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| | __NOTOC__ |
| | {{Chronic lymphocytic leukemia}} |
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| '''For patient information click [[{{PAGENAME}} (patient information)|here]]''' | | '''For patient information click [[{{PAGENAME}} (patient information)|here]]''' |
| {{Infobox_Disease |
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| Name = {{PAGENAME}} |
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| Image = Chronic_lymphocytic_leukemia.jpg |
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| Caption = Peripheral blood smear showing CLL cells |
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| DiseasesDB = 2641 |
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| ICD10 = {{ICD10|C|91|1|c|81}} |
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| ICD9 = {{ICD9|204.9}} |
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| ICDO = 9823/3 |
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| OMIM = |
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| MedlinePlus = 000532|
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| eMedicineSubj = med |
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| eMedicineTopic = 370 |
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| MeshID = D015462 |
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| }}
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| {{SI}} | | {{CMG}}; {{AE}} {{S.S}}, {{HL}} |
| {{CMG}} | |
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| {{Editor Help}} | | {{SK}} CLL; Small Lymphocytic Lymphoma; B-cell Chronic Lymphocytic Leukemia; B cell Chronic Lymphocytic Leukemia |
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| ==Overview== | | ==[[Chronic lymphocytic leukemia overview|Overview]]== |
| '''Chronic lymphocytic leukemia''' (also known as "chronic lymphoid leukemia" or "CLL"), is a type of [[leukemia]], or cancer of the white blood cells ([[lymphocytes]]). CLL affects a particular lymphocyte, the [[B cell]], which originates in the bone marrow, develops in the lymph nodes, and normally fights infection. In CLL, the DNA of a B cell is damaged, so that it can't fight infection, but it grows out of control and crowds out the healthy blood cells that can fight infection.
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| CLL is an abnormal neoplastic proliferation of B cells. The cells accumulate mainly in the bone marrow and blood. CLL is closely related to a disease called [[small lymphocytic lymphoma]] (SLL), a type of [[non-Hodgkin's lymphoma]] which presents primarily in the [[lymph nodes]]. The [[World Health Organization]] considers CLL and SLL to be "one disease at different stages, not two separate entities".<ref name="pmid10577857">{{cite journal |author=Harris NL, Jaffe ES, Diebold J, ''et al'' |title=World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997 |journal=J. Clin. Oncol. |volume=17 |issue=12 |pages=3835-49 |year=1999 |pmid=10577857 |doi=}}</ref>
| | ==[[Chronic lymphocytic leukemia historical perspective|Historical Perspective]]== |
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| 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, it is now recognized that these so-called T-cell CLLs are in fact a separate disease group and are currently classified as [[T-cell prolymphocytic leukemia]]s.
| | ==[[Chronic lymphocytic leukemia classification|Classification]]== |
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| [[Acute lymphocytic leukemia]] (ALL) is a disease of children, but CLL is a disease of adults. Most (>75%) people newly diagnosed with CLL are over age 50, and two-thirds are men. In the United States during 2007, it is estimated there will be 15,340 new cases diagnosed and 4,500 deaths<ref name="NCI-CLL-page1">{{cite web |url=http://www.cancer.gov/cancertopics/pdq/treatment/CLL/HealthProfessional/page1 |title=Chronic Lymphocytic Leukemia (PDQ®) Treatment: General Information |author=National Cancer Institute |accessdate=2007-09-04 |format= |work=}}</ref>, but because of prolonged survival, many more people are living with CLL. | | ==[[Chronic lymphocytic leukemia pathophysiology|Pathophysiology]]== |
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| Most people are diagnosed without symptoms as the result of a routine blood test that returns a high white blood cell count, but as it advances CLL results in [[swollen lymph nodes]], [[splenomegaly|spleen]], and [[hepatomegaly|liver]], and eventually [[anemia]] and infections. Early CLL is not treated, and late CLL is treated with chemotherapy and monoclonal antibodies. Survival varies from 5 years to more than 25 years. It is now possible to diagnose patients with short and long survival more precisely by examining the DNA mutations, and patients with slowly-progressing disease can be reassured and may not need any treatment in their lifetimes.<ref name="pmid15728813">{{cite journal |author=Chiorazzi N, Rai KR, Ferrarini M |title=Chronic lymphocytic leukemia |journal=N. Engl. J. Med. |volume=352 |issue=8 |pages=804-15 |year=2005 |pmid=15728813 |doi=10.1056/NEJMra041720}}</ref>
| | ==[[Chronic lymphocytic leukemia causes|Causes]]== |
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| ==Classification and prognosis== | | ==[[Chronic lymphocytic leukemia differential diagnosis|Differentiating Chronic lymphocytic leukemia from other Diseases]]== |
| ===Clinical staging===
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| Staging is done with the Rai staging system and the Binet classification (see details<ref name="NCI-CLL-page2">{{cite web |url=http://www.cancer.gov/cancertopics/pdq/treatment/CLL/HealthProfessional/page2 |title=Chronic Lymphocytic Leukemia (PDQ®) Treatment: Stage Information |author=National Cancer Institute |accessdate=2007-09-04 |format= |work=}}</ref>).
