View source for Chronic lymphocytic leukemia

{{Short description|Bone marrow cancer in which lymphocytes are overproduced}}
{{Redirect|B-cell CLL|the gene family|B-cell CLL/lymphoma}}
{{Infobox medical condition
| name = Chronic lymphocytic leukemia
| synonyms = B-cell chronic lymphocytic leukemia (B-CLL)<ref>{{cite book|last1=O'Brien|first1=Susan|last2=Gribben|first2=John G. | name-list-style = vanc |title=Chronic Lymphocytic Leukemia|date=2008|publisher=CRC Press|isbn=978-1-4200-6896-2|page=19|url=https://books.google.com/books?id=0HYZBwAAQBAJ&pg=PA19}}</ref>
| image = Chronic_lymphocytic_leukemia.jpg
| caption = Peripheral blood smear showing CLL cells
| pronounce = 
| field = [[Hematology]] and [[oncology]]
| symptoms = '''Early''': None<ref name="NCI2017Pt"/><br />'''Later''': Non-painful [[lymph nodes]] swelling, feeling tired, fever, weight loss, night sweats<ref name="NCI2017Pt"/>
| complications = 
| onset = Older than 50<ref name=SEER2017/>
| duration = 
| types = 
| causes = 
| risks = Family history, tobacco use, [[Agent Orange]], certain [[insecticides]]<ref name="NCI2017Pt"/><ref name=Nature2017/>
| diagnosis = [[Blood tests]]<ref name=Fer2018/>
| differential = [[Mononucleosis]], [[hairy cell leukemia]], [[acute lymphocytic leukemia]], [[persistent polyclonal B-cell lymphocytosis]]<ref name=Fer2018/>
| prevention = 
| treatment = [[Watchful waiting]], [[chemotherapy]], [[immunotherapy]], [[targeted therapy]], [[stem cell transplantation]]<ref name=Nature2017/><ref name=Fer2018/>
| medication = 
| prognosis = [[Five-year survival]] ~89% (US)
| frequency = 904,000 (2015)<ref name=GBD2015Pre>{{cite journal | title = Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015 | journal = Lancet | volume = 388 | issue = 10053 | pages = 1545–1602 | date = October 2016 | pmid = 27733282 | pmc = 5055577 | doi = 10.1016/S0140-6736(16)31678-6 | last1 = Vos | first1 = Theo | last2 = Allen | first2 = Christine | last3 = Arora | first3 = Megha | last4 = Barber | first4 = Ryan M. | last5 = Bhutta | first5 = Zulfiqar A. | last6 = Brown | first6 = Alexandria | last7 = Carter | first7 = Austin | last8 = Casey | first8 = Daniel C. | last9 = Charlson | first9 = Fiona J. | last10 = Chen | first10 = Alan Z. | last11 = Coggeshall | first11 = Megan | last12 = Cornaby | first12 = Leslie | last13 = Dandona | first13 = Lalit | last14 = Dicker | first14 = Daniel J. | last15 = Dilegge | first15 = Tina | last16 = Erskine | first16 = Holly E. | last17 = Ferrari | first17 = Alize J. | last18 = Fitzmaurice | first18 = Christina | last19 = Fleming | first19 = Tom | last20 = Forouzanfar | first20 = Mohammad H. | last21 = Fullman | first21 = Nancy | last22 = Gething | first22 = Peter W. | last23 = Goldberg | first23 = Ellen M. | last24 = Graetz | first24 = Nicholas | last25 = Haagsma | first25 = Juanita A. | last26 = Hay | first26 = Simon I. | last27 = Johnson | first27 = Catherine O. | last28 = Kassebaum | first28 = Nicholas J. | last29 = Kawashima | first29 = Toana | last30 = Kemmer | first30 = Laura | display-authors = 1 }}</ref>
| deaths = 60,700 (2015)<ref name=GBD2015De/>
}}
<!-- Definition and symptoms -->

'''Chronic lymphocytic leukemia''' ('''CLL''') is a type of [[cancer]] that affects the blood and [[bone marrow]].<ref name=":4">{{Cite journal |last=Shadman |first=Mazyar |date=2023-03-21 |title=Diagnosis and Treatment of Chronic Lymphocytic Leukemia: A Review |url=https://jamanetwork.com/journals/jama/fullarticle/2802611 |journal=JAMA |language=en |volume=329 |issue=11 |pages=918–932 |doi=10.1001/jama.2023.1946 |pmid=36943212 |issn=0098-7484|url-access=subscription }}</ref><ref name=":9">{{Cite web |title=What Is Chronic Lymphocytic Leukemia? |url=https://www.cancer.org/cancer/types/chronic-lymphocytic-leukemia/about/what-is-cll.html |access-date=2025-01-12 |website=www.cancer.org |language=en}}</ref> In CLL, the bone marrow makes too many [[lymphocytes]], which are a type of [[white blood cell]].<ref name=":4" /><ref name=":9" /> In patients with CLL, [[B cell]] lymphocytes can begin to collect in their blood, spleen, lymph nodes, and bone marrow.<ref name=":10">{{Citation |last1=Mukkamalla |first1=Shiva Kumar R. |title=Chronic Lymphocytic Leukemia |date=2025 |work=StatPearls |url=https://www.ncbi.nlm.nih.gov/books/NBK470433/ |access-date=2025-01-17 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=29261864 |last2=Taneja |first2=Alankrita |last3=Malipeddi |first3=Dhatri |last4=Master |first4=Samip R.}}</ref><ref name="Nature2017">{{cite journal |display-authors=6 |vauthors=Kipps TJ, Stevenson FK, Wu CJ, Croce CM, Packham G, Wierda WG, O'Brien S, Gribben J, Rai K |date=January 2017 |title=Chronic lymphocytic leukaemia |journal=Nature Reviews. Disease Primers |volume=3 |article-number=16096 |doi=10.1038/nrdp.2016.96 |pmc=5336551 |pmid=28102226}}</ref> These cells do not function well and crowd out healthy [[blood cells]].<ref name="NCI2017Pt">{{cite web |date=26 October 2017 |title=Chronic Lymphocytic Leukemia Treatment |url=https://www.cancer.gov/types/leukemia/hp/cll-treatment-pdq |access-date=19 December 2017 |website=National Cancer Institute}}</ref> CLL is divided into two main types:
# Slow-growing CLL (indolent CLL) 
# Fast-growing CLL<ref>{{Cite web |title=What Is Chronic Lymphocytic Leukemia? |url=https://www.cancer.org/cancer/types/chronic-lymphocytic-leukemia/about/what-is-cll.html |access-date=2025-01-17 |website=www.cancer.org |language=en}}</ref>
Many people do not have any symptoms when they are first diagnosed.<ref name=":4" /><ref name="NCI2017Pt" /> Those with symptoms (about 5-10% of patients with CLL) may experience the following:

* [[Fever]]s
* Fatigue
* [[Night sweats]]
* Unexplained weight loss
* Loss of appetite
* Painless [[lymph node]] swelling
* [[Splenomegaly|Enlargement of the spleen]], and/or
* A [[anemia|low red blood cell count]] ([[anemia]]).<ref name=":10" /><ref name="Nature2017" /><ref name="NCI2017Pt" /><ref name="Hall2018" />

These symptoms may worsen over time.<ref name=":4" /><ref name="NCI2017Pt" />

<!-- Cause and diagnosis -->While the exact cause of CLL is unknown, having a family member with CLL increases one's risk of developing the disease.<ref name=":10" /><ref name="Nature2017" /> Environmental risk factors include exposure to [[Agent Orange]], [[ionizing radiation]], and certain [[insecticide]]s.<ref name="Hall2018" /><ref name="Nature2017" /> The use of tobacco is also associated with an increased risk of having CLL.<ref name=":10" />

Diagnosis is typically based on [[blood test]]s that find high numbers of mature [[lymphocyte]]s and smudge cells.<ref name="Fer2018">{{cite book|last1=Ferri|first1=Fred F. | name-list-style = vanc |title=Ferri's Clinical Advisor 2018 E-Book: 5 Books in 1|date=2017|publisher=Elsevier Health Sciences|isbn=978-0-323-52957-0|page=750|url=https://books.google.com/books?id=wGclDwAAQBAJ&pg=PA750}}</ref>
[[File:Smudge cell in a peripheral blood smear.jpg|thumb|This is an example of how a smudge cell looks on a peripheral blood smear, which is a common finding in patients with chronic lymphocytic leukemia (CLL).]]

<!-- Treatment -->When patients with CLL are not experiencing symptoms (i.e. are [[asymptomatic]]), they only need careful observation.<ref name=":2" /> This is because there is currently no evidence that early intervention can alter the course of the disease.<ref name=":2">{{cite journal | vauthors = Stilgenbauer S, Furman RR, Zent CS | title = Management of chronic lymphocytic leukemia | journal = American Society of Clinical Oncology Educational Book. American Society of Clinical Oncology. Annual Meeting | issue = 35 | pages = 164–175 | date = 2015-05-01 | pmid = 25993154 | doi = 10.14694/EdBook_AM.2015.35.164 }}</ref>

Patients with CLL have an increased risk of developing serious infections.<ref name=":2" /> Doctors often routinely monitor patients for infections, treating them with antibiotics if a bacterial infection is present.<ref name=":2" />

In patients with significant signs or symptoms, treatment can involve [[chemotherapy]], [[immunotherapy]], or [[chemoimmunotherapy]].<ref name="Nature2017" /> The most appropriate treatment is based on the individual's age, physical condition, and whether they have the [[DEL17P13.1|del(17p)]] or [[TP53]] mutation.<ref>{{cite journal | vauthors = Hallek M | title = Chronic lymphocytic leukemia: 2020 update on diagnosis, risk stratification and treatment | journal = American Journal of Hematology | volume = 94 | issue = 11 | pages = 1266–1287 | date = November 2019 | pmid = 31364186 | doi = 10.1002/ajh.25595 | s2cid = 199000131 | doi-access = free }}</ref>

As of 2024, the recommended first-line treatments include:

# Bruton tyrosine kinase inhibitors ([[BTK inhibitor|BTKi]]), such as [[ibrutinib]], [[zanubrutinib]], and [[acalabrutinib]] 
# B-cell lymphoma-2 ([[Bcl-2|BCL-2]]) inhibitor, [[venetoclax]], plus a CD20 antibody [[obinutuzumab]], OR
# BTKi (i.e. ibrutinib) plus BCL-2 inhibitor (i.e. venetoclax)<ref>{{cite journal | vauthors = Patel K, Pagel JM | title = Current and future treatment strategies in chronic lymphocytic leukemia | journal = Journal of Hematology & Oncology | volume = 14 | issue = 1 | article-number = 69 | date = April 2021 | pmid = 33902665 | pmc = 8074228 | doi = 10.1186/s13045-021-01054-w | doi-access = free }}</ref><ref name=":15">{{Citation |last1=Schetelig |first1=Johannes |title=Chronic Lymphocytic Leukemia |date=2024 |work=The EBMT Handbook: Hematopoietic Cell Transplantation and Cellular Therapies |editor-last=Sureda |editor-first=Anna |url=https://www.ncbi.nlm.nih.gov/books/NBK608273/ |access-date=2025-01-22 |edition=8th |place=Cham (CH) |publisher=Springer |isbn=978-3-031-44079-3 |pmid=39437068 |last2=Dreger |first2=Peter |editor2-last=Corbacioglu |editor2-first=Selim |editor3-last=Greco |editor3-first=Raffaella |editor4-last=Kröger |editor4-first=Nicolaus}}</ref><ref name=":12" /><!-- Epidemiology and history -->

CLL is the most common type of leukemia in the Western world. It most commonly affects individuals over the age of 65, due to the accumulation of genetic mutations that occur over time.<ref name=SEER2017>{{cite web|title=Chronic Lymphocytic Leukemia – Cancer Stat Facts|url=https://seer.cancer.gov/statfacts/html/clyl.html|website=seer.cancer.gov|access-date=9 September 2022}}</ref><ref>{{Cite web|title=Genes and Cancer|url=https://cancer.ca/en/cancer-information/what-is-cancer/genes-and-cancer|url-status=live|archive-url=https://web.archive.org/web/20211116222602/https://cancer.ca/en/cancer-information/what-is-cancer/genes-and-cancer |archive-date=2021-11-16 }}</ref> CLL is rarely seen in individuals less than 40 years old.<ref name=":11">{{Cite web |title=Key Statistics for Chronic Lymphocytic Leukemia |url=https://www.cancer.org/cancer/types/chronic-lymphocytic-leukemia/about/key-statistics.html |access-date=2025-01-17 |website=www.cancer.org |language=en}}</ref> Men are more commonly affected than women, although the average lifetime risk for both genders are similar (around 0.5-1%).<ref name=":11" /><ref>{{cite journal | vauthors = Grywalska E, Zaborek M, Łyczba J, Hrynkiewicz R, Bębnowska D, Becht R, Sosnowska-Pasiarska B, Smok-Kalwat J, Pasiarski M, Góźdź S, Roliński J, Niedźwiedzka-Rystwej P | display-authors = 6 | title = Chronic Lymphocytic Leukemia-Induced Humoral Immunosuppression: A Systematic Review | journal = Cells | volume = 9 | issue = 11 | page = 2398 | date = November 2020 | pmid = 33147729 | pmc = 7693361 | doi = 10.3390/cells9112398 | doi-access = free }}</ref> It represented less than 1% of deaths from cancer between 1980 and 2015.<ref name="GBD2015De">{{cite journal |last1=Wang |first1=Haidong |last2=Naghavi |first2=Mohsen |last3=Allen |first3=Christine |last4=Barber |first4=Ryan M. |last5=Bhutta |first5=Zulfiqar A. |last6=Carter |first6=Austin |last7=Casey |first7=Daniel C. |last8=Charlson |first8=Fiona J. |last9=Chen |first9=Alan Zian |last10=Coates |first10=Matthew M. |last11=Coggeshall |first11=Megan |last12=Dandona |first12=Lalit |last13=Dicker |first13=Daniel J. |last14=Erskine |first14=Holly E. |last15=Ferrari |first15=Alize J. |display-authors=1 |date=October 2016 |title=Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980–2015: a systematic analysis for the Global Burden of Disease Study 2015 |journal=Lancet |volume=388 |issue=10053 |pages=1459–1544 |doi=10.1016/s0140-6736(16)31012-1 |pmc=5388903 |pmid=27733281 |last16=Fitzmaurice |first16=Christina |last17=Foreman |first17=Kyle |last18=Forouzanfar |first18=Mohammad H. |last19=Fraser |first19=Maya S. |last20=Fullman |first20=Nancy |last21=Gething |first21=Peter W. |last22=Goldberg |first22=Ellen M. |last23=Graetz |first23=Nicholas |last24=Haagsma |first24=Juanita A. |last25=Hay |first25=Simon I. |last26=Huynh |first26=Chantal |last27=Johnson |first27=Catherine O. |last28=Kassebaum |first28=Nicholas J. |last29=Kinfu |first29=Yohannes |last30=Kulikoff |first30=Xie Rachel}}</ref>
{{TOC limit|3}}

==Signs and symptoms==
Most people are diagnosed as having CLL based on the result of a routine blood test that shows a high [[white blood cell]] count, specifically a large increase in the number of circulating [[lymphocyte]]s.<ref name="Hall2018">{{cite journal | vauthors = Hallek M, Shanafelt TD, Eichhorst B | title = Chronic lymphocytic leukaemia | journal = Lancet | volume = 391 | issue = 10129 | pages = 1524–1537 | date = April 2018 | pmid = 29477250 | doi = 10.1016/S0140-6736(18)30422-7 | s2cid = 3517733 }}</ref> Most commonly, patients have no symptoms at first.<ref name="Hall2018" /> In a small number of cases, patients with CLL may present with enlarged [[lymph nodes]], partially in areas around the neck, armpit, or groin.<ref name="Hall2018" />  In rare circumstances, the disease is recognized only after the cancerous cells overwhelm the bone marrow, resulting in low red blood cells, neutrophils, or platelets.<ref name="Hall2018" /> This can then result in symptoms such as fever, easy bleeding/bruising, night sweats, weight loss, and increased tiredness.<ref name="Hall2018" /> In some instances, the cancerous cells can accumulate in the spleen and result in splenomegaly.<ref name=":10" />

===Complications===
About 25% of patients with CLL have very low levels of antibodies in their bloodstream ([[hypogammaglobulinemia]]) at diagnosis, with several more patients developing this throughout the course of their disease.<ref name=":18">{{Cite journal |last1=Gordon |first1=Max J. |last2=Ferrajoli |first2=Alessandra |date=November 2022 |title=Unusual complications in the management of chronic lymphocytic leukemia |url=https://onlinelibrary.wiley.com/doi/10.1002/ajh.26585 |journal=American Journal of Hematology |language=en |volume=97 |issue=S2 |pages=S26–S34 |doi=10.1002/ajh.26585 |pmid=35491515 |issn=0361-8609}}</ref> This decrease in antibodies increases the patient's risk of recurrent infections and other autoimmune complications, such as [[autoimmune hemolytic anemia]] and [[immune thrombocytopenia]].<ref name=":18" /> Autoimmune hemolytic anemia occurs in about 5-10% of CLL patients, which is when one's own immune system attacks its own red blood cells.<ref name=":18" />

A more serious complication called [[Richter's transformation]] (RT) occurs in 2-10% of patients with CLL.<ref name=":19">{{Cite journal |last1=Tadmor |first1=Tamar |last2=Levy |first2=Ilana |date=2021-10-14 |title=Richter Transformation in Chronic Lymphocytic Leukemia: Update in the Era of Novel Agents |journal=Cancers |language=en |volume=13 |issue=20 |page=5141 |doi=10.3390/cancers13205141 |doi-access=free |issn=2072-6694 |pmc=8533993 |pmid=34680290}}</ref> This is a process in which the original CLL cells convert to a far more aggressive disease that has the biology and histopathology of [[diffuse large B cell lymphoma]] or less commonly [[Hodgkin's lymphoma]].<ref name="pmid35384590">{{cite journal | vauthors = Sigmund AM, Kittai AS | title = Richter's Transformation | journal = Current Oncology Reports | volume = 24 | issue = 8 | pages = 1081–1090 | date = August 2022 | pmid = 35384590 | doi = 10.1007/s11912-022-01274-4 | s2cid = 247975378 | url = }}</ref><ref name=":19" /> These patients typically present with a sudden clinical deterioration that can be characterized by unexplained fevers or weight loss, asymmetric and rapid growth of lymph nodes, and/or a significant drop in the number of white blood cells, red blood cells, or platelets.<ref name=":19" /> Treatment for RT typically consists of various chemotherapy/chemo-immunotherapy protocols.<ref name=":19" />

