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


  • An estimated 18,740 people in the US were diagnosed during 2023, and 4,490 people died from the disease.15
  • Five-year survival rate is 88.0% in the US.15
  • CLL is most frequently diagnosed among people aged 65 to 74 years 15
  • In the US, 98% of CLL cases are diagnosed in people older than 44 years.15
  • The median age at diagnosis is 70 years.15

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 identified lesions 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 that lack discernible nucleoli and have 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

Numerous advances in the treatment of CLL have been made within the last few decades, including the introduction of novel classes of targeted small molecules such as BCL2 inhibitors, BTK inhibitors, or PI3K inhibitors. Randomized clinical trials have demonstrated improved progression-free survival with these therapeutics over chemoimmunotherapy in both the first-line and relapsed/refractory setting.11 These chemotherapy-free regimens have especially helped  improve outcomes in high-risk subgroups, albeit still with reduced activity relative to patients without these high-risk characteristics.

CLL is a chronic disease; therefore, most patients will relapse on or after treatment and require multiple lines of therapy, especially high-risk subgroups. The major treatment challenge has now shifted from having few therapeutic choices to how best to sequence and combine available agents.11,12

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

Ongoing clinical trials are investigating second-generation targeted agents, combination approaches, and novel treatment strategies; these include small molecules with novel targets, CAR-T cells that target different antigens, CAR natural killer cells, and bispecific antibodies.12,13,16

Relevant Cancer Targets


Learn about how BCL-2 plays a role in tumor survival and is a rational target for therapeutic intervention.MORE>


Learn about BTK and B cell signalingMORE>


Learn about MALT1 and NF-κB signalingMORE>


Learn about CD3 on T cells and bispecific targeting of CD20. MORE>


Learn about CD19 and B cell signalingMORE>

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  2. Global Burden of Disease Cancer Collaboration, Fitzmaurice C, Allen C, 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
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  4. Stilgenbauer S, Furman RR, Zent CS. Management of chronic lymphocytic leukemia. Am Soc Clin Oncol Educ Book. 2015:164-175.
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  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 ;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. Bewarder M, et al. Current Treatment Options in CLL. Cancers (Basel). 2021;13(10):2468.
  12. Davids MS. How should we sequence and combine novel therapies in CLL? Hematology Am Soc Hematol Educ Program. 2017 ;2017(1):346-353.
  13. Bose P, Gandhi V. Recent therapeutic advances in chronic lymphocytic leukemia. F1000Res. 2017;6:1924.
  14. Lu K, Wang X. Therapeutic advancement of chronic lymphocytic leukemia. J Hematol Oncol. 2012;5(55).
  15. NCI. Cancer Stat Facts: Chronic Lymphocytic Leukemia (CLL).Accessed March 2024.
  16. Scarfo L. Novel therapies and combinations in CLL refractory to BTK inhibitors and venetoclax. Hematology Am Soc Hematol Educ Program (2022) 2022 (1): 316–322.