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

  • 98% of CLL cases are diagnosed in persons older than 44 years.4
  • CLL is most frequently diagnosed among people aged 65 to 74 years.
  • The median ageat diagnosis is 70 years.
  • An estimated 191,000 persons globally were diagnosed with CLL during 2015, and 61,000 persons died from the disease.2
  • 83.2% of patients will survive 5 years past diagnosis.4

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).5

The cause of CLL is unknown. Gene-expression profiling and phenotypic studies suggest that CLL is probably derived from CD5+ B cells.6

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.7

  • The most recurrent genomic lesions that have been identified are deletions of chromosome 13q, 17p, and 11q, and trisomy of chromosome 12.7
  • As the TP53 tumor suppressor gene is located on chromosome 17p, TP53 mutations and 17p deletions are overlapping predictors of relapsed/refractory disease.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.8

A diagnosis of CLL is based on the International Workshop on CLL (iwCLL) criteria9:

  • There is a presence of at least 5 x 109 (5000/μL) B lymphocytes in the peripheral blood.
    • 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.
  • CLL cells coexpress B-cell surface antigens CD19, CD20, and CD23, and the T-cell surface antigen CD5.
  • Each leukemic cell clone is restricted to expression of either kappa or lambda immunoglobulin light chains, indicating monoclonality.

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.9

Modified Rai Staging System9
Low Risk Patients with lymphocytosis with leukemia cells in the blood and/or marrow (lymphoid cells >30%)
Intermediate Risk Patients with lymphocytosis, enlarged nodes in any site, and splenomegaly and/or hepatomegaly (lymph nodes being palpable or not)
High Risk Patients with disease-related anemia (as defined by a hemoglobin [Hb] level <110 g/L [11 g/dL]) or thrombocytopenia (as defined by a platelet count <100 x 109/L)
Binet Staging System9
Stage A Hb ≥100 g/L (10 g/dL), platelets ≥100 x 109/L, and ≤2 areas of nodal or organ enlargement
Stage B Hb ≥100 g/L (10 g/dL), platelets ≥100 x 109/L, and ≥3 areas of nodal or organ enlargement
Stage C All patients with Hb <100 g/L (10 g/dL) and/or a platelet count >100 x 109/L, irrespective of organomegaly

Newly diagnosed later-stage disease and relapsed/refractory (R/R) CLL have historically been difficult to treat.9,10 In addition, the choice of therapy for patients with the chromosomal aberrations del(11q) or del(17p) was challenging.9

However, insights into the molecular biology of CLL have very 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 include11,12:

  • 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 available agents.11

While allogenic stem cell transplant (Allo-SCT) remains the only potentially curative option, it is a risky procedure only suitable for more fit patients.13

Clinical trials are ongoing investigating second-generation targeted agents as well as combination approaches.11,12

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. 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.
  4. Howlader N, Noone AM, Krapcho M, et al. (eds). SEER Cancer Statistics Review, 1975-2014, National Cancer Institute. Bethesda, MD,, based on November 2016 SEER data submission, posted to the SEER website, April 2017.
  5. Stilgenbauer S, Furman RR, Zent CS. Management of chronic lymphocytic leukemia. Am Soc Clin Oncol Educ Book. 2015:164-175.
  6. Zhang S, Kipps TJ. The pathogenesis of chronic lymphocytic leukemia. Annu Rev Pathol. 2014;9:103- 118.
  7. Guieze R, Wu CJ. Genomic and epigenomic heterogeneity in chronic lymphocytic leukemia. Blood. 2015;23:445-453.
  8. 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.
  9. 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.
  10. Hallek A. Chronic lymphocytic leukemia: 2015 update on diagnosis, risk stratification, and treatment. Am J Hematol. 2015;90(5):446-460.
  11. 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.
  12. Bose P, Gandhi V. Recent therapeutic advances in chronic lymphocytic leukemia. F1000Res. 2017 Oct 31;6:1924.
  13. Lu K, Wang X. Therapeutic advancement of chronic lymphocytic leukemia. J Hematol Oncol. 2012;5(55).

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