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| ===Gene mutation status=== | | ==[[Chronic lymphocytic leukemia epidemiology and demographics|Epidemiology and Demographics]]== |
| Recent publications suggest that two<ref name="pmid11733578">{{cite journal |author=Rosenwald A, Alizadeh AA, Widhopf G, ''et al'' |title=Relation of gene expression phenotype to immunoglobulin mutation genotype in B cell chronic lymphocytic leukemia |journal=J. Exp. Med. |volume=194 |issue=11 |pages=1639-47 |year=2001 |pmid=11733578 |doi=}}</ref> or three<ref name="pmid12406914">{{cite journal |author=Ghia P, Guida G, Stella S, ''et al'' |title=The pattern of CD38 expression defines a distinct subset of chronic lymphocytic leukemia (CLL) patients at risk of disease progression |journal=Blood |volume=101 |issue=4 |pages=1262-9 |year=2003 |pmid=12406914 |doi=10.1182/blood-2002-06-1801}}</ref> prognostic groups of CLL exist based on the maturational state of the cell. This distinction is based on the maturity of the lymphocytes as discerned by the immunoglobulin variable-region [[heavy chain]] (IgV<sub>H</sub>) gene mutation status.<ref name="pmid16983131">{{cite journal |author=Shanafelt TD, Byrd JC, Call TG, Zent CS, Kay NE |title=Narrative review: initial management of newly diagnosed, early-stage chronic lymphocytic leukemia |journal=Ann. Intern. Med. |volume=145 |issue=6 |pages=435-47 |year=2006 |pmid=16983131 |doi=|url=http://www.annals.org/cgi/content/full/145/6/435}}</ref> High risk patients have an immature cell pattern with few mutations in the DNA in the IgV<sub>H</sub> antibody gene region whereas low risk patients show considerable mutations of the DNA in the antibody gene region indicating mature lymphocytes.
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| Since assessment of the IgV<sub>H</sub> antibody DNA changes is difficult to perform, the presence of either [[cluster of differentiation]] [[CD38|38]] ([[CD38]]) or Z-chain–associated protein kinase-70 ([[ZAP-70]]) may be surrogate markers of high risk subtype of CLL.<ref name="pmid16983131"/> Their expression correlates with a more immature cellular state and a more rapid disease course. Unmutated IGVH survive worse than mutated and are associated with aggressive CLL. The ZAP70 (AKA Zeta-Associated Protein) presence on the CLL cell correlates with unmutated immunoglobulin genes and a poor prognosis. Conversely, its absence indicates the presence of mutated genes and a good clinical outcome. Patients positive for ZAP70 have a CLL more aggressive in nature and mor refractory to treatment. They are more likely to evolve to more unfavorable cytogenetic abnormalitites.
