Chronic lymphocytic leukemia (CLL)

Exploring dysfunctional pathways, mechanisms, and biomarkers in CLL to discover new insights into the progression of the disease.1


of leukemia cases diagnosed globally are CLL.2


of patients with CLL overexpress the BCL-2 protein.3

Incidence & Mortality

  • The median age at diagnosis is 70 years.3
  • CLL is most frequently diagnosed among people aged 65 to 74 years.3
  • 98% of CLL cases are diagnosed in persons older than 44 years.3
  • An estimated 21,040 persons in the US were diagnosed with CLL during 2020, and 4,060 persons died from the disease.3
  • 86.1% of patients will survive 5 years past diagnosis.3

CLL is a slow-progressing cancer in which mature clonal B lymphocytes accumulate in the bone marrow, blood, and other lymphoid tissues.

  • Complications associated with CLL include recurrent infection and autoimmune diseases, risk of secondary malignancy, and transformation to diffuse large B-cell lymphoma (DLBCL).4

The cause of CLL is unknown. Gene-expression profiling and phenotypic studies suggest that CLL is potentially derived from CD5+ B cells.5

Vast genetic and epigenetic heterogeneity among patients and within individual patient samples has been observed; this likely contributes to the variability in clinical course among patients with CLL.6

  • The most recurrent genomic lesions that have been identified are deletions of chromosome 13q, 17p, and 11q, and trisomy of chromosome 12.6
  • Unmutated IgVH is associated with more aggressive disease, poor prognosis, and decreased survival.7

The most relevant prognostic parameters are IgVH mutational status, serum β2-microglobulin, and the presence of del(17p) and/or TP53 mutations. Typically, high-risk CLL is defined in part by a genetic aberration of the TP53 gene (ie, del(17p) or TP53 mutation).8

Many patients are incidentally diagnosed with asymptomatic CLL when lymphocytes are detected in the peripheral blood during evaluation for other illnesses or in a routine physical exam.9

A diagnosis of CLL is based on the updated International Workshop on CLL (iwCLL) criteria:8

  • There is a presence of at least 5 x 109 (5000/μL) B lymphocytes in the peripheral blood sustained for 3 months.
    • Clonality of circulating B lymphocytes must be confirmed by flow cytometry.
    • Cells are characteristically small, mature lymphocytes with a narrow border of cytoplasm and a dense nucleus lacking discernible nucleoli and having partially aggregated chromatin.
    • Gumprecht nuclear shadows, or smudge cells, found as cellular debris, are additional morphologic features commonly associated with CLL
  • CLL cells co-express the surface antigen CD5 together with the B-cell antigens CD19, CD20, and CD23.
  • Each leukemic cell clone is restricted to expression of either kappa or lambda immunoglobulin light chains, indicating monoclonality.
  • Additional tests are not essential to diagnose CLL, but may help predict the prognosis or assess the tumor burden, including: molecular genetics, mutational status of IgVH and variable heavy stereotypes, immunophenotypic markers, serum markers, and marrow examination.

Two staging systems, the Rai and Binet systems, are currently used worldwide in the evaluation of patients with CLL both in routine practice and clinical trial settings.10

Newly diagnosed later-stage disease and relapsed/refractory (R/R) CLL have historically been difficult to treat.10,11 However, insights into the molecular biology of CLL have recently provided several novel agents for use as first-line and relapsed/refractory therapy, and we have recently seen a paradigm shift in the management of CLL. Targets include:12,13

  • The B-cell receptor signaling pathway
  • The BCL-2 family of proteins
  • CD-20
  • Phosphatidylinositol 3-kinase (PI3K)

The major treatment challenge has now shifted from having few therapeutic choices to how best to sequence and combine available agents.12

While allogenic stem cell transplant (Allo-SCT) remains the only potentially curative option, it is a risky procedure only suitable for more fit patients.14

Clinical trials are ongoing investigating second-generation targeted agents as well as combination approaches.12,13

Relevant Biomarker Pathways

  1. Anderson MA, Huang D, Roberts A. Targeting BCL2 for the treatment of lymphoid malignancies. Semin Hematol. 2014;51(3):219-227.
  2. Global Burden of Disease Cancer Collaboration, Fitzmaurice C, Allen C, Barber RM, et al. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: A systematic analysis for the Global Burden of Disease Study. JAMA Oncol. 2017;3(4):524-548.
  3. Howlader N, Noone AM, Krapcho M, Miller D, Brest A, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics Review, 1975-2017, National Cancer Institute. Bethesda, MD,, based on November 2019 SEER data submission, posted to the SEER web site, April 2020.
  4. Stilgenbauer S, Furman RR, Zent CS. Management of chronic lymphocytic leukemia. Am Soc Clin Oncol Educ Book. 2015:164-175.
  5. Zhang S, Kipps TJ. The pathogenesis of chronic lymphocytic leukemia. Annu Rev Pathol. 2014;9:103-118.
  6. Guieze R, Wu CJ. Genomic and epigenomic heterogeneity in chronic lymphocytic leukemia. Blood. 2015;23:445-453.
  7. Hamblin TJ, et al. Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood. 1999;94(6):1848-1854.
  8. Hallek M, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018 Jun 21;131(25):2745-2760.
  9. Stilgenbauer S, Schnaiter A, Paschka P, et al. Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial. Blood. 2014;123(21):3247-3254.
  10. Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute–Working Group 1996 guidelines. Blood. 2008;111(12):5446-5456.
  11. Hallek A. Chronic lymphocytic leukemia: 2015 update on diagnosis, risk stratification, and treatment. Am J Hematol. 2015;90(5):446-460.
  12. Davids MS. How should we sequence and combine novel therapies in CLL? Hematology Am Soc Hematol Educ Program. 2017 Dec 8;2017(1):346-353.
  13. Bose P, Gandhi V. Recent therapeutic advances in chronic lymphocytic leukemia. F1000Res. 2017 Oct 31;6:1924.
  14. Lu K, Wang X. Therapeutic advancement of chronic lymphocytic leukemia. J Hematol Oncol. 2012;5(55).
  15. Hanada M, Delia D, Aiello A, Stadtmauer E, Reed JC. Bcl-2 gene hypomethylation and high-level expression in B-cell chronic lymphocytic leukemia. Blood. 1993;82(6):1820-1828.

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