CLL has also been reported to convert into other more aggressive diseases such as [[lymphoblastic lymphoma]], [[hairy cell leukemia]], high grade [[T cell lymphoma]]s,<ref name="pmid36012912">{{cite journal | vauthors = D'Addona M, Giudice V, Pezzullo L, Ciancia G, Baldi C, Gorrese M, Bertolini A, Campana A, Fresolone L, Manzo P, Zeppa P, Serio B, Selleri C | title = Hodgkin Lymphoma and Hairy Cell Leukemia Arising from Chronic Lymphocytic Leukemia: Case Reports and Literature Review | journal = Journal of Clinical Medicine | volume = 11 | issue = 16 | date = August 2022 | page = 4674 | pmid = 36012912 | pmc = 9410146 | doi = 10.3390/jcm11164674 | url = | doi-access = free }}</ref> [[acute myeloid leukemia]],<ref name="pmid32162729">{{cite journal | vauthors = Liu H, Miao Y, Ferrajoli A, Tang G, McDonnell T, Medeiros LJ, Hu S | title = Leukemic phase of Richter transformation: A mimic of acute myeloid leukemia that responded to Ibrutinib monotherapy | journal = American Journal of Hematology | volume = 95| issue = 10| pages = 1221–1223| date = March 2020 | pmid = 32162729 | doi = 10.1002/ajh.25782 | s2cid = 212677249 | url = | doi-access = free }}</ref> lung cancer, brain cancer, [[melanoma]] of the eye or skin,<ref name="pmid33739791">{{cite journal | vauthors = Trimech M, Letourneau A, Missiaglia E, De Prijck B, Nagy-Hulliger M, Somja J, Vivario M, Gaulard P, Lambert F, Bisig B, de Leval L | title = Angioimmunoblastic T-Cell Lymphoma and Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: A Novel Form of Composite Lymphoma Potentially Mimicking Richter Syndrome | journal = The American Journal of Surgical Pathology | volume = 45 | issue = 6 | pages = 773–786 | date = June 2021 | pmid = 33739791 | doi = 10.1097/PAS.0000000000001646 | hdl = 2268/289883 | s2cid = 232301854 | url = | hdl-access = free }}</ref><ref name="pmid1512794">{{cite journal | vauthors = Travis LB, Curtis RE, Hankey BF, Fraumeni JF | title = Second cancers in patients with chronic lymphocytic leukemia | journal = Journal of the National Cancer Institute | volume = 84 | issue = 18 | pages = 1422–7 | date = September 1992 | pmid = 1512794 | doi = 10.1093/jnci/84.18.1422 | url = }}</ref> [[salivary gland tumor]]s, and [[Kaposi's sarcoma]]s.<ref name="pmid31570695">{{cite journal | vauthors = Kumar V, Ailawadhi S, Bojanini L, Mehta A, Biswas S, Sher T, Roy V, Vishnu P, Marin-Acevedo J, Alegria VR, Paulus A, Aulakh S, Iqbal M, Manochakian R, Tan W, Chanan-Khan A, Ailawadhi M | title = Trends in the risk of second primary malignancies among survivors of chronic lymphocytic leukemia | journal = Blood Cancer Journal | volume = 9 | issue = 10 | article-number = 75 | date = September 2019 | pmid = 31570695 | pmc = 6768881 | doi = 10.1038/s41408-019-0237-1 | url = }}</ref> While some of these conversions have been termed RTs, the World Health Organization<ref name="pmid27345622">{{cite journal | vauthors = Soilleux EJ, Wotherspoon A, Eyre TA, Clifford R, Cabes M, Schuh AH | title = Diagnostic dilemmas of high-grade transformation (Richter's syndrome) of chronic lymphocytic leukaemia: results of the phase II National Cancer Research Institute CHOP-OR clinical trial specialist haemato-pathology central review | journal = Histopathology | volume = 69 | issue = 6 | pages = 1066–1076 | date = December 2016 | pmid = 27345622 | doi = 10.1111/his.13024 | s2cid = 205171057 | url = }}</ref> and most reviews<ref name="pmid35384590" /> have defined RT as a conversion of CLL/SLL into a disease with DLBCL or HL histopathology.<ref>{{cite journal | vauthors = Tsimberidou AM, Keating MJ | title = Richter syndrome: biology, incidence, and therapeutic strategies | journal = Cancer | volume = 103 | issue = 2 | pages = 216–228 | date = January 2005 | pmid = 15578683 | doi = 10.1002/cncr.20773 | s2cid = 21552054 | doi-access = free }}</ref>

Gastrointestinal (GI) involvement can also rarely occur with chronic lymphocytic leukemia.<ref name=":18" /> Some of the reported manifestations include [[Intussusception (medical disorder)|intussusception]], small intestinal bacterial contamination, colitis, and bleeding.<ref name=":18" /> Usually, GI complications with CLL occur after [[Richter's transformation|Richter transformation]].  Two cases to date have been reported of GI involvement in chronic lymphocytic leukemia without Richter's transformation.<ref>Bitetto AM, Lamba G, Cadavid G, Shah D, Forlenza T, Rotatori F, Rafiyath SM. Colonic perforation secondary to chronic lymphocytic leukemia infiltration without [[Richter's transformation|Richter transformation]]. Leuk Lymphoma. 2011 May;52(5):930-3.</ref>

==Causes==
The exact cause of CLL is unknown. However, family history has been strongly correlated with the development of disease.<ref name=":10" /> Environmental factors may also play a role in the development of CLL.<ref name=":10" /> For instance, exposure to [[Agent Orange]] increases the risk of CLL, and exposure to [[hepatitis C virus]] may increase the risk.<ref name="Strati2018">{{cite journal | vauthors = Strati P, Jain N, O'Brien S | title = Chronic Lymphocytic Leukemia: Diagnosis and Treatment | journal = Mayo Clinic Proceedings | volume = 93 | issue = 5 | pages = 651–664 | date = May 2018 | pmid = 29728204 | doi = 10.1016/j.mayocp.2018.03.002 | type = Review | doi-access = free }}</ref>  There is no clear association between ionizing radiation exposure and the risk of developing CLL.<ref name="Strati2018" /> Blood transfusions have been ruled out as a risk factor.<ref name="Nature2017" />

== Mechanism ==
[[File:Diagram showing the cells CLL afects CRUK 296.svg|thumb|A diagram showing the cells affected by CLL]]CLL results from an unusual growth and expansion of white blood cells. This manifestation typically begins with a single [[hematopoietic stem cell]] that acquires certain [[mutation]]s over time that allows it to continue to expand and grow at a faster rate than other cells.<ref name=":13">{{cite journal |vauthors=Delgado J, Nadeu F, Colomer D, Campo E |date=September 2020 |title=Chronic lymphocytic leukemia: from molecular pathogenesis to novel therapeutic strategies |journal=Haematologica |volume=105 |issue=9 |pages=2205–2217 |doi=10.3324/haematol.2019.236000 |pmc=7556519 |pmid=33054046}}</ref> Each patient with CLL may be affected by a different set of mutations, making these cells sometimes difficult to target and treat. Some of the most common mutations that have been found in CLL-affected cells include the following: ''NOTCH1'', ''TP53'', ''ATM'', and ''SF3B1''.<ref name=":13" />

CLL can also be caused by a number of [[Epigenetics|epigenetic changes]], which are adaptations that add a tag to specific DNA sequences, rather than altering the sequence itself. In CLL, these changes can be classified into the addition of three different methyl subgroups (naïve B-cell-like, memory B-cell-like, and intermediate), which impact how much that DNA sequence is transcribed.<ref>{{cite journal |vauthors=Jarošová M, Plevová K, Kotašková J, Doubek M, Pospíšilová Š |date=October 2019 |title=The importance of complex karyotype in prognostication and treatment of chronic lymphocytic leukemia (CLL): a comprehensive review of the literature |journal=Leukemia & Lymphoma |volume=60 |issue=10 |pages=2348–2355 |doi=10.1080/10428194.2019.1576038 |pmid=30773964 |s2cid=73483725}}</ref><ref name=":0">{{Cite book |title=WHO classification of tumours of haematopoietic and lymphoid tissues |vauthors=Swerdlow SH |publisher=World Health Organization,, International Agency for Research on Cancer |year=2017 |isbn=978-92-832-4494-3 |edition=Revised 4th |location=Lyon |page=219 |oclc=1011064243}}</ref> Some relevant genetic mutations may be inherited. Since there is no one single mutation that is associated with CLL in all cases, an individual's susceptibility may be impacted when multiple mutations that are associated with an increase in the risk of CLL are co-inherited.<ref name=":1">{{cite journal |vauthors=Sava GP, Speedy HE, Houlston RS |date=January 2014 |title=Candidate gene association studies and risk of chronic lymphocytic leukemia: a systematic review and meta-analysis |journal=Leukemia & Lymphoma |volume=55 |issue=1 |pages=160–167 |doi=10.3109/10428194.2013.800197 |pmid=23647060 |s2cid=207510537}}</ref> Up until 2020, 45 susceptibility loci have been identified. Of these loci, 93% are linked to the alteration of 30 gene expressions involved in immune response, cell survival, or Wnt signaling.<ref name=":13" />

As CLL cells accumulate, they begin to promote inflammation and an immunosuppressive environment through the release of different chemical signals.<ref name=":13" />

CLL is commonly preceded by a pre-cancerous state known as [[monoclonal B-cell lymphocytosis]] (MBL).<ref name=":13" /> This occurs when there is in an increase in a specific type of white blood cells but the number remains less than 5 billion cells per liter (L) (5 billion/L) of blood.<ref name=":13" /> This subtype, termed chronic lymphocytic leukemia-type MBL (CLL-type MBL) is an asymptomatic, indolent, and chronic disorder in which people exhibit a mild increase in the number of circulating [[B-cell]] lymphocytes. These B-cells are [[monoclonal]], which means they are produced by a single ancestral B-cell. They share some of the same cell marker proteins, [[Chromosomal abnormality|chromosome abnormalities]], and [[Mutation|gene mutations]] that are found in CLL.<ref name="pmid30573042">{{cite journal |vauthors=Jaffe ES |date=January 2019 |title=Diagnosis and classification of lymphoma: Impact of technical advances |journal=Seminars in Hematology |volume=56 |issue=1 |pages=30–36 |doi=10.1053/j.seminhematol.2018.05.007 |pmc=7394061 |pmid=30573042 |doi-access=free}}</ref><ref name="pmid30268574">{{cite journal |vauthors=Angelillo P, Capasso A, Ghia P, Scarfò L |date=December 2018 |title=Monoclonal B-cell lymphocytosis: Does the elderly patient need a specialistic approach? |journal=European Journal of Internal Medicine |volume=58 |pages=2–6 |doi=10.1016/j.ejim.2018.09.006 |pmid=30268574 |s2cid=52892403}}</ref>

CLL-type MBL can be separated into two groups:

# Low-count MBL has monoclonal B-cell blood counts of <0.5 billion cells/[[liter]] (i.e. 0.5 billion/L) 
# High-count MBL has blood monoclonal B-cell counts ≥0.5 billion/L but <5 billion/L.<ref name="pmid30855005">{{cite journal |vauthors=Tresckow JV, Eichhorst B, Bahlo J, Hallek M |date=January 2019 |title=The Treatment of Chronic Lymphatic Leukemia |journal=Deutsches Ärzteblatt International |volume=116 |issue=4 |pages=41–46 |doi=10.3238/arztebl.2019.0041 |pmc=6415618 |pmid=30855005}}</ref>

Low-count MBL rarely if ever progresses to CLL, while high-count CLL/SLL MBL does so at a rate of around 1% per year.<ref name=":13" /> Thus, CLL may present in individuals with a long history of having high-count MBL. There is no established treatment for these individuals except monitoring for development of the disorder's various complications (see [[Monoclonal B-cell lymphocytosis#Treatment|treatment of MBL complications]]) and for their progression to CLL.<ref name="pmid30308438">{{cite journal |vauthors=Choi SM, O'Malley DP |date=December 2018 |title=Diagnostically relevant updates to the 2017 WHO classification of lymphoid neoplasms |journal=Annals of Diagnostic Pathology |volume=37 |pages=67–74 |doi=10.1016/j.anndiagpath.2018.09.011 |pmid=30308438 |s2cid=52963674}}</ref><ref name="Hall2017">{{cite journal |vauthors=Hallek M |date=September 2017 |title=Chronic lymphocytic leukemia: 2017 update on diagnosis, risk stratification, and treatment |journal=American Journal of Hematology |volume=92 |issue=9 |pages=946–965 |doi=10.1002/ajh.24826 |pmid=28782884 |doi-access=free}}</ref>

