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Chronic lymphocytic leukemia

Last updated: May 13, 2020

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Chronic lymphocytic leukemia (CLL) belongs to the group of low-grade non-Hodgkin lymphomas (NHL) and is a B-cell lymphoma that presents with lymphocytic leukocytosis. CLL is the most common form of leukemia in adults and is typically considered a disease of the elderly. Clinical features include painless lymphadenopathy, fatigue, chronic pruritus, and an increased susceptibility to infections. Important diagnostic markers are smudge cells (Gumprecht shadows) in a blood smear, a high percentage of small, mature lymphocytes in the bone marrow, and detection of B-CLL antigens in flow cytometry. The Rai staging system is primarily based on lymphocyte count, sites of lymphatic tissue involvement, anemia, and platelet count. The medical treatment of CLL consists of chemotherapy and monoclonal antibodies, but does not necessarily increase survival time. Allogeneic stem cell transplantation, which is the only curative treatment option, is often not viable because of the advanced age of most patients.





References:[1][2]

  • 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

References:[3]

Epidemiological data refers to the US, unless otherwise specified.

Risk factors

References:[2]

Rai staging system

Stage Finding Median survival
0 Low risk Isolated lymphocytosis > 150 months
I Intermediate risk + Lymphadenopathy 101 months
II + Hepatomegaly and/or splenomegaly 71 months
III High risk + Anemia (Hb < 11 g/dL) 19 months
IV + Thrombocytopenia (< 100,000/μL) 19 months

References:[4][5]

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

References:[6]

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!

References:[2][3]

Laboratory analysis

Bone marrow aspiration

Bone marrow aspiration is not necessary to confirm the diagnosis but may be helpful in investigating cytopenia of unknown origin, for instance, during later stages of the disease.

Additional diagnostic procedures

In CLL, the smudge cells on peripheral smear appear to be Crushed Little Lymphocytes.

References:[3][4][7][8][9][10][11]

The differential diagnoses listed here are not exhaustive.

Principles of treatment

The treatment regimen is primarily based on the risk of disease progression according to the Rai staging system, whether the patient is symptomatic or has comorbidities, and the patient's age and level of fitness.

CLL is a low-grade malignancy, noted for its slow rate of cell division and disease progression; treatment is often not necessary or is unlikely to improve survival time.

Medical therapy is palliative and the only curative treatment option is stem cell transplantation!

Treatment regimens

References:[8][12][13]

References:[14][15]

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

Prognostic factors

  • Advanced age is associated with a poor overall survival rate
  • Genetic abnormalities: e.g., del(17p13) is associated with a poor overall survival rate because of the high risk of disease progression and poor response to chemotherapy.
  • β-2 microglobulin levels: correlate with the severity of the disease
  • Blood lymphocyte doubling time: Rapid doubling is associated with a high risk of disease progression.

References:[5]

  1. Rai KR, Stilgenbauer S. Staging and Prognosis of Chronic Lymphocytic Leukemia. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/staging-and-prognosis-of-chronic-lymphocytic-leukemia.Last updated: December 20, 2016. Accessed: April 14, 2017.
  2. Rai KR, Stilgenbauer S. Pathophysiology and Genetic Features of Chronic Lymphocytic Leukemia. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/pathophysiology-and-genetic-features-of-chronic-lymphocytic-leukemia.Last updated: February 2, 2018. Accessed: April 1, 2018.
  3. Graham RL, Cooper B, Krause JR. T-cell prolymphocytic leukemia. Proc (Bayl Univ Med Cent). 2013; 26 (1): p.19-21.
  4. Rai KR, Stilgenbauer S. Clinical Presentation, Pathologic Features, Diagnosis, and Differential Diagnosis of Chronic Lymphocytic Leukemia. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/clinical-presentation-pathologic-features-diagnosis-and-differential-diagnosis-of-chronic-lymphocytic-leukemia.Last updated: February 1, 2018. Accessed: April 1, 2018.
  5. Mir MA. Chronic Lymphocytic Leukemia (CLL). In: Besa EC, Chronic Lymphocytic Leukemia (CLL). New York, NY: WebMD. http://emedicine.medscape.com/article/199313. Updated: February 3, 2017. Accessed: April 14, 2017.
  6. Le T, Bhushan V, Bagga HS. First Aid for the USMLE Step 2 CK. McGraw-Hill Medical ; 2009
  7. Rodrigues CA, Gonçalves MV, Ikoma MR, et al. Diagnosis and treatment of chronic lymphocytic leukemia: recommendations from the Brazilian Group of Chronic Lymphocytic Leukemia. Rev Bras Hematol Hemoter. 2016; 38 (4): p.346-357. doi: 10.1016/j.bjhh.2016.07.004 . | Open in Read by QxMD
  8. Craig FE, Foon KA. Flow cytometric immunophenotyping for hematologic neoplasms. Blood. 2008; 111 (8): p.3941-3967. doi: 10.1182/blood-2007-11-120535 . | Open in Read by QxMD
  9. Seiter K. Chronic Lymphocytic Leukemia (CLL) Guidelines. In: Besa EC, Chronic Lymphocytic Leukemia (CLL) Guidelines. New York, NY: WebMD. http://emedicine.medscape.com/article/2500004. Updated: August 26, 2016. Accessed: April 14, 2017.
  10. Dusse LMS, Silva TP, Freitas LG, Vieira LM, Sabino A de P, Carvalho M das G. Gumprecht shadows: when to use this terminology?. Rev Bras Hematol Hemoter. 2013; 38 (4): p.346–357. doi: 10.1590/s1676-24442013000500004 . | Open in Read by QxMD
  11. Chronic Lymphoid Leukemia (Liver). http://www.pathologyatlas.ro/chronic-lymphoid-leukemia-liver.php. Updated: January 30, 2009. Accessed: April 1, 2018.
  12. Negrin RS, Rai KR. Hematopoietic Cell Transplantation in Chronic Lymphocytic Leukemia. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/hematopoietic-cell-transplantation-in-chronic-lymphocytic-leukemia.Last updated: January 9, 2017. Accessed: April 14, 2017.
  13. Rai KR, Stilgenbauer S. Selection of Initial Therapy for Symptomatic or Advanced Chronic Lymphocytic Leukemia. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/selection-of-initial-therapy-for-symptomatic-or-advanced-chronic-lymphocytic-leukemia.Last updated: July 5, 2016. Accessed: April 14, 2017.
  14. 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
  15. 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
  16. CLL Staging. http://www.lls.org/leukemia/chronic-lymphocytic-leukemia/diagnosis/cll-staging. Updated: April 14, 2017. Accessed: April 14, 2017.
  17. 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
  18. 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
  19. 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
  20. 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.
  21. 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
  22. Nabhan C, Rosen ST. Chronic lymphocytic leukemia: a clinical review.. Journal of the American Medical Association. 2014; 312 (21): p.2265-2276. doi: 10.1001/jama.2014.14553 . | Open in Read by QxMD