Chronic Lymphocytic Leukemia (CLL)

What is CLL?

Distinction between CLL and SLL¹

CLL is the most common type of chronic leukemia characterized by aberrant proliferation of mature monoclonal B cells in the bone marrow. CLL and SLL are denoted as “CLL/SLL” because they are different manifestations of the same disease.¹

In CLL, accumulation of malformed B lymphocytes occurs predominately in blood and bone marrow¹

Higher proportion of abnormal compared to healthy B cells in blood

In SLL, malformed B lymphocytes accumulate in the lymph nodes¹

Healthy B Cells

Abnormal B Cells

Incidence

Recently reported age-adjusted incidence of 4.6 per 100,000 per year in the US population²

Prevalence

In 2021, there were an estimated 215,107 people living with CLL in the United States²

Risk factors associated with CLL

Median age at diagnosis is 70 years with incidence increasing with age³

More common in men³

Highest incidence in Caucasian population and Western countries¹

Genetic basis and can develop in families. First-degree relatives of patients with CLL have double the risk of CLL¹

For more information on CLL description, epidemiology, and symptoms, please see CLL slide deck and infographic in the related resources at the bottom of the page.

Diagnosis

Initial clinical evaluation^1,3-6

Patient history and physical examination

Laboratory testing

Histopathology

Immunophenotyping

Test type	Diagnostic test	Finding necessary for establishing a diagnosis of CLL³,⁴
Laboratory testing	Diagnostic test: Complete blood count	Finding necessary for establishing a diagnosis of CLL³,⁴: ≥5000 B lymphocytes/µL in the peripheral blood for at least 3 months
Histopathology	Diagnostic test: Blood smear	Finding necessary for establishing a diagnosis of CLL³,⁴: Leukemic cells in blood smear are typically small, mature lymphocytes and have a narrow border of cytoplasm, a dense nucleus without discernible nuclei, and partially aggregated chromatin
Immunophenotyping	Diagnostic test: Flow cytometry	Finding necessary for establishing a diagnosis of CLL³,⁴: Confirms clonality of circulating B lymphocytes; usually positive for CD5 antigen and the B-cell markers, CD23 and CD19; weak expression of surface membrane immunoglobulin (CD20 and CD79b)

Diagnosis of CLL is established by blood counts, blood smears, and immunophenotyping of circulating B lymphocytes⁴

For more information on CLL diagnosis, please see CLL slide deck and infographic in the related resources at the bottom of the page.

Symptoms

CLL is usually asymptomatic and discovered via routine blood tests¹

Approximately 5% to 10% of CLL cases will present with B symptoms such as¹

Unexplained fevers (>100.5 °F)

Unintentional weight loss (≥10% over 6 months or less)

Night sweats

Early satiety

Fatigue

Other symptoms of CLL¹

Swollen lymph nodes

Increased frequency of infections

Autoimmune cytopenia

Enlarged liver or spleen

To gain a medical oncologist’s perspective on when patients with CLL need therapy, you will find Dr Thompson’s and Dr Roeker’s video in the related resources at the bottom of the page.

Staging

Factors that weigh into staging patients with CLL include^7,8:

Risk of progression

Results of evaluating lymphocytosis

Degree of lymph node, spleen, and liver enlargement

Presence of anemia

Presence of thrombocytopenia

Staging systems^7,8

Rai and Binet: Although widely used in clinical practice, the Rai and Binet classifications are not sufficient to determine if the patient will present with rapidly progressive or indolent disease.

CLL-IPI: The CLL-IPI combines genetic, biochemical, and clinical parameters into a prognostic model with 4 risk subgroups: low, intermediate, high, and very high.

Currently, genetic, epigenetic, and molecular markers are the focus of attention in
prognostication of CLL^7,8

Rai Staging System (Primarily United States)⁹

Stage/risk	Characteristics
0 (Low)	Characteristics: Lymphocytosis, lymphocytes in blood >5 x 10⁹/L clonal B cells and/or >40% lymphocytes in the bone marrow
I (Intermediate)	Characteristics: Lymphocytosis with enlarged node(s)
II (Intermediate)	Characteristics: Lymphocytosis with splenomegaly, hepatomegaly, or both
III (High)	Characteristics: Lymphocytosis with anemia (hemoglobin <11.0 g/dL or hematocrit <33%)
IV (High)	Characteristics: Lymphocytosis with thrombocytopenia (platelets <100,000/µL)

