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Diagnosing Chronic Lymphocytic Leukemia

Medical editor Geir Tjønnfjord MD
Oslo University Hospital


Chronic lymphocytic leukemia has an insidious debut. Suspicion of the disease occurs in patients who have lasting lymphocytosis, possibly combined with anemia, thrombocytopenia, enlarged lymph nodes and/or a B-symptom. The patient often does not have symptoms at the time of diagnosis and the disease is discovered coincidentally by examination for other reasons.

Three out of five patients are asymptomatic when the diagnosis is made. 

The disease is characterized by an elevation of small, mature-appearing lymphocytes in blood, bone marrow, and lymphoid organs.

Previously, it was common to use the expression chronic lymphocytic leukemia in patients who presented with lasting lymphocytosis with mature-appearing lymphocytes. In the majority of cases, this fits with how we use the description also today, however, with the introduction of new diagnostic methods, such as immunophenotyping and karyotyping, it is evident that leukemic forms of non-Hodgkin's lymphoma are an important differential diagnostic group. It is essential to differentiate between leukemia of B-cell and T-cell types.


  • Suspicion of chronic lymphocytic leukemia 


  • Confirm the diagnosis
  • Prognostic assessment
  • Assess whether there is indication for treatment 








Norsk selskap for hematologi. Handlingsprogram for kronisk lymfatisk leukemi [Online] 2005 [hentet 15. april 2007]; tilgjengelig fra: URL:


In chronic lymphatic leukemia there is almost always a presence of clonal proliferation of B-lymphocytes with a characteristic immunophenotype CD5+C19+CD20+CD23+. The physiological parallel to the malignant cells is a small population of CD5+ B-lymphocytes localized in the mantel zone of secondary lymph node follicles. CD5+ B-lymphocytes belong to their own B-cell line. They dominate early in the oncogenesis and are known for secretion of natural auto-antibodies.

Cytogenetic anomalies

IgVH gene

Whether the IgVH gene has undergone somatic hypermutation or not, chronic lymphatic leukemia is separated into two disease groups: mutated and unmutated, which have very different prognoses. In patients with an unmutated IgVH gene, the median survival is 8–9 years, while it appears the survival for patients with a mutated IgVH gene is no different from an age-adapted normal population. The median survival is > 24 years.


A series of cytogenetic anomalies have been described, but none of these are specific for chronic lymphatic leukemia. They are also not primary events in the disease development, but appear later in the disease course. They do not have a diagnostic value like the translocations t(14;18)(q32;q21) and t(11;14)(q13;q32) appearing in follicular lymphoma and mantel cell lymphoma respectfully, however, these cytogenetic anomalies still have a great prognostic value. 


The most common cytogenetic anomalies are del 6q, del 13q, del 11q, del 17p, and trisomi 12, and are evident in 80% of patients using fluorescence in situ hybridization (FISH).

Median survival for the different deletions:

  • del 17p - median survival is 30 months 
  • del 11q - median survival is 68 months

These cytogentic anomalies are associated with poor prognosis and often poor and/or short-lasting effect of chemotherapy.

  • del 13q - median survival has not been reached in published studies, but 60% survive after 192 months

This karyotype is associated with a good prognosis.

Conventional chemotherapy is dependent on functioning signal pathways for apoptosis in the tumor cells to be effective. However, for del 17p in particular, this is not the case. The p53 signal pathway, which is a central signal pathway for apoptosis, is defective.

Expression of CD 38 and ZAP-70 (zeta-associated protein) was introduced as a possible surrogate marker for the unmutated IgVH gene, but none of the markers show full correlation to VH mutation status. They both appear to contribute with independent prognostic information.


The clinical examination should include:


  • Lymph node palpation
  • Liver and spleen palpation
  • Height and weight

Blood tests


ABO typing, hemoglobin, leukocytes with differential counting, thrombocytes, blood smear, LD, albumin, creatinine, Na, K, Ca, phosphate, urate, glucose, CRP.

  • Protein electrophoresis of serum/plasma and quantification of Ig
  • Direct antiglobulin test (DAT). DAT should be repeated in all patients with anemia and before starting treatment.
  • Reticulocytes – determination of reticulocytes should be done in all patients with anemia before starting treatment.
  • Biochemical kidney and liver parameters. Determination of these parameters including urate should be done at the time of diagnosis and treatment start (at minimum).

Flow cytometry of blood or bone marrow

Immunophenotyping of lymphocytes in blood (or bone marrow) should be performed in all patients and at least in all who need treatment/before start of treatment. Additionally, immunophenotyping may be performed in patients with mild lymphocytosis to confirm the diagnosis and in patients with atypical morphology to exclude leukemized forms of other chronic lymphoproliferative diseases.