==Diagnosis==
[[File:Chronic lymphocytic leukemia - high mag.jpg|thumb|[[Micrograph]] of a lymph node affected by B-CLL showing a characteristic proliferation center (right of image), composed of larger, lighter-staining, cells, [[H&E stain]]]]
The diagnosis of CLL is based on the demonstration of an abnormal population of B lymphocytes in the blood, bone marrow, or tissues that display an unusual but characteristic pattern of molecules on the cell surface. CLL is usually first suspected by a diagnosis of [[lymphocytosis]], an increase in a type of white blood cell, on a [[complete blood count]] test. This frequently is an incidental finding on a routine physician visit. Most often the lymphocyte count is greater than 5000 cells per microliter (μL) of blood but can be much higher.<ref name=Hall2017/> The presence of lymphocytosis in a person who is elderly should raise strong suspicion for CLL, and a confirmatory diagnostic test, in particular [[flow cytometry]] should be performed unless clinically unnecessary.<ref>{{cite web |url=https://www.lecturio.com/concepts/chronic-lymphocytic-leukemia/| title=Chronic Lymphocytic Leukemia
|website=The Lecturio Medical Concept Library |access-date= 9 July 2021}}</ref>

=== Classification ===
In order to be diagnosed with CLL, the patient must have a white blood cell count greater than 5 billion cells per liter (L) (5 billion/L) of blood. If CLL-type cells are mainly found in the lymph nodes or lymphoid tissue (such as the spleen), a diagnosis of '''small lymphocytic lymphoma (SLL)''' is made.<ref name=":14">{{cite journal |display-authors=6 |vauthors=Kreuzberger N, Damen JA, Trivella M, Estcourt LJ, Aldin A, Umlauff L, Vazquez-Montes MD, Wolff R, Moons KG, Monsef I, Foroutan F, Kreuzer KA, Skoetz N |date=July 2020 |title=Prognostic models for newly-diagnosed chronic lymphocytic leukaemia in adults: a systematic review and meta-analysis |journal=The Cochrane Database of Systematic Reviews |volume=2020 |issue=7 |article-number=CD012022 |doi=10.1002/14651858.CD012022.pub2 |pmc=8078230 |pmid=32735048}}</ref> When these cancerous cells appear mostly in the blood, the disease is classified as CLL.<ref name=":14" /><ref name=":3">{{cite journal |vauthors=Rai KR, Jain P |date=March 2016 |title=Chronic lymphocytic leukemia (CLL)-Then and now |journal=American Journal of Hematology |volume=91 |issue=3 |pages=330–340 |doi=10.1002/ajh.24282 |pmid=26690614 |doi-access=free}}</ref>

===Clinical staging===

Staging, which helps determine the extent of the disease, is done using one of two systems: the Rai staging system (most commonly used in the United States)<ref name="Woyach_2021">{{Citation |last1=Woyach |first1=Jennifer A. |title=Chronic Lymphocytic Leukemia |date=2022 |work=Harrison's Principles of Internal Medicine |editor-last=Loscalzo |editor-first=J |url=http://accessmedicine.mhmedical.com/content.aspx?aid=1156754614 |access-date=2023-01-29 |edition=21 |place=New York, NY |publisher=McGraw-Hill Education |last2=Byrd |first2=John C. |editor2-last=Fauci |editor2-first=Anthony S. |editor3-last=Kasper |editor3-first=Dennis L. |editor4-last=Hauser |editor4-first=Stephen L. |editor5-last=Longo |editor5-first=D |editor6-last=Jameson |editor6-first=J}}</ref> or the Binet classification(most commonly used in Europe).<ref name="Woyach_2021" /><ref name="NCI2017Pt" /><ref name=":16">{{Cite journal |last1=Hallek |first1=Michael |last2=Al-Sawaf |first2=Othman |date=2021 |title=Chronic lymphocytic leukemia: 2022 update on diagnostic and therapeutic procedures |journal=American Journal of Hematology |language=en |volume=96 |issue=12 |pages=1679–1705 |doi=10.1002/ajh.26367 |pmid=34625994 |issn=1096-8652|doi-access=free }}</ref> These systems are simple, requiring the use of only physical examination and blood test results.<ref name=":16" />

==== Rai staging system<ref name=":16" /> ====
* <u>Low-risk disease</u> ''(formerly Stage 0)'': characterized by lymphocytosis with cancer cells in the blood and/or bone marrow without [[lymphadenopathy]], [[hepatosplenomegaly]], [[anemia]], or [[thrombocytopenia]]
* <u>Intermediate-risk disease</u> ''(formerly Stage I/II)'': characterized by lymphocytosis, swollen lymph nodes (may be palpable or not), spleen enlargement, and/or liver enlargement  
* <u>High-risk disease</u> ''(formerly Stage III/IV)'': characterized by lymphocytosis with associated anemia (hemoglobin <11 g/dL) OR thrombocytopenia (<100,000/mm<sup>3</sup>) with or without lymphadenopathy, hepatomegaly, splenomegaly, or anemia

==== Binet classification<ref>{{cite journal |display-authors=6 |vauthors=Binet JL, Auquier A, Dighiero G, Chastang C, Piguet H, Goasguen J, Vaugier G, Potron G, Colona P, Oberling F, Thomas M, Tchernia G, Jacquillat C, Boivin P, Lesty C, Duault MT, Monconduit M, Belabbes S, Gremy F |date=July 1981 |title=A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis |journal=Cancer |volume=48 |issue=1 |pages=198–206 |doi=10.1002/1097-0142(19810701)48:1<198::aid-cncr2820480131>3.0.co;2-v |pmid=7237385 |s2cid=38619478 |doi-access=}}</ref> ====
This classification system is based on the number of areas within the body that have been affected and the presence of anemia or thrombocytopenia.<ref name=":16" /> Areas of involvement include the (1) head and neck (considered one), (2) one or both of the armpits, (3) the groin, (4) the spleen, and (5) the liver.<ref name=":16" /> They are considered affected if a lymph node greater than 1&nbsp;cm in diameter is present and/or the spleen or liver are palpable.<ref name=":16" />
* ''Clinical stage A'': characterized by no anemia (Hb <u>></u> 10 g/dL) or thrombocytopenia (platelets <u>></u> 100 billion/L) and no greater than two areas of lymphoid involvement (described above)  
* ''Clinical stage B'': characterized by no anemia (Hb <u>></u> 10 g/dL) or thrombocytopenia (platelets <u>></u> 100 billion/L) with three or more areas of lymphoid involvement 
* ''Clinical stage C'': characterized by anemia (Hb < 10 g/dL) and/or thrombocytopenia (platelets < 100 billion/L) regardless of the number of areas of lymph node or organ enlargement

====Array-based karyotyping====
{{Main|Virtual karyotype}}

Array-based karyotyping is a cost-effective alternative to [[Fluorescence in situ hybridization|FISH]] for detecting chromosomal abnormalities in CLL. Several clinical validation studies have shown >95% concordance with the standard CLL FISH panel.<ref>{{cite journal |display-authors=6 |vauthors=Lehmann S, Ogawa S, Raynaud SD, Sanada M, Nannya Y, Ticchioni M, Bastard C, Kawamata N, Koeffler HP |date=March 2008 |title=Molecular allelokaryotyping of early-stage, untreated chronic lymphocytic leukemia |journal=Cancer |volume=112 |issue=6 |pages=1296–1305 |doi=10.1002/cncr.23270 |pmid=18246537 |s2cid=205651767 |doi-access=free}}</ref><ref>{{cite journal |display-authors=6 |vauthors=Sargent R, Jones D, Abruzzo LV, Yao H, Bonderover J, Cisneros M, Wierda WG, Keating MJ, Luthra R |date=January 2009 |title=Customized oligonucleotide array-based comparative genomic hybridization as a clinical assay for genomic profiling of chronic lymphocytic leukemia |journal=The Journal of Molecular Diagnostics |volume=11 |issue=1 |pages=25–34 |doi=10.2353/jmoldx.2009.080037 |pmc=2607562 |pmid=19074592}}</ref><ref>{{cite journal |display-authors=6 |vauthors=Schwaenen C, Nessling M, Wessendorf S, Salvi T, Wrobel G, Radlwimmer B, Kestler HA, Haslinger C, Stilgenbauer S, Döhner H, Bentz M, Lichter P |date=January 2004 |title=Automated array-based genomic profiling in chronic lymphocytic leukemia: development of a clinical tool and discovery of recurrent genomic alterations |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=101 |issue=4 |pages=1039–1044 |bibcode=2004PNAS..101.1039S |doi=10.1073/pnas.0304717101 |pmc=327147 |pmid=14730057 |doi-access=free}}</ref><ref>{{cite journal |display-authors=6 |vauthors=Pfeifer D, Pantic M, Skatulla I, Rawluk J, Kreutz C, Martens UM, Fisch P, Timmer J, Veelken H |date=February 2007 |title=Genome-wide analysis of DNA copy number changes and LOH in CLL using high-density SNP arrays |journal=Blood |volume=109 |issue=3 |pages=1202–1210 |doi=10.1182/blood-2006-07-034256 |pmid=17053054 |doi-access=free}}</ref><ref>{{cite journal |display-authors=6 |vauthors=Gunn SR, Mohammed MS, Gorre ME, Cotter PD, Kim J, Bahler DW, Preobrazhensky SN, Higgins RA, Bolla AR, Ismail SH, de Jong D, Eldering E, van Oers MH, Mellink CH, Keating MJ, Schlette EJ, Abruzzo LV, Robetorye RS |date=September 2008 |title=Whole-genome scanning by array comparative genomic hybridization as a clinical tool for risk assessment in chronic lymphocytic leukemia |journal=The Journal of Molecular Diagnostics |volume=10 |issue=5 |pages=442–451 |doi=10.2353/jmoldx.2008.080033 |pmc=2518739 |pmid=18687794}}</ref>

=== Molecular examination of peripheral blood and flow cytometry ===
The combination of the microscopic examination of the peripheral blood and analysis of the lymphocytes by [[flow cytometry]] to confirm clonality and molecular expression is needed to establish the diagnosis of CLL.<ref name=":20">{{Cite journal |last1=Didehban |first1=Shiva |last2=Jafari |first2=Elham |last3=Hosseini |first3=Ali |last4=Khorasani |first4=Parisa |date=2024 |title=Evaluation of the Findings of Peripheral Blood Smear, Bone Marrow Aspiration and Biopsy, Iron Storage, and Immunophenotype in Patients with Chronic Lymphocytic Leukemia |journal=Iranian Journal of Pathology |volume=19 |issue=2 |pages=152–159 |doi=10.30699/IJP.2024.2011275.3170 |issn=1735-5303 |pmc=11304456 |pmid=39118798}}</ref> Both are easily accomplished with a small sample of blood.