Binet Staging System (Primarily Europe)¹⁰

Stage	Characteristics
A	Characteristics: <3 areas of lymphoid tissue are enlarged, with no anemia or thrombocytopenia
B	Characteristics: ≥3 areas of lymphoid tissue are enlarged, with no anemia or thrombocytopenia
C	Characteristics: Anemia (hemoglobin <10 g/dL) and/or thrombocytopenia (platelets <100,000/µL) are present, with any number of enlarged areas

CLL-IPI Risk Group Criteria and Scoring¹¹

Table of CLL International Prognostic Index — Table outlining CLL-IPI risk group criteria and scoring system based on age (≤65 years = 0 points, >65 years = 1 point), clinical stage (Binet A or Rai 0 = 0 points, Binet B-C or Rai I-IV = 1 point), serum β2M (in mg/L or μ/mL; ≤3.5 = 0 points, >3.5 = 2 points), IGHV mutational status (mutated = 0 points, unmutated = 2 points) and TP53 status (no abnormality = 0 points, deletion 17p [FISH] and/or TP53 mutation [sequencing] = 4 points).

5-year Survival by CLL-IPI Risk Group^3,11

CLL-IPI score	Risk	5-year survival
0-1	Risk: Low	5-year survival: 93.2%
2-3	Risk: Intermediate	5-year survival: 79.3%
4-6	Risk: High	5-year survival: 63.3%
7-10	Risk: Very High	5-year survival: 23.3%

To gain a medical oncologist’s perspective on prognostic testing, you will find Dr Thompson’s and Dr Roeker’s video in the related resources at the bottom of the page.

High-risk CLL

High-risk CLL is based on a combination of factors, including genomic biomarkers, as well as patient- and treatment-related risk factors¹²

Factors associated with high-risk CLL^12-14

Factors associated with high-risk CLL in a 3-circle graphic — Factors associated with high-risk CLL include genomic biomarkers (del[17p]/TP53 mutation, cytogenetic complexity, unmutated IGHV and del[11q]), treatment-related factors (intolerance toward a targeted therapy and resistance mutations in BTK, PLCG2, and BCL2), and patient-related risk factors (clinical stage: Binet C or Rai III/IV, age >65 years, contraindication to a targeted therapy, and restricted access to CLL specialists or targeted therapy).

Identifying high-risk CLL using established prognostic factors¹²

Patient with CLL prognostic factors listed, including clinical staging, cytogenetic complexity, chromosomal aberrations, and molecular markers — Identifying high-risk CLL in patients diagnosed with CLL involves clinical staging (Rai or Binet system), analysis of cytogenetic complexity (complex karyotype [≥3 CA], high complex karyotype [≥5 CA], or noncomplex karyotype), chromosomal aberrations [including del(17p), del(11q), del(13q) and trisomy 12], and molecular biomarkers (TP53 and/or IGHV), and can help with optimal assessment of treatment options and likely outcomes.

High-risk CLL by clinical staging systems^3,7

High-risk CLL—Binet

Factors associated with high-risk CLL by Binet staging system

Anemia (hemoglobin <10 g/dL)

Thrombocytopenia (platelets <100 x 10⁹/L)

Any number of areas of lymphoid tissue enlargement

Referred to as stage C

High-risk CLL—Rai

Factors associated with high-risk CLL by Rai staging system

Lymphocytosis in blood and/or bone marrow

AND

Anemia (hemoglobin <11 g/dL)

OR

Thrombocytopenia (platelets <100 x 10⁹/L)

Referred to as high risk or stage III/IV

Genomic biomarkers

Genomic Biomarkers used in CLL prognostication

Biomarker testing is performed at diagnosis to derive prognostic and predictive information from genetic mutations and chromosomal abnormalities associated with CLL, which can inform the treatment plan⁷

The following biomarkers are associated with poor prognosis in patients with CLL

Del(17p)^7,15

Graph showing 10% prevalence at diagnosis

TP53 mutation⁸

Graph showing 8% prevalence at diagnosis

IGHV unmutated^7,14,15

Graph showing 40% prevalence at diagnosis

Complex karyotype¹⁶

Graph showing 15% prevalence at diagnosis

For patients with CLL in which treatment is indicated, the presence or absence of del(17p) and TP53 mutations are most often used to direct treatment selection¹⁴

In some cases, acquired resistance during CLL treatment can necessitate additional biomarker testing prior to beginning a new line of therapy^17,18

Chromosomal aberrations may be associated with high-risk CLL

Approximately 80% of patients with CLL carry at least 1 of 4 chromosomal alterations (listed below)³