Bone marrow examination

Examinations of bone marrow are not required to diagnose the leukemia, but are considered necessary before starting treatment. This is partly because the examination contributes to clarifying the cause of cytopenia and partly because the bone marrow examination is necessary to evaluate the response to treatment. The examination may also contribute to diagnostic information in atypical lymphocyte morphology or low CLL score.  



A definite diagnosis requires at a minimum: lymphocytosis, characteristic morphology of blood smear using light microscopy, and characteristic immunophenotype.

Close to 80% of the patients have a lymph node tumor when the diagnosis is made and about half of the patients have splenomegaly. It is very common to find leukemic organ infiltration in almost all organs during autopsy, but this is rarely the cause of clinical symptoms.  

The diagnosis requires evidence of lasting lymphocytosis ( > 5 x 109/l). When the diagnosis is made, the lymphocyte value is most often > 40 x 109/l and sometimes > 100 x 109/l. The leukemic cells resemble normal lymphocytes and are 1.5–2 times larger than erythrocytes. They have very sparse basophilic cytoplasm and most often have a round-oval nucleus with condensed chromatin without a distinct nucleolus.

Diagnostic criteria for chronic lymphocytic leukemia


The diagnosis requires lasting (> 6 months) lymphocytosis > 5 x 109/l. Patients with clonal B-cell lymphocytosis between 3 and 5 x 109/l and morphology consistent with chronic lymphocytic leukemia may develop clinical symptoms. For lymphocytosis < 10 x 109/l, detection of monoclonal lymphocyte population with characteristic immunophenotype is necessary to make the diagnosis. 

Lymphocyte morphology

In typical lymphocytic leukemia, >90% of the cells are small or medium lymphocytes with condensed chromatin (like pine tree bark), diffuse or no nucleolus, and with very sparse cytoplasm (high nuclei/cytoplasm ratio). In 15% of patients, the morphology is atypical due to the high number of prolymphocytes (>10%, but <55 %) or low nucleus/cytoplasma ratio).


CD19, CD20, CD23, CD5, k or l light chains. CD5 expression cannot be detected in 5–10% of cases and membrane-bound Ig cannot be found in an equivalent amount of cases.


CLL Score
Marker CLL (score) Other leukemia/NHL score
mIg Weak/negative (1) Moderate/strong (0)
CD5 Positive (1)        Negative (0)
CD23 Positive (1) Negative (0)
CD79b or CD22 Weak/negative (1) Moderate/strong (0)
FMC7 Negative (1) Positive (0)

Score 4–5 in about 90% of cases with chronic lymphocytic leukemia, score 0–1 in about 90% of cases of the other leukemia and about 75% of cases with leukemized NHL. The remaining have a score of 2.

Bone marrow aspirate

More than 30% lymphocytes in a smear with not too few cells (not obligatory).

The diagnosis is confirmed by evidence of monoclonal population of B-cells with characteristic immunophenotype and morphology in blood.

About 15% of patients have anemia, normocytic and normochromic, at the debut of the disease. In 20%, a positive direct antiglobulin test can be detected (DAT+) at some point during the disease course due to the production of IgG auto-antibodies in non-neoplastic B lymphocytes. Only 8% of patients develop autoimmune hemolytic anemia.

Thrombocytopenia is observed in almost all patients with advanced illness, which is due to reduced thrombopoiesis. Also, immune-mediated thrombocytopenia occurs due to thrombocyte-specific auto-antibodies at any time during the course of the disease.

Hypogammaglobulinemia is detected early in the disease course in at least half of patients and in about 5% of the patients, a monoclonal gammopathy can be detected, usually of the IgM type. The paraprotein has the same specificity as that which is detected on the surface of the leukemic cells.  

Bone marrow is always infiltrated by leukemic cells, but the growth pattern varies.


Staging and some laboratory parameters provide a certain amount of prognostic information, but are not a suitable basis for estimating the prognosis at the time of diagnosis.  

Prognostic Factors

Parameter Median survival (years)

Infiltration of bone marrow:

diffuse  3-5
sporadic  10


< 50 x 109/l  6
> 50 x 109/l  3-4

Doubling time:

> 12 months  10
< 12 months  5

Prolymphocytes in blood:

< 5 % prolymphocytes  6
> 5 % prolymphocytes  3-4

In the last 10 years, the knowledge of the biology of disease has increased significantly, and with the help of this knowledge, the conditions are much better for communicating the patient's prognosis at the time of diagnosis.  

Patients who do not need treatment are routinely checked (frequency is adapted individually).

At follow-up visits, anamnesis is emphasized and the clinical examination should focus on lymphoid organs, and laboratory parameters such as hemoglobulin, leukocytes with differential count, and thrombocytes.

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