A [[flow cytometer]] instrument can examine the expression of molecules on individual cells. This requires the use of specific antibodies to cell-surface molecules that have fluorescent tags that are recognized by the instrument.<ref>{{Cite journal |last1=Cossarizza |first1=Andrea |last2=Chang |first2=Hyun-Dong |last3=Radbruch |first3=Andreas |last4=Abrignani |first4=Sergio |last5=Addo |first5=Richard |last6=Akdis |first6=Mübeccel |last7=Andrä |first7=Immanuel |last8=Andreata |first8=Francesco |last9=Annunziato |first9=Francesco |last10=Arranz |first10=Eduardo |last11=Bacher |first11=Petra |last12=Bari |first12=Sudipto |last13=Barnaba |first13=Vincenzo |last14=Barros-Martins |first14=Joana |last15=Baumjohann |first15=Dirk |date=December 2021 |title=Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition) |journal=European Journal of Immunology |volume=51 |issue=12 |pages=2708–3145 |doi=10.1002/eji.202170126 |issn=1521-4141 |pmc=11115438 |pmid=34910301}}</ref> In CLL, the lymphocytes are all genetically identical since they are derived from the same B cell lineage. CLL cells can express the typical B-cell markers such as CD19 and CD20, as well as abnormal surface markers such as CD5 and CD23.<ref name="Strati2018" />

On a peripheral blood smear, CLL cells resemble normal lymphocytes, although slightly smaller. They are also very fragile and susceptible to breaking when smeared onto a glass slide, giving rise to "smudge" or "smear" cells, which are a hallmark of the disease.<ref name=":20" /><ref name="isbn1-4051-4265-0">{{cite book|author=Bain, Barbara J.|url=https://archive.org/details/bloodcellspracti00bain|title=Blood Cells: A Practical Guide|publisher=Blackwell Publishing Limited|year=2006|isbn=978-1-4051-4265-6|page=[https://archive.org/details/bloodcellspracti00bain/page/n449 439]|url-access=limited}}</ref> Smudge cells are a result of CLL cells lacking [[vimentin]], a type of [[cytoskeleton]] proteins which is a structural component in a cell which maintains the cell's internal shape and mechanical resilience).<ref name="Wintrobe">{{cite book|title=Wintrobe's clinical hematology|date=2014|publisher=Lippincott Williams & Wilkins|isbn=978-1-4511-7268-3|editor1-last=Greer|editor1-first=John P.|edition=Thirteenth|editor2-last=Arber|editor2-first=Daniel A.|editor3-last=Glader|editor3-first=Bertil|editor4-last=List|editor4-first=Alan F.|editor5-last=Means Jr.|editor5-first=Robert T.|editor6-last=Paraskevas|editor6-first=Frixos|editor7-last=Rodgers|editor7-first=George M.|editor8-last=Foerster|editor8-first=John|name-list-style=vanc}}</ref>{{rp|1899}}<ref>{{cite journal|vauthors=Patteson AE, Carroll RJ, Iwamoto DV, Janmey PA|date=December 2020|title=The vimentin cytoskeleton: when polymer physics meets cell biology|journal=Physical Biology|volume=18|issue=1|page=011001|doi=10.1088/1478-3975/abbcc2 |pmc=8240483 |pmid=32992303}}</ref>[[File:Smear cells.jpg|thumb|right|Smudge cells in peripheral blood]]

=== Surface markers ===
The atypical molecular pattern on the surface of the cell includes the co-expression of cell surface markers [[cluster of differentiation|clusters of differentiation]] [[CD5 (protein)|5]] (CD5) and [[CD23|23]]. In addition, all the CLL cells within one individual are [[clonal selection|clonal]], that is, genetically identical. In practice, this is inferred by the detection of only one of the mutually exclusive [[Immunoglobulin light chain|antibody light chains]], kappa or lambda, on the entire population of the abnormal B cells. Normal B lymphocytes consist of a stew of different antibody-producing cells, resulting in a mixture of both kappa- and lambda-expressing cells. The lack of the normal distribution of these B cells is one basis for demonstrating [[clonality]], the key element for establishing a diagnosis of any B cell malignancy (B cell [[non-Hodgkin lymphoma]]).<ref>{{cite journal | pmid=27169754 | year=2016 | last1=Roepman | first1=P. | last2=Boots | first2=C. M. | last3=Scheidel | first3=K. C. | last4=Sprong | first4=T. | last5=De Bruin | first5=P. | last6=De Weerdt | first6=O. | last7=Groenen | first7=P. J. | last8=Kummer | first8=J. A. | title=Molecular clonality assessment shows high performance to predict malignant B-cell non-Hodgkin's lymphoma using cytological smears | journal=Journal of Clinical Pathology | volume=69 | issue=12 | pages=1109–1115 | doi=10.1136/jclinpath-2016-203757 | s2cid=30952923 }}</ref> The Matutes's CLL score allows the identification of a homogeneous subgroup of classical CLL, that differs from atypical/mixed CLL for the five markers' expression (CD5, CD23, [[FMC7]], CD22, and immunoglobulin light chain)
Matutes's CLL scoring system is very helpful for the differential diagnosis between classical CLL and the other B cell chronic lymphoproliferative disorders, but not for the immunological distinction between mixed/atypical CLL and [[mantle cell lymphoma]] (MCL malignant B cells).<ref name="pmid7523797">{{cite journal | vauthors = Matutes E, Owusu-Ankomah K, Morilla R, Garcia Marco J, Houlihan A, Que TH, Catovsky D | title = The immunological profile of B-cell disorders and proposal of a scoring system for the diagnosis of CLL | journal = Leukemia | volume = 8 | issue = 10 | pages = 1640–1645 | date = October 1994 | pmid = 7523797 }}</ref> Discrimination between CLL and MCL can be improved by adding non-routine markers such as CD54<ref name="CD54">{{cite journal | vauthors = Deans JP, Polyak MJ | title = FMC7 is an epitope of CD20 | journal = Blood | volume = 111 | issue = 4 | pages = 2492; author reply 2493-2492; author reply 2494 | date = February 2008 | pmid = 18263793 | doi = 10.1182/blood-2007-11-126243 | doi-access = free }}</ref> and CD200.<ref name="CD200">{{cite journal | vauthors = Palumbo GA, Parrinello N, Fargione G, Cardillo K, Chiarenza A, Berretta S, Conticello C, Villari L, Di Raimondo F | display-authors = 6 | title = CD200 expression may help in differential diagnosis between mantle cell lymphoma and B-cell chronic lymphocytic leukemia | journal = Leukemia Research | volume = 33 | issue = 9 | pages = 1212–1216 | date = September 2009 | pmid = 19230971 | doi = 10.1016/j.leukres.2009.01.017 }}</ref> Among routine markers, the most discriminating feature is the CD20/CD23 mean fluorescence intensity ratio. FMC7 expression can be misleading for borderline cases.<ref name="MCL-CLL">{{cite journal | vauthors = Zare H, Bashashati A, Kridel R, Aghaeepour N, Haffari G, Connors JM, Gascoyne RD, Gupta A, Brinkman RR, Weng AP | display-authors = 6 | title = Automated analysis of multidimensional flow cytometry data improves diagnostic accuracy between mantle cell lymphoma and small lymphocytic lymphoma | journal = American Journal of Clinical Pathology | volume = 137 | issue = 1 | pages = 75–85 | date = January 2012 | pmid = 22180480 | pmc = 4090220 | doi = 10.1309/AJCPMMLQ67YOMGEW }}</ref>

===Related diseases===

In the past, cases with similar microscopic appearance in the blood but with a T cell phenotype were referred to as T-cell CLL. However, these are now recognized as a separate disease group and are currently classified as [[T-cell prolymphocytic leukemia]]s (T-PLL).<ref>{{cite web|url=http://www.accessmedicine.com/content.aspx?aid=2149838 |title=T Cell Prolymphocytic Leukemia |publisher=AccessMedicine |access-date=2009-02-04 |archive-url=https://web.archive.org/web/20110707080329/http://www.accessmedicine.com/content.aspx?aid=2149838 |archive-date=2011-07-07 }}</ref><ref name="pmid10442186">{{cite journal | vauthors = Ascani S, Leoni P, Fraternali Orcioni G, Bearzi I, Piccioli M, Materazzi M, Zinzani PL, Gherlinzoni F, Falini B, Pileri SA | display-authors = 6 | title = T-cell prolymphocytic leukaemia: does the expression of CD8+ phenotype justify the identification of a new subtype? Description of two cases and review of the literature | journal = Annals of Oncology | volume = 10 | issue = 6 | pages = 649–653 | date = June 1999 | pmid = 10442186 | doi = 10.1023/A:1008349422735 | doi-access = free }}</ref> An accurate diagnosis of T-PLL is important as it is a rare and aggressive disease.<ref>{{cite journal | vauthors = Sud A, Dearden C | title = T-cell Prolymphocytic Leukemia | journal = Hematology/Oncology Clinics of North America | volume = 31 | issue = 2 | pages = 273–283 | date = April 2017 | pmid = 28340878 | doi = 10.1016/j.hoc.2016.11.010 }}</ref>

CLL should not be confused with [[acute lymphoblastic leukemia]], a highly aggressive leukemia most commonly diagnosed in children, and highly treatable in the pediatric setting.

