Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is a hematologic malignancy characterized by excess production of monoclonal B lymphocytes in the peripheral blood. When the involvement is primarily nodal, the condition is called small lymphocytic lymphoma (SLL). The disease usually presents in older adults, with a median age of 70 years. Clinical presentation is often asymptomatic and diagnosis is made when abnormal lymphocytosis is seen on laboratory testing. Cytopenias can also be seen. The B cells are functionally incompetent lymphocytes and thus may result in recurrent infections. Treatment can vary from watchful waiting for early stages to chemotherapy for later stages. Median survival is around 10 years.

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Chronic lymphocytic leukemia (CLL) is a lymphoproliferative neoplasm characterized by accumulation of functionally impaired lymphocytes, often monoclonal in origin.


  • CLL is identical to small lymphocytic lymphoma (SLL), both of which are considered manifestations of B-cell neoplasm.
  • The term CLL is used when the disease manifests primarily in the blood.
  • The term SLL is used when involvement is primarily nodal. 


  • Most common type of leukemia in adults
  • Incidence: approximately 4–6 cases per 100,000 population/year in the United States
  • 1.5 times more prevalent in men than in women
  • Incidence increases with age, with a median age at presentation of 70 years.


  • Risk factors include:
    • Family history
    • Age
  • No clear link with environmental or occupational factors



Hematopoiesis starts with a hematopoietic stem cell, which is prompted to divide and differentiate with appropriate chemical stimuli (hemopoietic growth factors).

  • Myeloid stem cells: eventually differentiate into platelets, erythrocytes, granulocytes (neutrophils, basophils, eosinophils), and monocytes
  • Lymphoid stem cells: give rise to lymphocytes
    • IL-6: B-cell stimulatory factor
    • IL-2: stimulates T-cell proliferation and differentiation
Bone marrow hematopoiesis

Bone marrow hematopoiesis:
Proliferation and differentiation of the formed elements of blood:
In CML, there is sustained proliferation of cells in the granulocytic line (myeloblasts → neutrophils, basophils, eosinophils). Both mature and maturing cells are seen; thus, there are cells that are only partially effective.
CFU-GEMM: colony-forming unit–granulocyte, erythrocyte, monocyte, megakaryocyte
CFU-GM: colony-forming unit—granulocyte macrophage
GM-CSF: granulocyte macrophage colony-stimulating factor
M-CSF: macrophage colony-stimulating factor
G-CSF: granulocyte colony-stimulating factor
NK: natural killer
TPO: thrombopoietin

Image by Lecturio. License: CC BY-NC-SA 4.0


  • Monoclonal B-cell lymphocytosis (MBL):
    • Defined as < 5000 B lymphocytes/μL in the peripheral blood 
    • This asymptomatic proliferation of monoclonal B-cells precedes CLL/SLL.
    • Also seen in otherwise healthy individuals, notably increased in those > 60 years of age
    • Without lymphadenopathy, organomegaly, cytopenias, or extramedullary involvement
    • Unknown cause but is believed to develop because of different factors, including bone marrow microenvironment and genetic and epigenetic modifications
  • MBL to CLL/SLL:
    • B lymphocytes: ≥ 5000/μL 
    • Further alterations in the genetic makeup likely contribute to the evolution to CLL/SLL.
    • Initially asymptomatic
    • As B-cell development arrests between pre-B cells and mature B cells in the bone marrow:
      • Cells become immunologically dysfunctional. 
      • About 1% per year progress to CLL.
    • Manifestations seen:
      • Lymphadenopathy
      • Hepatosplenomegaly
      • Other cell line cytopenias (erythrocytes and platelets)
      • Hypogammaglobulinemia and increased risk of infections
  • CLL/SLL can transform to more aggressive and more resistant forms (i.e., evolves histologically to diffuse large B-cell lymphoma through Richter transformation).

Clinical Presentation


  • 20%–50% are asymptomatic at presentation.
  •  Insidious onset of “B” symptoms:
    • Weight loss
    • Fatigue
    • Fever and night sweats without evidence of infection
  • Recurrent opportunistic infections

Physical examination

  • Painless lymphadenopathy in 50%–90% of patients (most common finding):
    • Can be generalized or localized
    • Size is variable.
    • Most common locations:
      • Cervical
      • Supraclavicular
      • Axillary
    • Characteristics:
      • Firm
      • Rounded
      • Discrete
      • Nontender
      • Mobile on palpation
  • Splenomegaly: palpably enlarged in 25%–55% of cases
  • Hepatomegaly: palpably enlarged in 15%–25% of cases
  • Skin infiltration: “leukemia cutis” 
    • Mostly involves the face (lesions can be macules, papules, ulcers)
    • Seen in < 5% of cases
    • Poor prognosis if with Richter transformation
Appearance of a patient with a rare chronic lymphocytic leukemia

Rare CLL infiltration of the ears, eyebrows, and nose (A) and the toes (B). Bilateral nonpitting edema on the backs of the hands (C).

