Chronic lymphocytic leukemia - Knowledge @ AMBOSS 12/9/21, 12:46 AM

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Chronic lymphocytic leukemia

Last updated: October 29, 2021

Summary

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.

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Definition

Chronic lymphocytic leukemia: low-grade B-cell lymphoma with lymphocytic

leukocytosis

References:[1][2]

Epidemiology

Sex: > (∼ 2:1)

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

References:[3]
Epidemiological data refers to the US, unless otherwise specified.

Etiology

Risk factors

Advanced age

Environmental factors: organic solvents

Family history

References:[2]

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Classification

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

References:[4][5]

Pathophysiology

Acquired mutations in hematopoietic stem cells → increased proliferation of leukemic

B cells with impaired maturation and differentiation in the bone marrow, resulting in:
Suppression of the proliferation of normal blood cells

Immunosuppression
Hypogammaglobulinemia

Granulocytopenia
Thrombocytopenia
Anemia

Infiltration of the lymph nodes, liver, and spleen

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References:[6]

Clinical features

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

Weight loss, fever, night sweats, fatigue (B symptoms)

Painless lymphadenopathy
Hepatomegaly and/or splenomegaly may occur.
Repeated infections
Severe bacterial infections (e.g., necrotic erysipelas)

Mycosis (candidiasis)
Viral infections (herpes zoster)
Symptoms of anemia and thrombocytopenia
Dermatologic symptoms

Leukemia cutis
Chronic pruritus
Chronic urticaria

Lymphadenopathy is a typical finding in lymphoid malignancies such as CLL

and helps to differentiate CLL from CML, a myeloid malignancy!

References:[2][3]

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Diagnostics

Laboratory analysis

CBC
Persistent lymphocytosis with a high percentage of small mature lymphocytes
Findings that indicate suppression of normal myelopoiesis:
Granulocytopenia
Low RBC count (due to autoimmune hemolysis)

Low platelet count

Blood smear: : smudge cells (Gumprecht shadows) – mature lymphocytes that rupture
easily and appear as artifacts on 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 (CD5, 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

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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 disease).

In CLL, the smudge cells on peripheral smear appear to be Crushed Little

Lymphocytes.

References:[3][4][7][8][9][10][11]

Differential diagnoses

Acute lymphoblastic leukemia (ALL)

Autoimmune hemolytic anemia (AIHA)
Mantle cell lymphoma

Hairy cell lymphoma

The differential diagnoses listed here are not exhaustive.

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Treatment

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)
Chemotherapy

If CD 20 positive: rituximab

Targeted therapy with ibrutinib

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

< 65–70 years

FCR: fludarabine, cyclophosphamide, rituximab

Stem cell transplantation

> 65–70 years

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Chlorambucil + monoclonal antibody (e.g., rituximab)

Possibly a single agent: chlorambucil or rituximab

Ibrutinib

Del(17p13) positive
Enrollment in clinical trials is recommended.

No standard approach; options include:

Monoclonal antibody (e.g., alemtuzumab)

References:[8][12][13]

Complications

Immunosuppression with subsequent infections (most common cause of death)

Secondary malignancies

Hyperviscosity syndrome

Autoimmune hemolytic anemia (of both the warm and cold agglutinin type)
Richter transformation or Richter syndrome: transformation into a high-grade NHL
(usually diffuse large B cell lymphoma)

Occurrence: ∼ 5% of cases

Diagnostic indicators:
Rapidly progressive lymphadenopathy → lymph node biopsy required

New onset of B symptoms

↑ LDH

Treatment: similar to symptomatic CLL and advanced stages

References:[14][15]
We list the most important complications. The selection is not exhaustive.

Prognosis

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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.

References:[5]

References

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