===Differential diagnosis===
{| class="wikitable"
|-
! Lymphoid disorders that can present as chronic leukemia and can be confused with typical B-cell chronic lymphoid leukemia<ref>{{cite book |title=Harrison's Principles of Internal Medicine |isbn=978-0-07-180216-1 |page=695 |edition=19 |chapter=Malignancies of Lymphoid Cells|last1=Kasper |first1=Dennis L. |last2=Fauci |first2=Anthony S. |last3=Hauser |first3=Stephen L. |last4=Longo |first4=Dan L. |last5=Larry Jameson |first5=J. |last6=Loscalzo |first6=Joseph |date=17 April 2015 |publisher=McGraw Hill Professional }}</ref>
|-
| [[Follicular lymphoma]]
|-
| [[Splenic marginal zone lymphoma]]
|-
| [[Nodal marginal zone B cell lymphoma]]
|-
| [[Mantle cell lymphoma]]
|-
| [[Hairy cell leukemia]]
|-
| [[Prolymphocytic leukemia]] (B cell or T cell)
|-
| [[Lymphoplasmacytic lymphoma]]
|-
| [[Sézary syndrome]]
|-
| Smoldering [[adult T cell leukemia/lymphoma]]
|}

Hematologic disorders that may resemble CLL in their clinical presentation, behavior, and microscopic appearance include mantle cell lymphoma, marginal zone lymphoma, B cell prolymphocytic leukemia, and lymphoplasmacytic lymphoma.
* [[B cell prolymphocytic leukemia]], a related, but more aggressive disorder, has cells with similar phenotype, but are significantly larger than normal lymphocytes and have a prominent nucleolus. The distinction is important as the prognosis and therapy differ from CLL.<ref>{{Cite web|url=https://icgc.org/icgc/cgp/64/355/1026091|title=France – Lymphoproliferative Syndrome B-Cell Prolymphocytic Leukemia {{!}}|website=icgc.org|access-date=2016-11-18}}</ref>
* [[Hairy cell leukemia]] is also a neoplasm of B lymphocytes, but the neoplastic cells have a distinct morphology under the microscope (hairy cell leukemia cells have delicate, hair-like projections on their surfaces) and unique marker molecule expression.<ref>{{cite web |url=https://www.lecturio.com/concepts/hairy-cell-leukemia/| title=Hairy Cell Leukemia|website=The Lecturio Medical Concept Library |access-date= 24 July 2021}}</ref>

All the B cell malignancies of the blood and bone marrow can be differentiated from one another by the combination of cellular microscopic morphology, marker molecule expression, and specific tumor-associated gene defects. This is best accomplished by evaluation of the patient's blood, bone marrow, and occasionally lymph node cells by a [[pathologist]] with specific training in blood disorders. A flow cytometer is necessary for cell marker analysis, and the detection of genetic problems in the cells may require visualizing the DNA changes with fluorescent probes by [[fluorescent in situ hybridization|FISH]].<ref>{{cite journal | vauthors = Langer-Safer PR, Levine M, Ward DC | title = Immunological method for mapping genes on Drosophila polytene chromosomes | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 79 | issue = 14 | pages = 4381–4385 | date = July 1982 | pmid = 6812046 | pmc = 346675 | doi = 10.1073/pnas.79.14.4381 | doi-access = free | bibcode = 1982PNAS...79.4381L }}</ref>

==Treatment==
CLL treatment focuses on controlling and limiting the progress of the disease and its symptoms, as it remains incurable {{as of|2017|lc=yes}}. In patients with few to no symptoms, [[watchful waiting]] with close observation is generally appropriate.<ref name="NCI2017Pt" />

Treatment is recommended when patients become symptomatic or experience one of the following:

* Dangerous drops in their red blood cell or platelet count
* A doubling of their white blood cells in 6 months or less
* Significant splenomegaly 
* Severe swelling of the lymph nodes, and/or
* Richter transformation<ref name=":15" />

As of 2024, first-line treatment for CLL involves the use of targeted [[biological therapy]].<ref name=":15" /> Other treatment options include:  [[chemotherapy]], [[radiation therapy]], [[bone marrow transplantation]], and supportive or palliative care.<ref name=":15" />

Radiation therapy is usually only done in patients with SLL who have symptomatic localized disease, such as bulky lymph nodes.<ref name=":17">{{Cite web |title=NCCN Guidelines for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Version 1.2025 |url=https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1478 |access-date=2025-01-22 |website=National Comprehensive Cancer Network |language=en}}</ref> In special circumstances, patients can develop massive splenomegaly that may lead to the destruction of red blood cells, white blood cells, and platelets.<ref name=":17" /> In these cases, the patient may be treated with steroids or IVIG; however, if the patient does not respond to these treatments, they may have to undergo a [[splenectomy]], removal of the spleen.<ref name=":17" />

CLL treatment regimens vary depending on the patient's age, physical health, and progression of their disease. There are several agents that may be used for the treatment of CLL.<ref name="NCI2017Pt" />

Treatment approaches for SLL and CLL are usually the same.<ref>{{Cite web |title=What Is Chronic Lymphocytic Leukemia? |url=https://www.cancer.org/cancer/types/chronic-lymphocytic-leukemia/about/what-is-cll.html |access-date=2025-11-04 |website=www.cancer.org |language=en}}</ref>

===Decision to treat===
While it is generally considered incurable, CLL progresses slowly in most cases. Many people with CLL lead normal and active lives for many years—in some cases for decades. Because of its slow onset, asymptomatic early-stage CLL (Rai 0, Binet A) is, in general, not treated since it is believed that early-stage CLL intervention does not improve survival time or quality of life. Instead, the condition is monitored over time to detect any change in the disease pattern.<ref name="NCI2017Pt" /><ref name=CTO>{{cite journal |author=Janssens |title=Rituximab for Chronic Lymphocytic Leukemia in Treatment-Naïve and Treatment-Experienced Patients |journal=Contemporary Oncology |volume=3 |issue=3 |pages=24–36 |year=2011 |url=http://www.onclive.com/publications/contemporary-oncology/2011/fall-2011/Rituximab-for-Chronic-Lymphocytic-Leukemia-in-Treatment-Nave-and-Treatment-Experienced-Patients|display-authors=etal}}</ref><ref name=":7">{{cite journal | vauthors = Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, Hillmen P, Keating M, Montserrat E, Chiorazzi N, Stilgenbauer S, Rai KR, Byrd JC, Eichhorst B, O'Brien S, Robak T, Seymour JF, Kipps TJ | display-authors = 6 | title = iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL | journal = Blood | volume = 131 | issue = 25 | pages = 2745–2760 | date = June 2018 | pmid = 29540348 | doi = 10.1182/blood-2017-09-806398 | s2cid = 206956090 | doi-access = free }}</ref>

There are two widely used staging systems in CLL to determine when and how to treat the patient: The Rai staging system, used in the United States, and the Binet system in Europe. Both these systems attempt to characterize the disease based on the bulk and marrow failure.<ref name="NCI2017Pt" /><ref name="Woyach_2021" />  A "watchful waiting" strategy is used for most patients with CLL.<ref name="Woyach_2021" />  The International Workshop on CLL (iwCLL) has issued guidelines with specific markers that should be met to initiate treatment, generally based on evidence for progressive symptomatic disease (summarized as "active disease").<ref name=":7" />

===Targeted biological therapy===

[[Targeted therapy]] attacks cancer cells at a specific target, with the aim of not harming normal cells. In patients with CLL, B-cell receptor (BCR) signaling appears to play a vital role in the growth and survival of CLL cells.<ref name=":16" /> BCR signaling is supported by a number of different tyrosine kinase inhibitors (such as BTK, PI3K, etc.), which can all be targeted in order to help interfere with the growth of these CLL cells.<ref name=":16" /> Another mechanism that CLL cells use to avoid destruction involves the use of proteins in the B-cell lymphoma (Bcl-2) family.<ref name=":16" /> By blocking the function of those Bcl-2 proteins, targeted drugs can prevent further progression of CLL-related tumors.<ref name=":16" />

Some of the most common biological drugs used to treat CLL include:

* [[Tyrosine kinase inhibitor|Bruton tyrosine kinase inhibitors]] (''including ibrutinib, acalabrutinib''',''' and zanubrutinib'')
* [[Bcl-2 inhibitor|BCL-2 inhibitors]] (''including venetoclax''), and
* [[Phosphoinositide 3-kinase inhibitor|Phosphatidylinositol 3-kinase inhibitors]] (''including idelalisib and duvelisib'').<ref name="NCI2017Pt" /><ref name="Kh2018">{{cite journal |vauthors=Khan M, Siddiqi T |date=December 2018 |title=Targeted Therapies in CLL: Monotherapy Versus Combination Approaches |journal=Current Hematologic Malignancy Reports |volume=13 |issue=6 |pages=525–533 |doi=10.1007/s11899-018-0481-7 |pmid=30535947 |s2cid=54473182}}</ref>

=== Monoclonal antibodies ===

==== Anti-CD20 antibodies ====
CD20 is a protein that is found on the surface of B-cells and thus serves as an important target in the treatment of many B-cell malignances, including CLL.<ref name=":16" /> Some CD20 antibodies that have been used for the treatment of CLL include:<ref name=":16" />

* '''[[Rituximab]]'''
* '''[[Ofatumumab]]''' 
* '''[[Obinutuzumab]]'''

These agents are usually used in refractory/relapsed disease or in combination with other agents, like chlorambucil (CLB), fludarabine, or venetoclax.<ref name="NCI2017Pt" /><ref name="Kh2018" /><ref name=":16" />

==== Other monoclonal antibodies ====

* '''Alemtuzumab''' targets the CD52 receptor, which is usually found on the surface of many immune cells. This agent is also primarily used in refractory disease.<ref name=":16" />

===Chemotherapy===
Monotherapy using [[alkylating agent]]s (i.e.  chlorambucil and bendamustine) served as a front-line therapy for CLL for many years.<ref name=":16" /> In fact, chlorambucil (CLB), was the "gold standard" treatment for CLL for several decades.<ref name=":16" /> However, researchers found that it was not very effective at helping patients achieve remission; thus, it may not be used as frequently in practice anymore.<ref name=":16" />

