Chronic lymphocytic leukemia

Last updated: October 26, 2022

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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.

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. [1]

  • 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.

Risk factors

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

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

Lymphadenopathy is a typical finding in lymphoid malignancies such as CLL and helps to differentiate CLL from CML, a myeloid malignancy.

References:[3][4]

General principles [1][2][5]

  • 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 Rai staging system) and the presence of prognostic markers are used to guide management.

Laboratory studies [1][2][5][6]

Obtain a CBC, peripheral blood smear, and flow cytometry for all patients.

The occurrence of both AIHA and ITP is known as Evans syndrome. [5][6]

In CLL, the smudge cells on a peripheral blood smear look like Crushed Little Lymphocytes.

Prognostic markers in CLL [5]

Biopsies [1]

Rai staging system

Rai staging system [2][6][9]
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 [2]

  • Binet staging system: commonly used for staging and informing treatment decisions in European countries
  • CLL international prognostic index (CLL-IPI): risk stratification score based on age, clinical stage (Rai or Binet), and the presence of prognostic molecular markers
Binet staging system [2]
Definition Additional findings
Stage A
  • < 3 involved lymph areas
Stage B
  • ≥ 3 involved lymph areas
Stage C

The differential diagnoses listed here are not exhaustive.

General principles [2][10]

Management should be specialist guided. Consider enrollment in a clinical trial.

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 [2]

Pharmacotherapy

  • 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. [11][12][13]
Overview of pharmacotherapy for CLL [11][14]
Therapy Examples Indications
Targeted therapies Small molecule inhibitors
  • Preferred treatment option for most patients
  • May be used alone or in combination with a monoclonal antibody, e.g., venetoclax PLUS obinutuzumab
Monoclonal antibodies
Chemoimmunotherapy
  • May be used in patients without del(17p) or TP53 mutation

Allogeneic stem cell transplantation [15][16]

  • Curative treatment for CLL
  • High-risk procedure with a 20% mortality rate [1][15][16]
  • Consider for young patients with few or no comorbidities and:

Supportive care [2][16]

Evaluate for and manage any complications, including:

Live vaccines are contraindicated in patients with CLL because of the risk of severe complications. [2]

Infectious diseases are common in patients with CLL. Evaluating for and managing infectious diseases can reduce the risk of severe illness and complications. [16]

References:[17][18]

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

Prognostic factors [6]

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  10. Mitra A, Dwyre DM, Schivo M, et al. Leukoerythroblastic reaction in a patient with COVID‐19 infection. Am J Hematol. 2020; 95 (8): p.999-1000. doi: 10.1002/ajh.25793 . | Open in Read by QxMD
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