Image: “Cutaneous manifestations in a patient with chronic lymphocytic leukemia involving the head, neck and distal extremities” by Lu C, Li L, Qiao Q, Liu G, Fang L. License: CC BY 3.0



  • CBC:
    • Lymphocytosis: lymphocytes ≥ 5000/μL and may be as high as 100,000 (≥ 3 months)
    • Anemia 
    • Thrombocytopenia
    • Neutropenia
  • Peripheral blood smear:
    • Lymphocytosis
    • Smudge cells (smeared-out lymphocytes) present
    • Small, monomorphic lymphocytes with “cracked”/“cracked earth” chromatin
  •  Flow cytometry (immunophenotypic analysis tests):
    • Antibodies specific to proteins on the surface of B cells (such as CD5, CD19, CD20, and CD23)
    • Kappa and lambda immunoglobulin light chains
  • Immunoglobulins: 
    • Hypogammaglobulinemia seen in 25% of patients
    • Usually with 3 low immunoglobulin classes (IgM, IgG, IgA)
  • Other laboratory findings: 
    • ↑ LDH
    • ↑ β₂-microglobulin
    • ↑ AST, ALT
    • ↑ Uric acid
  • Bone marrow aspiration and biopsy:
    • Not required for diagnosis of CLL
    • Normal to increased cellularity
    • Lymphocytes > 30% of all nucleated cells 
  • Lymph node biopsy:
    • Performed if with lymph node enlargement
    • Involved node is diffusely effaced. 
    • Small lymphocytes with irregular nuclei and condensed chromatin
    • Pseudofollicles or proliferation centers (pool of predominantly paraimmunoblasts and prolymphocytes): pathognomonic of CLL/SLL
  • FISH analysis: detects genetic abnormalities/mutations associated with CLL
Blood smear from an adult with marked lymphocytosis

Blood smear from an adult man with marked lymphocytosis:
The predominant lymphocytes have very sparse pale cytoplasm, round to slightly oval nuclei, and no evident nucleoli, and 3 damaged “smudge cells” are present, characteristic of the majority of cases of CLL.

Image: “B-cell chronic lymphocytic leukemia (B-CLL)” by The Armed Forces Institute of Pathology (AFIP). License: Public Domain


  • Abdominal ultrasonography: hepatosplenomegaly
  • CT scan: if enlarged abdominal or pelvic nodes are suspected based on evidence of complications, such as jaundice or ureteral obstruction


Binet staging system

Based on the involvement of 5 possible lymphoid-bearing areas (lymph node enlargement is ≥ 1 cm): 

  • Cervical lymph nodes
  • Axillary lymph nodes
  • Inguinofemoral lymph nodes
  • Spleen
  • Liver 
Table: Binet staging system
A (low risk)≤ 2 lymphoid areas enlargedSame as age-matched controls
B (intermediate risk)≥ 3 lymphoid areas enlarged84 months
C (high risk)Presence of anemia (Hb < 10 g/dL) or thrombocytopenia (platelets < 100,000/µL)24 months

Rai staging system

Classifying 3 different stages, based on:

  • Physical examination findings
  • CBC
Table: Rai staging system
Low0Lymphocytosis in blood or bone marrow> 150 months
IntermediateILymphocytosis + enlarged lymph nodes101 months
IILymphocytosis + enlarged liver or spleen with or without lymphadenopathy71 months
HighIIILymphocytosis + anemia (hemoglobin < 11 g/dL) with or without enlarged liver, spleen, or lymph nodes19 months
IVLymphocytosis + thrombocytopenia (platelet count < 100,000/µL) with or without anemia or enlarged liver, spleen, or lymph nodes

Other variables

  • Other factors considered that affect clinical outcomes:
    • Lymphocyte doubling time (LDT) (< 12 months = aggressive disease)
    • β₂-microglobulin levels (higher level = poorer prognosis)
    • Genetic abnormalities such as:
      • del(17p) mutations (worse outcome with chemoimmunotherapy)
      • TP53 mutations (worse outcome with chemoimmunotherapy)
      • Unmutated immunoglobulin heavy chain variable (IGHV) region (shorter survival)
  • The del(17p) mutation, TP53 mutation, and IGHV mutation status affect choice of treatment (i.e., positive response to targeted therapy).

Management and Prognosis

Management principles

  • Keep vaccinations up to date.
  • Not all patients with CLL require treatment, as staging has shown that some individuals have survival similar to that of the general population.
  • Follow patients for the most common disease-related complications:
    • Infection
    • Anemia
    • Thrombocytopenia
    • Tumor lysis syndrome


  • Recommended for patients with SLL with single nodal site and early-stage asymptomatic CLL:
    • Binet stage A or B
    • Rai stage < III
  • Clinical examination and CBC every 3 months for 1 year:
    • Decide whether the patient has aggressive disease based on findings.
    • Those with clinically stable disease can have longer intervals between examinations.
  • Some patients would require treatment within a few years, but others can remain without symptoms and not require treatment for many years.