Combination [[chemotherapy regimen]]s can be effective in both newly diagnosed and relapsed CLL. Combinations of fludarabine with alkylating agents (cyclophosphamide) produce higher response rates and longer progression-free survival than single agents:
* '''FC''' ([[fludarabine]] with [[cyclophosphamide]])<ref name="pmid16219797">{{cite journal | vauthors = Eichhorst BF, Busch R, Hopfinger G, Pasold R, Hensel M, Steinbrecher C, Siehl S, Jäger U, Bergmann M, Stilgenbauer S, Schweighofer C, Wendtner CM, Döhner H, Brittinger G, Emmerich B, Hallek M | display-authors = 6 | title = Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia | journal = Blood | volume = 107 | issue = 3 | pages = 885–891 | date = February 2006 | pmid = 16219797 | doi = 10.1182/blood-2005-06-2395 | doi-access = free }}</ref><ref name=":16" />
* '''FR''' (fludarabine with [[rituximab]])<ref name="pmid12393429">{{cite journal | vauthors = Byrd JC, Peterson BL, Morrison VA, Park K, Jacobson R, Hoke E, Vardiman JW, Rai K, Schiffer CA, Larson RA | display-authors = 6 | title = Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: results from Cancer and Leukemia Group B 9712 (CALGB 9712) | journal = Blood | volume = 101 | issue = 1 | pages = 6–14 | date = January 2003 | pmid = 12393429 | doi = 10.1182/blood-2002-04-1258 | doi-access = free }}</ref><ref name=":16" />
* '''FCR''' (fludarabine, cyclophosphamide, and rituximab)<ref name="pmid15767648">{{cite journal | vauthors = Keating MJ, O'Brien S, Albitar M, Lerner S, Plunkett W, Giles F, Andreeff M, Cortes J, Faderl S, Thomas D, Koller C, Wierda W, Detry MA, Lynn A, Kantarjian H | display-authors = 6 | title = Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia | journal = Journal of Clinical Oncology | volume = 23 | issue = 18 | pages = 4079–4088 | date = June 2005 | pmid = 15767648 | doi = 10.1200/JCO.2005.12.051 | doi-access = free }}</ref><ref name=":16" />

Although the purine analogue fludarabine was shown to give superior response rates to [[chlorambucil]] (CLB) as primary therapy, the early use of fludarabine has not been shown to improve overall survival, and some clinicians prefer to reserve fludarabine for relapsed disease.<ref name="pmid11114313">{{cite journal |display-authors=6 |vauthors=Rai KR, Peterson BL, Appelbaum FR, Kolitz J, Elias L, Shepherd L, Hines J, Threatte GA, Larson RA, Cheson BD, Schiffer CA |date=December 2000 |title=Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia |journal=The New England Journal of Medicine |volume=343 |issue=24 |pages=1750–1757 |doi=10.1056/NEJM200012143432402 |pmid=11114313 |doi-access=free}}</ref><ref name="pmid16856041">{{cite journal |vauthors=Steurer M, Pall G, Richards S, Schwarzer G, Bohlius J, Greil R |date=July 2006 |title=Purine antagonists for chronic lymphocytic leukaemia |journal=The Cochrane Database of Systematic Reviews |volume=3 |issue=3 |article-number=CD004270 |doi=10.1002/14651858.CD004270.pub2 |pmc=8407449 |pmid=16856041 |veditors=Steurer M}}</ref>

Chemoimmunotherapy with FCR has shown to improve response rates, progression-free survival, and overall survival in a large randomized trial in CLL patients selected for good physical fitness.<ref name="pmid20888994">{{cite journal | vauthors = Hallek M, Fischer K, Fingerle-Rowson G, Fink AM, Busch R, Mayer J, Hensel M, Hopfinger G, Hess G, von Grünhagen U, Bergmann M, Catalano J, Zinzani PL, Caligaris-Cappio F, Seymour JF, Berrebi A, Jäger U, Cazin B, Trneny M, Westermann A, Wendtner CM, Eichhorst BF, Staib P, Bühler A, Winkler D, Zenz T, Böttcher S, Ritgen M, Mendila M, Kneba M, Döhner H, Stilgenbauer S | display-authors = 6 | title = Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial | journal = Lancet | volume = 376 | issue = 9747 | pages = 1164–1174 | date = October 2010 | pmid = 20888994 | doi = 10.1016/S0140-6736(10)61381-5 | s2cid = 28834830 }}</ref>

===Stem cell transplantation===
[[Autologous stem cell transplantation]], using the recipient's own cells, is not curative.<ref name="Williams_2010_8"/>  Younger individuals, if at high risk for dying from CLL, may consider [[allogeneic]] [[hematopoietic stem cell transplantation]] (HSCT). Myeloablative (bone marrow killing) forms of [[allogeneic stem cell transplantation]], a high-risk treatment using blood cells from a healthy donor, may be curative, but treatment-related toxicity is significant.<ref name="Williams_2010_8"/> An intermediate level, called reduced-intensity conditioning [[allogeneic stem cell transplantation]], may be better tolerated by older or frail patients.<ref name="pmid19147079">{{cite journal | vauthors = Gribben JG | title = Stem cell transplantation in chronic lymphocytic leukemia | journal = Biology of Blood and Marrow Transplantation | volume = 15 | issue = 1 Suppl | pages = 53–58 | date = January 2009 | pmid = 19147079 | pmc = 2668540 | doi = 10.1016/j.bbmt.2008.10.022 }}</ref><ref name="Dreger">{{cite journal | vauthors = Dreger P, Brand R, Hansz J, Milligan D, Corradini P, Finke J, Deliliers GL, Martino R, Russell N, Van Biezen A, Michallet M, Niederwieser D | display-authors = 6 | title = Treatment-related mortality and graft-versus-leukemia activity after allogeneic stem cell transplantation for chronic lymphocytic leukemia using intensity-reduced conditioning | journal = Leukemia | volume = 17 | issue = 5 | pages = 841–848 | date = May 2003 | pmid = 12750695 | doi = 10.1038/sj.leu.2402905 | s2cid = 10144544 | doi-access =  }}</ref>

===Refractory CLL===
"Refractory" CLL is a disease that no longer responds favorably to treatment within six months following the last cancer therapy.<ref name=":7"/> In this case, more aggressive targeted therapies, such as BCR or BCL2 pathway inhibitors, have been associated with increased survival.<ref>{{cite journal | vauthors = Molica S, Giannarelli D, Mirabelli R, Levato L, Shanafelt TD | title = The magnitude of improvement in progression-free survival with targeted therapy in relapsed/refractory chronic lymphocytic leukemia based on prognostic risk category: a systematic review and meta-analysis | journal = Leukemia & Lymphoma | volume = 60 | issue = 7 | pages = 1644–1649 | date = July 2019 | pmid = 30516079 | doi = 10.1080/10428194.2018.1543882 | s2cid = 54544330 }}</ref>

==Prognosis==
Prognosis can be affected by the type of genetic mutation that the person with CLL has.<ref>{{cite journal | vauthors = Bosch F, Dalla-Favera R | title = Chronic lymphocytic leukaemia: from genetics to treatment | journal = Nature Reviews. Clinical Oncology | volume = 16 | issue = 11 | pages = 684–701 | date = November 2019 | pmid = 31278397 | doi = 10.1038/s41571-019-0239-8 | s2cid = 195804409 }}</ref> Some examples of genetic mutations and their prognoses are: mutations in the ''IGHV'' region are associated with a median overall survival (OS) of more than 20–25 years, while no mutations in this region is associated with a median OS of 8–10 years; deletion of chromosome 13q is associated with a median OS of 17 years; and [[trisomy]] of chromosome 12, as well as [[Deletion (genetics)|deletion]] of chromosome 11q, is associated with a median OS of 9–11 years.<ref name="NCI2017Pt" /> While prognosis is highly variable and dependent on various factors including these mutations, the average [[Five-year survival rate|5-year relative survival]] is 89.3% in the US as of 2021.<ref name=":6">{{Cite web |title=Chronic Lymphocytic Leukemia – Cancer Stat Facts |url=https://seer.cancer.gov/statfacts/html/clyl.html |access-date=2025-11-04 |website=SEER |publisher=[[National Cancer Institute]] at the [[National Institutes of Health]]}}</ref> Telomere length has been suggested to be a valuable prognostic indicator of survival.<ref>{{cite journal | vauthors = Rossi D, Lobetti Bodoni C, Genuardi E, Monitillo L, Drandi D, Cerri M, Deambrogi C, Ricca I, Rocci A, Ferrero S, Bernocco E, Capello D, De Paoli L, Bergui L, Boi M, Omedè P, Massaia M, Tarella C, Passera R, Boccadoro M, Gaidano G, Ladetto M | display-authors = 6 | title = Telomere length is an independent predictor of survival, treatment requirement and Richter's syndrome transformation in chronic lymphocytic leukemia | journal = Leukemia | volume = 23 | issue = 6 | pages = 1062–1072 | date = June 2009 | pmid = 19340005 | doi = 10.1038/leu.2008.399 | doi-access = free | hdl = 2434/663837 | hdl-access = free }}</ref> In addition, a person's sex has been found to have an impact on CLL prognosis and treatment efficacy. More specifically, females have been found to survive longer (without disease progression) than males, when treated with certain medications.<ref>{{cite journal | vauthors = Al-Sawaf O, Robrecht S, Bahlo J, Fink AM, Cramer P, von Tresckow J, Maurer C, Bergmann M, Seiler T, Lange E, Kneba M, Stilgenbauer S, Döhner H, Kiehl MG, Jäger U, Wendtner CM, Fischer K, Goede V, Hallek M, Eichhorst B, Hopfinger G | display-authors = 6 | title = Impact of gender on outcome after chemoimmunotherapy in patients with chronic lymphocytic leukemia: a meta-analysis by the German CLL study group | journal = Leukemia | volume = 31 | issue = 10 | pages = 2251–2253 | date = October 2017 | pmid = 28745332 | doi = 10.1038/leu.2017.221 | s2cid = 6542508 }}</ref>

As of 2022, the most commonly used prognostic score is the CLL International Prognostic Index (CLL-IPI).<ref name=":16" /> This system takes into account the following factors:<ref name=":16" />

# ''TP53'' gene deletion and/or mutation
# Mutated immunoglobulin heavy chain variable (''IGHV'') 
# Serum B<sub>2</sub>-microglobulin levels
# Clinical stage (see the Rai and Binet staging systems above)
# Age