| | ==[[Chronic lymphocytic leukemia risk factors|Risk Factors]]== |
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| ===Fluorescence in situ hybridization (FISH)=== | | ==[[Chronic lymphocytic leukemia screening|Screening]]== |
| In addition to the maturational state, the prognosis of patients with CLL is dependent on the genetic changes within the neoplastic cell population. These genetic changes can be identified by fluorescent probes to chromosomal parts using a technique referred to as [[fluorescent in situ hybridization]] (FISH).<ref name="pmid16983131"/> Compared with fluorescence in-situ hybridization (FISH), conventional metaphase cytogenetics play ONLY a MINOR prognostic role in CLL, so far, due to technical problems resulting from a limited proliferation of CLL cells in-vitro. Therefore conventional cytogenetics may define subgroups with a high risk of progression. FISH can be done (in CLL) on dividing and non-dividing cells. FISH doesn't tell about IgVH mutations nor does it define the presence of trisomy either. FISH is useful as long as there are CLL cells to test; you can't do it in a complete response (CR).The application of FISH to study interphase nuclei gives important prognostic information with B-cell CLL, especially for patients with 11q-, trisomy 12, 13q- and 17q-. PCR has extreme sensitivity as well as being quite specific.
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| The procedure of FISH involves cell cultures which are prepared after which metaphase and prometaphase chromosomes are fixed to a glass slide. A DNA probe is then hybridized onto the chromosome; the probe is labeled with fluorochrome which can be detected with fluorescent microscopy. FISH can be done on dividing and non-dividing cells. Inversions will be missed as probes detect sequences not precise locations. Small mutations, such as small deletions and insertions, will also be missed. FISH is a cytogenetic technology that looks at 200-500 blood cells (obtained with a bone marrow biopsy). Because of the small size it is not as sensitive as PCR.
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| PCR amplifies a fragment of DNA. It is at least 2-3 logs more sensitive than cytogenetic technology like FISH. PCR measurement requires a sample blood draw which is less invasive and intense than a bone marrow biopsy (with FISH).
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| Four main genetic aberrations are recognized in CLL cells that have a major impact on disease behavior.
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| # Deletions of part of the short arm of chromosome 17 (del 17p13) which target the cell cycle regulating protein p53 (a tumore suppressor gene) are particularly deleterious. Patients with this abnormality have significantly short interval before they require therapy and a shorter survival. This abnormality is found in 5-10% of patients with CLL.
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| # Deletions of the long arm on chromosome 11 (del 11q22-q23) are also unfavorable although not to the degree seen with del 17p. The abnormality targets the ATM gene and occurs infrequently in CLL (5-10%).
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| # Trisomy 12, an additional chromosome 12, is a relatively frequent finding occurring in 20-25% of patients and imparts an intermediate prognosis. It has a higher frequency of DNA aneuploidy.
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| # Deletion of the long arm of chromosome 13 (del 13q14) is the most common abnormality in CLL with roughly 50% of patients with cells containing this defect. These patients (along with those of normal karyotype)have the best prognosis and most will live many years, even decades, without the need for therapy. The gene targeted by this deletion is a segment that likely produces small inhibitory RNA molecules that affect expression of important death inhibiting genes.
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| The presence of 17p- typifies cells that are resistant to fludarabine, alkylators and rituxumab.
| | ==[[Chronic lymphocytic leukemia natural history, complications and prognosis|Natural History, Complications and Prognosis]]== |
| 11q- portends a decreased RR to fludrabine as well as an early relapse after bone marrow transplant (BMT).
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| Both the 17p- and the 11q- have a decreased progression-free survival (PFS) and overall survival (OS).
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| ==Symptoms and signs== | |
| Most people are diagnosed without symptoms as the result of a routine blood test that returns a high white blood cell count, but as it advances CLL results in swollen lymph nodes, spleen, and liver, and eventually anemia and infections.
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| Uncommonly, CLL presents as enlargement of the lymph nodes without a high white blood cell count or no evidence of the disease in the blood. This is referred to as [[small lymphocytic lymphoma]].
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| The increase in lymphocytes and precursors in the bone marrow impairs the production of other [[leucocytes]] causing a decrease in such cell types.
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| A high beta-2-microglobulin level may be seen and is an independent adverse prognostic factor for CR and OS.