  • Recommended for patients with symptomatic or active disease:
    • Advanced stage (Binet stage C, Rai stage III or IV)
    • Progressive lymphocytosis (LDT < 6 months)
    • Progressive marrow failure (i.e., worsening anemia, thrombocytopenia)
    • Massive or enlarging splenomegaly
    • Enlarging or symptomatic lymphadenopathy (e.g., compressive laryngeal symptoms)
    • “B” symptoms:
      • Unintentional weight loss > 10% over 6 months
      • Symptoms (e.g., fatigue) that impair work or activities of daily living
      • Prolonged fever or night sweats without evidence of infection
  • Treatment options: 
    • No standard 1st-line treatment regimen 
    • Different factors are considered in the choice of therapies (i.e., patient performance status, associated mutations, goals of care).
    • With unmutated IGHV status, genetic mutation del(17p) or TP53, targeted therapies achieve better responses: 
      • Tyrosine kinase inhibitors (ibrutinib, acalabrutinib)
      • Venetoclax
      • Monoclonal antibodies (rituximab, obinutuzumab) can be combined with above.
    • With mutated IGHV status, targeted therapy is an option, but chemoimmunotherapy is also considered for fit patients:
      • Fludarabine, cyclophosphamide, rituximab
      • Chlorambucil-based regimen
      • Bendamustine and rituximab
    • If relapsed CLL, consider allogeneic hematopoietic stem cell transplantation (for fit patients)

Richter transformation

  • Richter transformation (RT) is the development of diffuse large B-cell lymphoma in patients with CLL/SLL.
  • Seen in 2%–9% of patients with CLL
  • Median time to transformation: 23 months after diagnosis
  • Manifested by:
    • Significant increase in lymphadenopathy at 1 or more sites
    • Splenomegaly
    • Increase in constitutional symptoms
  • Lab findings:
    • Elevated LDH in > 50% of patients with RT
    • Anemia, with Hb < 11 g/dL
    • Thrombocytopenia, with platelet count < 100,000 
  • Rapidly progressive, with survival approximately 5–8 months after transformation
  • Diagnosis is made by biopsy of an enlarging lymph node or other worrisome sites.
  • Treatment: regimen of chemotherapy and rituximab (similar to that for aggressive lymphoma).


  • Median survival: approximately 10 years
  • In < 30% of patients, a benign clinical course of up to 20 years is seen, with cause of death that is not related to CLL.
  • Those with aggressive disease go through a rapid decline and die from complications related to CLL.
  • Patients who are on treatment may have partial to complete response, but eventually relapse occurs.

Differential Diagnosis

  • Hairy cell leukemia: rare, chronic B-cell leukemia characterized by the accumulation of small mature B lymphocytes that have hair-like projections visible on microscopy. The abnormal cells accumulate in the peripheral blood, bone marrow (causing fibrosis), and spleen. The condition is also seen in the elderly. In about 20% of cases, lymphocytosis with cytopenias are seen. While CLL and hairy cell leukemia share features of splenomegaly and cytopenias, lymph node involvement is not common in hairy cell leukemia.
  • Follicular lymphoma (FL), or nodular lymphoma: a common subtype of non-Hodgkin lymphoma. The condition presents with painless peripheral lymphadenopathy. Both CLL and FL have small tumor cells, but FL has a notable nodular growth pattern. CLL at times has prominent proliferation centers that can look similar to FL. CD5 expressed in CLL is not a feature of FL.
  • Mantle cell lymphoma, or intermediate lymphocytic lymphoma: type of mature-B-cell neoplasm. The malignant cells of mantle cell lymphoma at times have similarities to CLL, having nuclear irregularities. There is also expression of CD5 and CD20. In contrast to CLL, though, mantle cell lymphoma stains positive for cyclin D1 (which is negative in CLL).
  • Transient lymphocytosis: infections such as infectious mononucleosis or toxoplasmosis can cause significant lymphocytosis. In infections, though, the elevation of lymphocytes is temporary, often no more than a few weeks. The lymphocytes are not clonal and do not infiltrate the bone marrow.


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  2. Freeman, A.S., et al. (2020). Classification of the hematopoietic neoplasms. UpToDate. Retrieved April 25, 2021, from
  3. Mukkamalla, S., Taneja, A., Malipeddi D. (2021). Chronic lymphocytic leukemia. StatPearls.
  4. Rai, K.R., Stilgenbauer, S. (2021). Overview of the treatment of chronic lymphocytic leukemia. UpToDate. Retrieved April 26, 2021, from
  5. Rai, K.R., Stilgenbuaer, S. (2021). Staging and prognosis of chronic lymphocytic leukemia. UpToDate. Retrieved June 3, 2021, from
  6. Rai, K., Stilgenbauer, S., Aster, J. (2021). Clinical features and diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma. UpToDate. Retrieved April 26, 2021, from
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