==Epidemiology==
CLL is the most common type of leukemia in the Western world compared to non-Western regions such as Asia, Latin America, and Africa.<ref name=":8">{{Cite web|title=Chronic lymphocytic leukaemia – Symptoms, diagnosis and treatment {{!}} BMJ Best Practice|url=https://bestpractice.bmj.com/topics/en-gb/275#main-content|access-date=2021-11-29|website=bestpractice.bmj.com}}</ref> It is observed globally that males are twice as likely than females to acquire CLL.<ref name=":8" /> CLL is primarily a disease of older adults, with 9 out of 10 cases occurring after the age of 50 years.<ref name="Maxine_2022">{{Cite book|title=Current medical diagnosis & treatment 2022|date=2022| vauthors = Papadakis MA, McPhee SJ, Rabow MW, McQuaid KR |isbn=978-1-264-26938-9|edition=Sixty-first|location=[New York]|oclc=1264228575}}</ref> The median age of diagnosis is 70 years.<ref name="Maxine_2022" /> In young people, new cases of CLL are twice as likely to be diagnosed in men than in women.<ref name=":5">{{Cite book|title=Harrison's principles of internal medicine|date=2018| vauthors = Jameson JL, Kasper DL, Longo DL, Fauci AS, Hauser SL, Loscalzo J |isbn=978-1-259-64403-0|edition=20th|location=New York|oclc=1029074059}}</ref> In older people, however, this difference becomes less pronounced: after the age of 80 years, new cases of CLL are diagnosed equally between men and women.<ref name=":5" />

According to the [[American Cancer Society]], they estimate that there will about 23,690 new cases of CLL with about 4,460 deaths from CLL in the United States throughout 2025.<ref name=":11" /> [[Five-year survival]] following diagnosis is approximately 89% in the United States as of 2021.<ref name=":6" /> It represents less than 1% of deaths from cancer.<ref name="GBD2015De" />

Because of the prolonged survival, which was typically about 10 years in past decades, but which can extend to a normal life expectancy, the [[prevalence]] (number of people living with the disease) is much higher than the [[incidence (epidemiology)|incidence]] (new diagnoses).<ref name="NCI2017Pt" /> CLL is the most common type of leukemia in the UK, accounting for 38% of all leukemia cases. Approximately 3,200 people were diagnosed with the disease in 2011.<ref>{{cite web|title=Chronic lymphocytic leukaemia (CLL) statistics|url=http://www.cancerresearchuk.org/cancer-info/cancerstats/types/leukaemia-cll/|website=Cancer Research UK|access-date=27 October 2014}}</ref>

In Western populations, subclinical "disease" can be identified in 3.5% of normal adults,<ref>{{cite journal | vauthors = Rawstron AC, Green MJ, Kuzmicki A, Kennedy B, Fenton JA, Evans PA, O'Connor SJ, Richards SJ, Morgan GJ, Jack AS, Hillmen P | display-authors = 6 | title = Monoclonal B lymphocytes with the characteristics of "indolent" chronic lymphocytic leukemia are present in 3.5% of adults with normal blood counts | journal = Blood | volume = 100 | issue = 2 | pages = 635–639 | date = July 2002 | pmid = 12091358 | doi = 10.1182/blood.V100.2.635 | doi-access = free }}</ref> and in up to 8% of individuals over the age of 70.<ref>{{cite web |url=https://my.clevelandclinic.org/health/diseases/6210-chronic-lymphocytic-leukemia| title=Chronic Lymphocytic Leukemia
|website=Cleveland Clinic |access-date= 9 July 2021}}</ref> That is, small clones of B cells with the characteristic CLL phenotype can be identified in many healthy elderly persons. The clinical significance of these cells is unknown.

CLL seems to be more rare in Asian countries, such as Japan, China, and Korea, accounting for less than 10% of all leukemias in those regions.<ref name="Williams_2010_8">{{Cite book | vauthors = Kaushansky K, Lichtman M, Beutler E, Kipps T, Prchal J, Seligsohn U |title=Williams Hematology | publisher=McGraw-Hill | year=2010 |edition=8th |isbn= 978-0-07-162151-9}}</ref>{{rp|1432}}<ref name=Review_Shansai>{{cite journal | vauthors = Shanshal M, Haddad RY | title = Chronic lymphocytic leukemia | journal = Disease-a-Month | volume = 58 | issue = 4 | pages = 153–167 | date = April 2012 | pmid = 22449365 | doi = 10.1016/j.disamonth.2012.01.009 }}<!--| access-date = 2 January 2013 --></ref> A low incidence is seen in Japanese immigrants to the US, and in African and Asian immigrants to Israel.<ref name="Williams_2010_8"/>

Of all [[lymphoproliferative disorders|cancers involving the same class of blood cell]], 7% of cases were CLL/SLL as of 2001.<ref name="isbn0-7817-5007-5">{{cite book | vauthors = Turgeon ML | title = Clinical hematology: theory and procedures | publisher = Lippincott Williams & Wilkins | location = Hagerstown, MD | year = 2005 | page = 283 | isbn = 978-0-7817-5007-3 | quote = Frequency of lymphoid neoplasms.  (Source:  Modified from WHO Blue Book on Tumour of Hematopoietic and Lymphoid Tissues. 2001, p. 2001.) }}</ref>{{Update inline|date=November 2021}}

People who live near areas with considerable industrial pollution have an elevated risk of developing leukemia, particularly CLL.<ref>{{cite journal | vauthors = Boonhat H, Lin RT | title = Association between leukemia incidence and mortality and residential petrochemical exposure: A systematic review and meta-analysis | journal = Environment International | volume = 145 | article-number = 106090 | date = December 2020 | pmid = 32932064 | doi = 10.1016/j.envint.2020.106090 | s2cid = 221748665 | doi-access = free | bibcode = 2020EnInt.14506090B }}</ref>

==Research directions==
In light of newer targeted therapies such as [[Tyrosine kinase inhibitor|Bruton tyrosine kinase inhibitors]] and [[Monoclonal antibody|anti-CD20 monoclonal antibodies]], the need for [[bone marrow transplant]]s in patients with CLL has become rare.<ref>{{cite journal | vauthors = Pérez-Carretero C, González-Gascón-Y-Marín I, Rodríguez-Vicente AE, Quijada-Álamo M, Hernández-Rivas JÁ, Hernández-Sánchez M, Hernández-Rivas JM | title = The Evolving Landscape of Chronic Lymphocytic Leukemia on Diagnosis, Prognosis and Treatment | journal = Diagnostics | volume = 11 | issue = 5 | page = 853 | date = May 2021 | pmid = 34068813 | pmc = 8151186 | doi = 10.3390/diagnostics11050853 | doi-access = free }}</ref><ref>{{Cite journal |last1=Hampel |first1=Paul J. |last2=Parikh |first2=Sameer A. |date=2022-11-29 |title=Chronic lymphocytic leukemia treatment algorithm 2022 |journal=Blood Cancer Journal |language=en |volume=12 |issue=11 |page=161 |doi=10.1038/s41408-022-00756-9 |pmc=9708674 |pmid=36446777}}</ref> Bone marrow transplants are only recommended in specific cases when front-line therapies have either failed and/or the patient continues to relapse.<ref>{{cite journal | vauthors = Kharfan-Dabaja MA, Kumar A, Hamadani M, Stilgenbauer S, Ghia P, Anasetti C, Dreger P, Montserrat E, Perales MA, Alyea EP, Awan FT, Ayala E, Barrientos JC, Brown JR, Castro JE, Furman RR, Gribben J, Hill BT, Mohty M, Moreno C, O'Brien S, Pavletic SZ, Pinilla-Ibarz J, Reddy NM, Sorror M, Bredeson C, Carpenter P, Savani BN | display-authors = 6 | title = 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 | journal = Biology of Blood and Marrow Transplantation | volume = 22 | issue = 12 | pages = 2117–2125 | date = December 2016 | pmid = 27660167 | pmc = 5116249 | doi = 10.1016/j.bbmt.2016.09.013 }}</ref><ref name=":16" />

There have been major advances in the treatment of patients with CLL over the past 10 years or so.<ref name=":12">{{Cite journal |last1=Odetola |first1=Oluwatobi |last2=Ma |first2=Shuo |date=October 2023 |title=Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL) |journal=Current Hematologic Malignancy Reports |volume=18 |issue=5 |pages=130–143 |doi=10.1007/s11899-023-00700-z |issn=1558-822X |pmc=10242240 |pmid=37278884}}</ref> Although this disease remains incurable, therapies such as [[Tyrosine kinase inhibitor|Bruton tyrosine kinase inhibitors]] (''including ibrutinib, acalabrutinib''',''' and zanubrutinib''), [[Bcl-2 inhibitor|BCL-2 inhibitors]] (''including venetoclax''), and [[Phosphoinositide 3-kinase inhibitor|phosphatidylinositol 3-kinase inhibitors]] (''including idelalisib and duvelisib'') allow patients with CLL to now live longer.<ref name=":12" />

Despite the great success of these new targeted biological therapies so far, more research is needed in order to establish clearer guidelines on the optimal combination and sequence of these agents based on the patient's specific clinical presentation.<ref name=":12" /><ref name=":16" /> Furthermore, for patients who do not respond to these agents, treatment options are limited.<ref name=":16" /> Thus, further research should be focused on discovering therapies that target other important chemical pathways.<ref name=":16" />

== Special Populations ==

===Pregnancy===
Leukemia is rarely associated with pregnancy, affecting only about one in 10,000 pregnant women.<ref name="Shapira">{{cite journal |vauthors=Shapira T, Pereg D, Lishner M |date=September 2008 |title=How I treat acute and chronic leukemia in pregnancy |journal=Blood Reviews |volume=22 |issue=5 |pages=247–259 |doi=10.1016/j.blre.2008.03.006 |pmid=18472198}}</ref>  Treatment for chronic lymphocytic leukemias can often be postponed until after the end of the pregnancy.  If treatment is necessary, then giving chemotherapy during the second or third trimesters is less likely to result in [[pregnancy loss]] or [[birth defect]]s than treatment during the [[first trimester]].<ref name="Shapira" />

== See also ==
* [[B-cell CLL/lymphoma]]

== References ==
{{Reflist}}

== External links ==

{{Medical resources
|  DiseasesDB      = 2641
|  ICD10           = {{ICD10|C|91|1|c|81}}
|  ICD9            = {{ICD9|204.1  V10.60}}
|  ICDO            = {{ICDO|9823|3}} (CLL)<br />9670/3 (SCL)
|  OMIM            =
|  MedlinePlus     = 000532
|  eMedicineSubj   = med
|  eMedicineTopic  = 370
|  MeshID          = D015451
}}
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