Chromosomal alteration	Description	Frequency	Risk
Del(13q)	Description: Critical region of del(13q14) contains miRNAs that regulate apoptosis and cell-cycle progression³,¹⁹	Frequency: 55% of patients with CLL³	Risk: Favorable prognosis when alone³,¹⁹
Del(11q)	Description: Frequently encompasses 11q23, which harbors the ATM gene; associated with bulky lymphoma and rapid progression³	Frequency: 10% of early disease 25% of advanced disease³,ᵃ	Risk: Poor prognosis³,¹⁹
Trisomy 12	Description: Role in CLL pathogenesis unclear; may be more common in SLL and cases with Richter transformation³,¹⁹	Frequency: 10%-20% of patients with CLL³	Risk: Intermediate prognosis³,¹⁹
Del(17p)	Description: 17p13 harbors the TP53 gene, which encodes tumor suppressor protein P53³	Frequency: 5%-8% of chemotherapy-naïve patients with CLL³	Risk: Poor prognosis; resistance to genotoxic chemotherapies³

^aChemotherapy naïve.

For more information on high-risk CLL and genomic biomarkers, please see the slide deck and infographic on these topics in the related resources at the bottom of the page.

ATM=ataxia-telangiectasia mutated; B2M=beta-2-microglobulin; BCL-2=B-cell lymphoma 2; BTK=Bruton’s tyrosine kinase; CA=chromosomal abnormality; CLL= chronic lymphocytic leukemia; CLL-IPI=International Prognostic Index for Chronic Lymphocytic Leukemia; FISH=fluorescence in situ hybridization; HCP=health care provider; IGHV=immunoglobulin heavy-chain variable region gene; PLCG2=phospholipase C gamma 2; SLL=small lymphocytic lymphoma; TP53=tumor protein 53.

References

Mukkamalla SKR, et al. Chronic lymphocytic leukemia. [Updated 2023 Mar 7]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470433/
SEER. Cancer Stat Facts: Leukemia — Chronic Lymphocytic Leukemia (CLL). Accessed August 12, 2024. https://seer.cancer.gov/statfacts/html/clyl.html
Hallek M, Al-Sawaf O. Am J Hematol. 2021;96(12):1679-1705.
Hallek M. Am J Hematol. 2019;94(11):1266-1287.
Kay NE, et al. Blood Rev. 2022;54:100930.
Lynch DT, et al. Mantle cell lymphoma. [Updated 2023 Jul 28]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK536985/
Leukemia & Lymphoma Society. Chronic lymphocytic leukemia. Accessed August 12, 2024. https://www.lls.org/sites/default/files/2023-07/PS34_CLL_Booklet_2023.pdf
Stefaniuk P, et al. Cancer Manag Res. 2021;13:1459-1476.
Leukemia & Lymphoma Society. Chronic lymphocytic leukemia. Accessed August 12, 2024. https://www.lls.org/sites/default/files/file_assets/PS34_CLL_Booklet_2019_FINAL.pdf
Eichhorst B, et al. Ann Oncol. 2021;32(1):23-33.
International CLL-IPI Working Group. Lancet Oncol. 2016;17(6):779-790.
Edelmann J, et al. Front Oncol. 2023;13:1106579.
Martinelli S, et al. Mediterr J Hematol Infect Dis. 2016;8(1):e2016047.
Campo E, et al. Haematologica. 2018;103(12):1956-1968.
Yun X et al. Biomark Res. 2020;8:40.
Baliakas P, et al. Blood. 2019;133(11):1205-1216.
Shadman M. JAMA. 2023;329(11):918-932.
Hallek M, et al. Blood. 2018;131(25):2745-2760.
Lee J, Wang YL. J Mol Diagn. 2020;22(9):1114-1125.

VV-MED-163244

What is CLL?

Distinction between CLL and SLL¹

Diagnosis

High-risk CLL

High-risk CLL is based on a combination of factors, including genomic biomarkers, as well as patient- and treatment-related risk factors¹²

High-risk CLL by clinical staging systems^3,7

What factors do you consider when treating patients with CLL?

What is your approach to prognostic testing in CLL?

References

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Please rate your satisfaction with the content on the following statements:

What is CLL?

Distinction between CLL and SLL1

Diagnosis

High-risk CLL

High-risk CLL is based on a combination of factors, including genomic biomarkers, as well as patient- and treatment-related risk factors12

High-risk CLL by clinical staging systems3,7

Related Resources

Downloadable PDFs

What factors do you consider when treating patients with CLL?

What is your approach to prognostic testing in CLL?

References

Please rate your satisfaction with the content on the following statements:

Please rate your satisfaction with the content on the following statements:

Distinction between CLL and SLL¹

High-risk CLL is based on a combination of factors, including genomic biomarkers, as well as patient- and treatment-related risk factors¹²

High-risk CLL by clinical staging systems^3,7