• Clinical science

Chronic lymphocytic leukemia (Small lymphocytic lymphoma)


Chronic lymphocytic leukemia (CLL) belongs to the group of low-grade non-Hodgkin lymphomas (NHL) and is a B-cell lymphoma that presents with lymphocytic leukocytosis. CLL is the most common form of leukemia in adults and is typically considered a disease of the elderly. Clinical features include painless lymphadenopathy, fatigue, chronic pruritus, and an increased susceptibility to infections. Important diagnostic markers are smudge cells (Gumprecht shadows) in a blood smear, a high percentage of small, mature lymphocytes in the bone marrow, and detection of B-CLL antigens in flow cytometry. The Rai staging system is primarily based on lymphocyte count, sites of lymphatic tissue involvement, anemia, and platelet count. The medical treatment of CLL consists of chemotherapy and monoclonal antibodies, but does not necessarily increase survival time. Allogeneic stem cell transplantation, which is the only curative treatment option, is often not viable because of the advanced age of most patients.





  • Sex: > (∼ 2:1)
  • Age: The median age at the time of diagnosis is 70–72 years. (The incidence of CLL increases with age.)
  • Most common type of leukemia in adults


Epidemiological data refers to the US, unless otherwise specified.


Risk factors

  • Advanced age
  • Environmental factors: organic solvents
  • Genetics: positive family history



Rai staging system

Stage Finding Median survival
0 Low risk Isolated lymphocytosis > 150 months
I Intermediate risk + Lymphadenopathy 101 months
II + Hepatomegaly and/or splenomegaly 71 months
III High risk + Anemia (Hb < 11 g/dL) 19 months
IV + Thrombocytopenia (< 100,000/μL) 19 months



Acquired mutations in hematopoietic stem cells → increased proliferation of leukemic B cells with impaired maturation and differentiation in the bone marrow, resulting in:


Clinical features

About half of cases of CLL remain asymptomatic for a long period, resulting in late or incidental diagnosis.

Lymphadenopathy is a typical finding in lymphomas such as CLL and helps to differentiate CLL from CML!



Laboratory analysis

  • CBC
  • Blood smear: smudge cells (Gumprecht shadows) – mature lymphocytes that rupture easily and appear as artifacts in a blood smear
    • False positive results possible: Smudge cells may also appear if the quality or handling of the blood sample was inadequate → Positive results are not sufficient to confirm the diagnosis of CLL.
  • Flow cytometry: detection of B-CLL immunophenotype (CD19, CD20, CD23), light chain restriction (kappa or lambda)
  • Serum antibody electrophoresis: antibody deficiency (decreased γ globulin fraction)

Bone marrow aspiration

Bone marrow aspiration is not necessary to confirm the diagnosis but may be helpful in investigating cytopenia of unknown origin, for instance, during later stages of the disease.

  • Bone marrow cytology and histology
    • High percentage (> 30%) of small, mature lymphocytes
    • Decreased number of myeloid progenitor cells

Additional diagnostic procedures

  • Genetics: FISH analysis to detect mutations associated with CLL (e.g., del(17p13))
  • Ultrasound: splenomegaly and/or hepatomegaly
  • Liver histology: periportal lymphocyte infiltration and centrilobular necrosis
  • Lymph node biopsy: A biopsy may be performed if the peripheral blood smear does not yield diagnostic clues, to confirm the diagnosis, or to differentiate CLL from other diseases (e.g., Hodgkin's disease).



Principles of treatment

The treatment regimen is primarily based on the risk of disease progression according to the Rai staging system, whether the patient is symptomatic or has comorbidities, and the patient's age and level of fitness.

  • Asymptomatic CLL (Rai stage 0, slow disease progression): observe and monitor disease progression
  • Symptomatic CLL or advanced stage (Rai stage > 0, accelerated disease progression)
  • Refractory CLL or early recurrence in fit, young patients: : allogeneic stem cell transplantation

CLL is a low-grade malignancy, noted for its slow rate of cell division and disease progression; treatment is often not necessary or is unlikely to improve survival time.

Medical therapy is palliative and the only curative treatment option is stem cell transplantation!

Treatment regimens




We list the most important complications. The selection is not exhaustive.


Prognostic factors

  • Advanced age is associated with a poor overall survival rate
  • Genetic abnormalities: e.g., del(17p13) is associated with a poor overall survival rate because of the high risk of disease progression and poor response to chemotherapy.
  • β-2 microglobulin levels: correlate with the severity of the disease
  • Blood lymphocyte doubling time: Rapid doubling is associated with a high risk of disease progression.