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| ==Diagnosis== | | ==Diagnosis== |
| CLL is usually first suspected by the presence of a [[lymphocytosis]], an increase in one type of the white blood cell, on a complete blood count (CBC) test. This frequently is an incidental finding on a routine physician visit. Most often the lymphocyte count is greater than 4000 cells per mm3 (microliter) of blood but can be much higher.
| | [[Chronic lymphocytic leukemia diagnostic study of choice|Diagnostic Study of Choice]] | [[Chronic lymphocytic leukemia clinical staging|Staging]] | [[Chronic lymphocytic leukemia history and symptoms|History and Symptoms]] | [[Chronic lymphocytic leukemia physical examination|Physical Examination]] | [[Chronic lymphocytic leukemia laboratory tests|Laboratory Findings]] | [[Chronic lymphocytic leukemia electrocardiogram|Electrocardiogram]] | [[Chronic lymphocytic leukemia chest x ray|Chest X Ray]] | [[Chronic lymphocytic leukemia CT|CT]] | [[Chronic lymphocytic leukemia MRI|MRI]] | [[Chronic lymphocytic leukemia echocardiography or ultrasound|Echocardiography or Ultrasound]] | [[Chronic lymphocytic leukemia other imaging findings|Other Imaging Findings]] | [[Chronic lymphocytic leukemia other diagnostic studies|Other Diagnostic Studies]] |
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| ===Pathology===
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| <div align="left">
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| <gallery heights="175" widths="175">
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| Image:CLL.jpg|CLL (more cytoplasmic space)<ref>http://picasaweb.google.com/mcmumbi/USMLEIIImages</ref>
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| Image:CLL Smudge Cell.jpg|CLL Smudge Cell<ref>http://picasaweb.google.com/mcmumbi/USMLEIIImages</ref>
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| </gallery>
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| </div>
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| ===Determining clonality===
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| 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. This atypical molecular pattern includes the co-expression of cells surface markers [[cluster of differentiation]] [[CD5 (protein)|5]] ([[CD5 (protein)|CD5]]) and [[cluster of differentiation]] [[CD23|23]] ([[CD23]]). In addition, all the CLL cells within one individual are functionally inert and clonal, that is genetically identical. In practice, this is inferred by the detection of only one of the mutually exclusive [[Light_chain#In_humans|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 kappa and lambda producing 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).
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| Clonality is confirmed by the combination of the microscopic examination of the peripheral blood and analysis of the lymphocytes by [[flow cytometry]]. The later is easily accomplished on a small amount of blood. A [[flow cytometer]] is an instrument that can examine the marker molecule expression on individual cells in fluids. This is accomplished using antibodies with fluorescent tags recognized by the instrument. In CLL, the lymphocytes are genetically clonal, of the B cell lineage (express marker molecules [[cluster of differentiation]] [[CD19|19]] ([[CD19]]) and [[CD20]]), and characteristically express the marker molecules [[CD5 (protein)|CD5]] and [[CD23]]. Morphologically, the cells resemble normal lymphocytes under the microscope, although slightly larger, and are fragile when smeared onto a glass slide giving rise to many broken cells (smudge cells).
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| ===Differential diagnosis===
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| 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.
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| * [[B cell prolymphocytic leukemia]] (B PLL), which is a related but more aggressive disorder, has cells with similar phenotype but that are signficantly larger than normal lymphocytes and have a prominent nucleolus suggests a related.
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| * [[Hairy cell leukemia]] is also a neoplasm of B lymphocytes but differs significantly from CLL by its morphology under the microscope ([[hairy cell leukemia]] cells have delicate, hair-like projections on their surface) and marker molecule expression.
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| 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 sophisticated instrument called 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).
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| ==Treatment== | | ==Treatment== |
| While 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, early-stage CLL is generally not treated since it is believed that early CLL intervention does not improve survival time or quality of life. Instead, the condition is monitored over time.
| | [[Chronic lymphocytic leukemia medical therapy|Medical therapy]] | [[Chronic lymphocytic leukemia surgery|Surgery]] | [[Chronic lymphocytic leukemia primary prevention|Primary prevention]] | [[Chronic lymphocytic leukemia secondary prevention|Secondary prevention]] | [[Chronic lymphocytic leukemia cost-effectiveness of therapy|Cost-effectiveness of therapy]] | [[Chronic lymphocytic leukemia future or investigational therapies|Future or Investigational Therapies]] |
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| The decision to start CLL treatment is taken when the patient's clinical symptoms or blood counts indicate that the disease has progressed to a point where it may affect the patient's quality of life.
