Chronic lymphocytic leukemia (CLL) is a type of B-cell malignancy that manifests with lymphocytic leukocytosis. CLL is the most common type of leukemia in adults and is typically diagnosed in older individuals (≥ 65 years of age). Clinical features include painless lymphadenopathy, fatigue, chronic pruritus, and increased susceptibility to infections. However, most cases are asymptomatic and diagnosed based on incidental laboratory findings. Diagnosis requires persistent monoclonal B-cell lymphocytosis (≥ 5000 cells/mm3 for ≥ 3 months) with immunophenotypic markers consistent with CLL on flow cytometry. Peripheral blood smear typically shows a high percentage of small mature lymphocytes and smudge cells (Gumprecht shadows). Several molecular markers are used to predict prognosis and guide treatment, the most important being the negative prognostic markers del(17p) and TP53 mutation. Advances in targeted therapy have improved patient outcomes in CLL and small molecule inhibitors (e.g., ibrutinib, venetoclax) are now first-line treatment for most patients. Chemoimmunotherapy may be an effective alternative for some patients. Patients with low-risk disease (Rai stage 0) should be managed expectantly. Allogeneic stem cell transplantation is a curative treatment option but is often not possible because of the older age and multiple comorbidities of most patients with CLL.
- Chronic lymphocytic leukemia: a type of proliferative B-cell malignancy that manifests with lymphocytic leukocytosis 
- Small lymphocytic lymphoma (SLL): a type of B-cell lymphoma with the same genetic and molecular markers as CLL that manifests primarily in the lymph nodes, bone marrow, and other lymphatic tissue rather than with leukocytosis 
Some sources classify CLL as a low-grade non-Hodgkin lymphoma because the origin cell is likely a mature B lymphocyte. However, as the malignant cells are present in the blood, it is considered to be a leukemia. SLL is the manifestation of this condition in lymphatic tissue, and is therefore considered to be a lymphoma. 
- Suppression of the proliferation of normal blood cells
- Infiltration of the lymph nodes, liver, and spleen
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
- Symptoms of anemia and thrombocytopenia
- Dermatologic symptoms
General principles 
- Diagnosis requires persistent monoclonal lymphocytosis plus CLL immunophenotype confirmed by flow cytometry.
- Most patients are asymptomatic and evaluated based on incidental laboratory findings.
- Biopsy may be indicated in certain patients, e.g., if the diagnosis is uncertain.
- Refer to hematology or oncology for further evaluation and management.
In patients with confirmed CLL, staging (e.g., using the ) and the presence of prognostic markers are used to guide management.
Laboratory studies 
- Diagnostic criteria
- Additional findings: may further support the diagnosis
Prognostic markers in CLL 
Indications for testing
- Confirmed CLL diagnosis
- Repeat testing prior to initiating or changing treatment
- Methods 
- Bone marrow aspiration and biopsy 
- Lymph node biopsy: Consider if the diagnosis is uncertain or for the diagnosis of SLL or Richter transformation.
|Rai staging system |
|Rai stage||Modified Rai stage||Findings|
|0||Low risk||Isolated lymphocytosis|
|I||Intermediate risk||Lymphocytosis||PLUS lymphadenopathy|
|II||PLUS hepatomegaly and/or splenomegaly|
|III||High risk||PLUS anemia (Hb < 11 g/dL)|
|IV||PLUS thrombocytopenia (platelets < 100,000/mm3)|
Other staging systems 
General principles 
Management should be specialist guided. Consider enrollment in a clinical trial.
Indications for anticancer therapy : based on disease risk (Rai staging) and disease activity 
Low-risk disease (Rai stage 0)
- Expectant management
- Regular follow-ups to assess for disease progression and indications for treatment 
- Intermediate risk disease (Rai stage I or II)
- Consider expectant management if stable and asymptomatic.
- Medical therapy: indicated for progressive or symptomatic disease (i.e., active disease )
- High-risk disease (Rai stage III or IV): medical therapy
- Low-risk disease (Rai stage 0)
- Anticancer therapy may include:
CLL is a malignancy with a slow rate of cell division and disease progression. Treatment of low-risk disease is usually not recommended and is unlikely to extend survival.
Pretreatment evaluation 
- Clinical assessment: physical examination, and functional status assessment (e.g., ECOG score)
- Laboratory studies
- Further testing (e.g., CT scan, bone marrow biopsy): may be necessary for patients enrolling in clinical trials.
- The pretreatment evaluation is used to determine which regimen is used.
- In most patients with CLL, a BTK inhibitor or BCL-2 inhibitor is the first-line treatment. 
|Overview of pharmacotherapy for CLL |
|Small molecule inhibitors|
|Chemoimmunotherapy|| || |
Allogeneic stem cell transplantation 
- Curative treatment for CLL
- High-risk procedure with a 20% mortality rate 
- Consider for young patients with few or no comorbidities and:
Supportive care 
Evaluate for and manage any complications, including:
- Infectious diseases
- Autoimmune cytopenias: Manage AIHA and ITP (e.g., with glucocorticoids) as needed.
- : Consider the need for G-CSF for .
Live vaccines are contraindicated in patients with CLL because of the risk of severe complications. 
Infectious diseases are common in patients with CLL. Evaluating for and managing infectious diseases can reduce the risk of severe illness and complications. 
- Immunosuppression with subsequent infections (most common cause of death)
- Secondary malignancies
- (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)
We list the most important complications. The selection is not exhaustive.