Chronic lymphocytic leukemia

Last updated: May 9, 2023

Summarytoggle arrow icon

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.

Definitiontoggle arrow icon

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]

Epidemiologytoggle arrow icon

  • 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


Epidemiological data refers to the US, unless otherwise specified.

Etiologytoggle arrow icon

Risk factors

Pathophysiologytoggle arrow icon

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

Clinical featurestoggle arrow icon

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.


Diagnosticstoggle arrow icon

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]

Classificationtoggle arrow icon

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

Differential diagnosestoggle arrow icon

The differential diagnoses listed here are not exhaustive.

Treatmenttoggle arrow icon

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]


  • 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
  • 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]

Complicationstoggle arrow icon


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

Prognosistoggle arrow icon

Prognostic factors [6]

Referencestoggle arrow icon

  1. Nabhan C, Rosen ST. Chronic lymphocytic leukemia: a clinical review.. JAMA. 2014; 312 (21): p.2265-2276.doi: 10.1001/jama.2014.14553 . | Open in Read by QxMD
  2. Jameson JL, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J. Harrison's Principles of Internal Medicine, Twentieth Edition (Vol.1 & Vol.2). McGraw-Hill Education / Medical ; 2018
  3. Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL.. Blood. 2018; 131 (25): p.2745-2760.doi: 10.1182/blood-2017-09-806398 . | Open in Read by QxMD
  4. Mir MA. Chronic Lymphocytic Leukemia (CLL). In: Besa EC, Chronic Lymphocytic Leukemia (CLL). New York, NY: WebMD. Updated: February 3, 2017. Accessed: April 14, 2017.
  5. Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS. Clinical staging of chronic lymphocytic leukemia.. Blood. 1975; 46 (2): p.219-34.
  6. Rai KR, Stilgenbauer S. Clinical Presentation, Pathologic Features, Diagnosis, and Differential Diagnosis of Chronic Lymphocytic Leukemia. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. Last updated: February 1, 2018. Accessed: April 1, 2018.
  7. Caligiuri M, Levi MM, Kaushansky K, et al. Williams Hematology, 9E. McGraw-Hill Education / Medical ; 2015
  8. Tsang M, Parikh SA. A Concise Review of Autoimmune Cytopenias in Chronic Lymphocytic Leukemia. Curr Hematol Malig Rep. 2017; 12 (1): p.29-38.doi: 10.1007/s11899-017-0366-1 . | Open in Read by QxMD
  9. 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
  10. Davis AS, Viera AJ, Mead MD. Leukemia: an overview for primary care.. Am Fam Physician. 2014; 89 (9): p.731-738.
  11. Eichhorst B, Robak T, Montserrat E, et al. Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021; 32 (1): p.23-33.doi: 10.1016/j.annonc.2020.09.019 . | Open in Read by QxMD
  12. Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib Regimens versus Chemoimmunotherapy in Older Patients with Untreated CLL. N Engl J Med. 2018; 379 (26): p.2517-2528.doi: 10.1056/nejmoa1812836 . | Open in Read by QxMD
  13. Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia. N Engl J Med. 2015; 373 (25): p.2425-2437.doi: 10.1056/nejmoa1509388 . | Open in Read by QxMD
  14. Brem EA, O’Brien S. Frontline Management of CLL in 2021. JCO Oncol Pract. 2022; 18 (2): p.109-113.doi: 10.1200/op.21.00258 . | Open in Read by QxMD
  15. Kharfan-Dabaja MA, Kumar A, Hamadani M, et al. Clinical Practice Recommendations for Use of Allogeneic Hematopoietic Cell Transplantation in Chronic Lymphocytic Leukemia on Behalf of the Guidelines Committee of the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2016; 22 (12): p.2117-2125.doi: 10.1016/j.bbmt.2016.09.013 . | Open in Read by QxMD
  16. Stilgenbauer S, Furman RR, Zent CS. Management of Chronic Lymphocytic Leukemia. Am Soc Clin Oncol Educ Book. 2015: p.164-175.doi: 10.14694/edbook_am.2015.35.164 . | Open in Read by QxMD
  17. Dearden C. Disease-specific complications of chronic lymphocytic leukemia. Hematology. 2008; 2008 (1): p.450-456.doi: 10.1182/asheducation-2008.1.450 . | Open in Read by QxMD
  18. Tadmor T, Shvidel L, Bairey O, et al. Richter's transformation to diffuse large B-cell lymphoma: A retrospective study reporting clinical data, outcome, and the benefit of adding rituximab to chemotherapy, from the Israeli CLLStudy Group. Am J Hematol. 2014; 89 (11): p.E218-E222.doi: 10.1002/ajh.23826 . | Open in Read by QxMD
  19. CLL Staging. Updated: April 14, 2017. Accessed: April 14, 2017.
  20. Wierda WG, Byrd JC, Abramson JS, et al. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 4.2020. Journal of the National Comprehensive Cancer Network. 2020; 18 (2): p.185-217.doi: 10.6004/jnccn.2020.0006 . | Open in Read by QxMD
  21. 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): p.5446-56.doi: 10.1182/blood-2007-06-093906 . | Open in Read by QxMD
  22. Rosenthal A. Small Molecule Inhibitors in Chronic Lymphocytic Lymphoma and B Cell Non-Hodgkin Lymphoma. Current Hematologic Malignancy Reports. 2017; 12 (3): p.207-216.doi: 10.1007/s11899-017-0383-0 . | Open in Read by QxMD

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