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| CLL treatment focuses on controlling the disease and its symptoms rather than on an outright cure. CLL is treated by [[chemotherapy]], [[radiation therapy]], [[biological therapy]], or [[bone marrow transplantation]]. Symptoms are sometimes treated surgically ([[splenectomy]] removal of enlarged spleen) or by [[radiation therapy]] ("de-bulking" swollen lymph nodes).
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| Clinical "staging systems" such as the Rai 4-stage system and the Binet classification can help to determine when and how to treat the patient.<ref name="NCI-CLL-page2"/>
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| Determining when to start treatment and by what means is often difficult; studies have shown there is no survival advantage to treating the disease too early. The National Cancer Institute Working Group has issued guidelines for treatment, with specific markers that should be met before it is initiated.<ref name="pmid8652811">{{cite journal |author=Cheson BD, Bennett JM, Grever M, ''et al'' |title=National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment |journal=Blood |volume=87 |issue=12 |pages=4990-7 |year=1996 |pmid=8652811 |doi=}}</ref>
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| Initial CLL treatments vary depending on the exact diagnosis and the progression of the disease, and even with the preference and experience of the health care practitioner. There are dozens of agents used for CLL therapy, and there is considerable research activity studying them individually or in combination with each other.<ref>{{cite web |url=http://www.cancer.gov/cancertopics/pdq/treatment/CLL/HealthProfessional/page5 |title=Chronic Lymphocytic Leukemia (PDQ®) Treatment: Stage I, II, III, and IV Chronic Lymphocytic Leukemia|author=National Cancer Institute |accessdate=2007-09-04 |format= |work=}}</ref>
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| ===Purine analogues=== | | ==Case Studies== |
| Although the purine analogue [[fludarabine]] was shown to give superior response rates than [[chlorambucil]] as primary therapy,<ref name="pmid11114313">{{cite journal |author=Rai KR, Peterson BL, Appelbaum FR, ''et al'' |title=Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia |journal=N. Engl. J. Med. |volume=343 |issue=24 |pages=1750-7 |year=2000 |pmid=11114313 |doi=}}</ref><ref name="pmid16856041">{{cite journal |author=Steurer M, Pall G, Richards S, Schwarzer G, Bohlius J, Greil R |title=Purine antagonists for chronic lymphocytic leukaemia |journal=Cochrane database of systematic reviews (Online) |volume=3 |issue= |pages=CD004270 |year=2006 |pmid=16856041 |doi=10.1002/14651858.CD004270.pub2}}</ref>
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| there is no evidence that early use of fludarabine improves overall survival, and some clinicians prefer to reserve fludarabine for relapsed disease.
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| ===Monoclonal antibodies===
| | [[Chronic lymphocytic leukemia case study one|Case #1]] |
| [[Monoclonal antibodies]] are [[alemtuzumab]] (directed against [[CD52]]) and [[rituximab]] (directed against [[CD20]]). | |
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| ===Combination chemotherapy===
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| Combination chemotherapy options are effective in both newly-diagnosed and relapsed CLL. Recently, randomized trials have shown that combinations of purine analogues (fludarabine) with alkylating agents (cyclophosphamide) produce higher response rates and a longer progression-free survival than single agents:
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| * [[fludarabine]] with [[cyclophosphamide]] <ref name="pmid16219797"> {{cite journal |author=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, German CLL Study Group. |title=Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia |journal=Blood |year=2006 |volume=107 |pages=885-91.|pmid16219797}} </ref>
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| * [[fludarabine]] with [[rituximab]]<ref name="pmid12393429">{{cite journal |author=Byrd JC, Peterson BL, Morrison VA, ''et al'' |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 |year=2003 |pmid=12393429 |doi=10.1182/blood-2002-04-1258}}</ref>
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| * FCR ([[fludarabine]], [[cyclophosphamide]], and [[rituximab]])<ref name="pmid15767648">{{cite journal |author=Keating MJ, O'Brien S, Albitar M, ''et al'' |title=Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia |journal=J. Clin. Oncol. |volume=23 |issue=18 |pages=4079-88 |year=2005 |pmid=15767648 |doi=10.1200/JCO.2005.12.051}}</ref>
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| * CHOP ([[cyclophosphamide]], [[doxorubicin]], [[vincristine]] and [[prednisolone]])
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| ===Stem cell transplantion===
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| Allogeneic [[Stem cell transplantation|bone marrow (stem cell) transplantation]] is rarely used as a first-line treatment for CLL due to its risk. There is increasing interest in the use of reduced intensity allogeneic stem cell transplantation, which offers the prospect of cure for selected patients with a suitable donor.<ref name="Dreger">{{cite journal | author=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; Chronic Leukemia Working Party of the EBMT | title=Treatment-related mortality and graft-versus-leukemia activity after allogeneic stem cell transplantation for chronic lymphocytic leukemia using intensity-reduced conditioning | journal=Leukemia | year=2003 | pages=841-8 | volume=17 | issue=5 | id=PMID 12750695}}</ref>
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| ===Refractory CLL===
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| "Refractory" CLL is a disease that no longer responds favorably to treatment. In this case more aggressive therapies, including [[lenalidomide]], flavopiridol, and bone marrow (stem cell) transplantation, are considered.<ref>{{cite web |url=http://www.cancer.gov/cancertopics/pdq/treatment/CLL/HealthProfessional/page6 |title=Chronic Lymphocytic Leukemia (PDQ®) Treatment: Refractory Chronic Lymphocytic Leukemia|author=National Cancer Institute|accessdate=2007-09-04 |format= |work=}}</ref> The monoclonal antibody, [[alemtuzumab]] (directed against [[CD52]]), may be used in patients with refractory, bone marrow-based disease.<!--
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| --><ref name="Keating">{{cite journal | author=Keating MJ, Flinn I, Jain V, Binet JL, Hillmen P, Byrd J, Albitar M, Brettman L, Santabarbara P, Wacker B, Rai KR | title=Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study | journal=Blood | year=2002 | pages=3554-61 | volume=99 | issue=10 | id=PMID 11986207}}</ref>
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| ==Epidemiology==
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| CLL is a disease of the elderly and is rarely encountered in individuals under the age of 40. Thereafter the disease incidence increases with age. Of note, subclinical "disease" can be identified in up to 7-8% of individuals over the age of 70. 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.
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| ==References==
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| {{Reflist|2}}
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| ==External links==
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| Forums:
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| *[http://www.ukcllforum.org.uk UK CLL Forum] - The UK's only specific forum for the patients, families, friends and carers of those diagnosed with Chronic Lymphocytic Leukaemia (CLL).
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| *[http://www.CLLForum.com CLL Forum] - Member supported, moderated, forum-based global community that provides friendly support, information and resources to people living with CLL and their caregivers.
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| *[http://www.cllsupport.org.uk UK CLL Support Association] - Registered charity that provides UK specific support to patients and caregivers.
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| Information Resources:
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| *[http://www.clltopics.org CLL Topics] - Non-profit educational and patient-advocacy organization (excellent resource.)
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| *[http://cll.ucsd.edu CLL Research Consortium] - NCI funded program project of leading clinician and scientists trying to cure CLL.
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| *[http://cllcanada.ca CLL Canada] - Repository of CLL research in laymen's terms.
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| *[http://www.leukemia-lymphoma.org/all_mat_toc.adp?item_id=3221&cat_id=1209 Leukemia & Lymphoma Society] - General CLL information.
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| *[http://www.lymphomation.org/type-CLL.htm Lymphomation.org] - Lymphoma website with a CLL resource page.
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| *[http://www.cancer.gov/cancerinfo/pdq/treatment/CLL/patient/ US National Cancer Institute] - General information about CLL.
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| Listservs and Groups:
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| *[http://www.acor.org/index.html ACOR Homepage] - Non-profit ACOR (Association of Cancer Online Resources) mailing list. Sign-up and receive email messages from other members of the mailing list.
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