenia is the dominant clinical feature among the complication in CLL, which should be treated with corticosteroids.

Steroids can also be used to improve bone marrow function prior to chemotherapy where there is significant bone marrow infiltration.

Some patients may experience a relapse and may be refractory to initial treatment.

Relapsed CLL is the term for disease that responded to therapy but, after 6 or more months, stopped responding. Refractory disease is the term for CLL that does not result in a remission (but may be stable) or disease that gets worse within 6 months of the last treatment. Many patients with relapsed but asymptomatic CLL can be monitored with no therapy for a period of time.

Allogeneic stem‐cell transplantation provides the best opportunity of achieving long‐term disease‐free survival for patients with high‐risk CLL, including those with TP53 abnormalities.

CLL can cause a number of complications. The major complications are:

• Recurrent infections
  • People with CLL are more vulnerable to infections due to hypogammaglobulinaemia, seem to have a higher risk of bacterial infections. The other factors involved are defective complement activity, normal T-lymphocyte dysfunction, and low neutrophils.
• Anemia
  • Some people with CLL develop autoimmune complications which primarily cause cytopenia and worsen the existing symptoms. The most common autoimmune complication is a warm antibody type autoimmune hemolytic anemia which is secondary to CLL.
• Transformation into other type of lymphoma
  • For a small number of people, CLL can sometimes transform into a different type of cancer. This is referred to as Richter transformation. It is a serious complication of CLL and is often fatal. It is characterised by the sudden transformation of the CLL into a significantly more aggressive form of large cell lymphoma. The most common symptoms of Richter’s syndrome arise from a sudden and dramatic increase in the size of lymph nodes characterised by usually painless areas of swelling in the neck, axilla, abdomen (spleen) or groin. Patients also often experience a dramatic unexplained weight loss, fevers and night sweats (often collectively referred to as B-symptoms).
• Hyperviscosity syndrome
  • Extremely high WBC counts may produce a hyperviscosity syndrome with altered central nervous system function and/or respiratory insufficiency. Symptoms include headache, dizziness, vertigo, hearing loss, visual disturbances and nystagmus.
• Malignancies
  • Patients with CLL have a higher risk of developing a secondary malignancies than the general population. The malignancies that are seen most frequently are melanoma, soft tissue sarcoma, colorectal cancer, lung cancer, squamous cell skin cancer and basal cell carcinoma.

The prognosis of patients with CLL varies widely at diagnosis. CLL is generally associated with long overall survival. Generally, about 7 out of 10 people will survive CLL for 5 years or more after being diagnosed.

Factors affecting the prognosis of patients with CLL:

• Patient‐related
  • Age : CLL occurs primarily in middle-aged and elderly adults, with worse prognosis in successive decades of life. In the UK, on average each year around 40% new cases were in people aged 75 and over. About 10% of CLL patients are reported to be younger than 55 years.
  • Gender : Men are about twice as likely as women to develop CLL. During the initial course of the disease the condition is relatively benign, but followed by a terminal progressive and resistant phase lasting a year or two. In the late phase there is considerable morbidity from the disease itself and from the complications of chemotherapy.
• Disease‐related
  • Cytogenetic abnormalities : Patients with a detectable deletion (17p) and/or TP53 mutations remain associated with the most unfavourable prognostic features, predicting poorer treatment responses and survival in CLL. Trisomy 12 and deletion (17p) are also suggesting a worse prognosis in CLL.
  • Lymphocyte doubling time : It is defined as the length of time it takes the absolute lymphocyte count to double from diagnosis, has also been found to have prognostic value in patients with CLL. Those patients whose lymphocyte counts doubled in less than 12 months had a significantly shorter median survival, whereas those with a longer lymphocyte doubling time experienced longer overall survival.
  • Disease stage : There is a relationship between the stage of the CLL and the prognosis. In general, patients diagnosed at an earlier stage have better long-term survival. Importantly, however, there is a wide range of outcomes even for patients who have the same stage, and the stage alone cannot predict the prognosis with certainty for each person. The Rai staging system divide CLL into 5 stages.

Rai stage grouping: