CLL affected about 904,000 people globally in 2015 and resulted in 60,700 deaths. The disease most commonly occurs in people over the age of 50. Males are affected more often than females. It is much less common in people from Asia.Five-year survival following diagnosis is approximately 83% in the United States. It represents less than 1% of deaths from cancer.
Most people are diagnosed without symptoms as the result of a routine blood test that shows a high white blood cell count. Less commonly, CLL may present with enlarged 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. In some individuals, the disease comes to light only after the cancerous cells overwhelm the bone marrow resulting in anemia producing tiredness or weakness.
Gastrointestinal (GI) involvement can rarely occur with chronic lymphocytic leukemia. Some of the reported manifestations include intussusception, small intestinal bacterial contamination, colitis, and others. Usually, GI complications with CLL occur after Richter transformation. Two cases to date have been reported of GI involvement in chronic lymphocytic leukemia without Richter's transformation.
CLL is caused by multiple genetic mutations and epigenetic changes. Men are about twice as likely to get CLL as women, and risk increases with age. It is relatively rare among Asians. Some relevant genetic mutations may be inherited; in around 9% of CLL cases a parent had CLL. Exposure to Agent Orange increases the risk of CLL, and exposure to certain insecticides[vague] may increase the risk. Exposure to ionizing radiation and viral infection have been explored as risk factors but there is little evidence. Blood transfusions have been ruled out as a risk factor.
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
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. The presence of lymphocytosis in an elderly individual should raise strong suspicion for CLL, and a confirmatory diagnostic test, in particular flow cytometry, should be performed unless clinically unnecessary.
A peripheral blood smear showing an abundance of damaged cells known as "smudge cells" can also indicate the presence of the disease (smudge cells are due to cancer cells lacking in vimentin, a cytoskeletal protein).:1899
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 coexpression of cell surface markers clusters of differentiation5 (CD5) and 23. In addition, all the CLL cells within one individual are clonal, that is, genetically identical. In practice, this is inferred by the detection of only one of the mutually exclusive 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).
The combination of the microscopic examination of the peripheral blood and analysis of the lymphocytes by flow cytometry to confirm clonality and marker molecule expression is needed to establish the diagnosis of CLL. Both are easily accomplished on a small amount of blood. A flow cytometer instrument can examine the expression of molecules on individual cells in fluids. This requires the use of specific antibodies to marker molecules with fluorescent tags recognized by the instrument. In CLL, the lymphocytes are genetically clonal, of the B cell lineage (expressing marker molecules clusters of differentiation 19 and 20), and characteristically express the marker molecules CD5 and CD23. These B cells resemble normal lymphocytes under the microscope, although slightly smaller, and are fragile when smeared onto a glass slide, giving rise to many broken cells, which are called "smudge" or "smear" cells.
Smudge cells in peripheral blood
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). Discrimination between CLL and MCL can be improved by adding non-routine markers such as CD54 and CD200. Among routine markers, the most discriminating feature is the CD20/CD23 mean fluorescence intensity ratio. In contrast, FMC7 expression can surprisingly be misleading for borderline cases.
Staging, determining the extent of the disease, is done with the Rai staging system or the Binet classification (see details) and is based primarily on the presence of a low platelet or red cell count. Early-stage disease does not need to be treated. CLL and SLL are considered the same underlying disease, just with different appearances.:1441
Array-based karyotyping is a cost-effective alternative to FISH for detecting chromosomal abnormalities in CLL. Several clinical validation studies have shown >95% concordance with the standard CLL FISH panel.
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 leukemias.
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.
Lymphoid disorders that can present as chronic leukemia and can be confused with typical B-cell chronic lymphoid leukemia
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.
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.
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 FISH.
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. Any of dozens of agents may be used for CLL therapy. An initial treatment regimen that contains fludarabine, cyclophosphamide, and rituximab (known as FCR) has demonstrated higher overall response rates and complete response rates.
Leukemia is rarely associated with pregnancy, affecting only about one in 10,000 pregnant women. 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 defects than treatment during the first trimester.
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, early-stage CLL is, in general, 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 to detect any change in the disease pattern.
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.
Clinical "staging systems" such as the Rai four-stage system and the Binet classification can help to determine when and how to treat the patient.
Determining when to start treatment and by what means is often difficult; no survival advantage is seen in treating the disease very early. The National Cancer Institute Working Group has issued guidelines for treatment, with specific markers that should be met before it is initiated.
Combination chemotherapy regimens are effective in both newly diagnosed and relapsed CLL. Combinations of fludarabine with alkylating agents (cyclophosphamide) produce higher response rates and a longer progression-free survival than single agents:
Although the purine analogue fludarabine was shown to give superior response rates to chlorambucil as primary therapy, no evidence shows early use of fludarabine improves overall survival, and some clinicians prefer to reserve fludarabine for relapsed disease.
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. This has been the first clinical trial demonstrating that the choice of a first-line therapy can improve the overall survival of patients with CLL.
"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. The monoclonal antibody alemtuzumab (directed against CD52) may be used in patients with refractory, bone marrow-based disease.
Prognosis depends on the subtype. Some subtypes have a median survival of 6–8 years, while others have a median survival of 22 years (which is a normal lifespan for older patients). Telomere length has been suggested to be a valuable prognostic indicator of survival.
CLL is primarily a disease of older adults, with a median age of 70 years at the time of diagnosis. Though less common, CLL sometimes affects people between 30 and 39 years of age. The incidence of CLL increases very quickly with increasing age.
In the United States during 2014, about 15,720 new cases are expected to be diagnosed, and 4,600 patients are expected to die from CLL. 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 (new diagnoses). 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.
In Western populations, subclinical "disease" can be identified in 3.5% of normal adults, and in up to 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.
In contrast, CLL is rare in Asian countries, such as Japan, China, and Korea, accounting for less than 10% of all leukemias in those regions.:1432 A low incidence is seen in Japanese immigrants to the US, and in African and Asian immigrants to Israel.
Rates of CLL are somewhat elevated in people exposed to certain chemicals. Under U.S. Department of Veterans' Affairs regulations, Vietnam veterans who served in-country or in the inland waterways of Vietnam and who later develop CLL are presumed to have contracted it from exposure to Agent Orange and may be entitled to compensation.
Research in 2008 is comparing different forms of bone marrow transplants to determine which patients are the best candidates and which approach is best in different situations.
Researchers at the Abramson Cancer Center of the University of Pennsylvania School of Medicine reported preliminary success in the use of gene therapy, through genetically modified T cells, to treat CLL. The findings, which were published in August 2011, were based on data from three patients who had modified T cells injected into their blood. The T cells had been modified to express genes that would allow the cells to proliferate in the body and destroy B cells including those causing the leukemia. Two patients went into remission, while the presence of leukemia in the third patient reduced by 70%. One of the patients had been diagnosed with CLL for 13 years, and his treatment was failing before he participated in the clinical trial. One week after the T cells were injected, the leukemia cells in his blood had disappeared. The T cells were still found in the bloodstream of the patients six months after the procedure, meaning they would be able to fight the disease should leukemia cells return. This was the first time scientists "have used gene therapy to successfully destroy cancer tumors in patients with advanced disease".
^ abHallek, M (September 2017). "Chronic lymphocytic leukemia: 2017 update on diagnosis, risk stratification, and treatment". American Journal of Hematology. 92 (9): 946–965. doi:10.1002/ajh.24826. PMID28782884.
^Greer, John P.; Arber, Daniel A.; Glader, Bertil; List, Alan F.; Means Jr., Robert T.; Paraskevas, Frixos; Rodgers, George M.; Foerster, John, eds. (2014). Wintrobe's clinical hematology (Thirteenth ed.). Lippincott Williams & Wilkins. ISBN978-1451172683.
^Bain, Barbara J. (2006). Blood Cells: A Practical Guide. Blackwell Publishing Limited. p. 439. ISBN978-1-4051-4265-6.
^Matutes E, Owusu-Ankomah K, Morilla R, Garcia Marco J, Houlihan A, Que TH, Catovsky D (1994). "The immunological profile of B-cell disorders and proposal of a scoring system for the diagnosis of CLL". Leukemia. 8 (10): 1640–5. PMID7523797.CS1 maint: Uses authors parameter (link)
^ abcdeKaushansky, K; Lichtman, M; Beutler, E; Kipps, T; Prchal, J; Seligsohn, U. (2010). Williams Hematology (8th ed.). McGraw-Hill. ISBN978-0071621519.
^Gale, Robert Peter; Rai, Kanti R., eds. (1987). Chronic lymphocytic leukemia : recent progress, future direction : proceedings of a Hyland Laboratories-UCLA symposium held in Napa, California, December 2–5, 1986. New York: Liss. ISBN9780845126585.
^Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS (Aug 1975). "Clinical staging of chronic lymphocytic leukemia". Blood. 46 (2): 219–34. PMID1139039.CS1 maint: Uses authors parameter (link)
^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 (Jul 1, 1981). "A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis". Cancer. 48 (1): 198–206. doi:10.1002/1097-0142(19810701)48:1<198::aid-cncr2820480131>3.0.co;2-v. PMID7237385.CS1 maint: Uses authors parameter (link)
^Lehmann S, Ogawa S, Raynaud SD, Sanada M, Nannya Y, Ticchioni M, Bastard C, Kawamata N, Koeffler HP (March 2008). "Molecular allelokaryotyping of early-stage, untreated chronic lymphocytic leukemia". Cancer. 112 (6): 1296–305. doi:10.1002/cncr.23270. PMID18246537.CS1 maint: Uses authors parameter (link)
^Pfeifer D, Pantic M, Skatulla I, Rawluk J, Kreutz C, Martens UM, Fisch P, Timmer J, Veelken H (February 2007). "Genome-wide analysis of DNA copy number changes and LOH in CLL using high-density SNP arrays". Blood. 109 (3): 1202–10. doi:10.1182/blood-2006-07-034256. PMID17053054.CS1 maint: Uses authors parameter (link)
^Ascani S, Leoni P, Fraternali Orcioni G, Bearzi I, Piccioli M, Materazzi M, Zinzani PL, Gherlinzoni F, Falini B, Pileri SA (June 1999). "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". Ann. Oncol. 10 (6): 649–53. doi:10.1023/A:1008349422735. PMID10442186.CS1 maint: Uses authors parameter (link)
^Cheson BD, Bennett JM, Grever M, Kay N, Keating MJ, O'Brien S, Rai KR (1996). "National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment". Blood. 87 (12): 4990–7. PMID8652811.CS1 maint: Uses authors parameter (link)
^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 (2006). "Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia". Blood. 107 (3): 885–91. doi:10.1182/blood-2005-06-2395. PMID16219797.CS1 maint: Uses authors parameter (link)
^Byrd JC, Peterson BL, Morrison VA, Park K, Jacobson R, Hoke E, Vardiman JW, Rai K, Schiffer CA, Larson RA (2003). "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)". Blood. 101 (1): 6–14. doi:10.1182/blood-2002-04-1258. PMID12393429.CS1 maint: Uses authors parameter (link)
^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 (2005). "Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia". J. Clin. Oncol. 23 (18): 4079–88. doi:10.1200/JCO.2005.12.051. PMID15767648.CS1 maint: Uses authors parameter (link)
^Rai KR, Peterson BL, Appelbaum FR, Kolitz J, Elias L, Shepherd L, Hines J, Threatte GA, Larson RA, Cheson BD, Schiffer CA (2000). "Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia". N. Engl. J. Med. 343 (24): 1750–7. doi:10.1056/NEJM200012143432402. PMID11114313.CS1 maint: Uses authors parameter (link)
^Steurer M, Pall G, Richards S, Schwarzer G, Bohlius J, Greil R (2006). Steurer, Michael, ed. "Purine antagonists for chronic lymphocytic leukaemia". Cochrane Database of Systematic Reviews. 3 (3): CD004270. doi:10.1002/14651858.CD004270.pub2. PMID16856041.CS1 maint: Uses authors parameter (link)
^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 (2010). "Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial". Lancet. 376 (9747): 1164–74. doi:10.1016/S0140-6736(10)61381-5. PMID20888994.CS1 maint: Uses authors parameter (link)
^Associated Press, published in the New York Times. November 1, 2013 F.D.A. Clears New Cancer-Fighting Drug From Roche
^Keating MJ, Flinn I, Jain V, Binet JL, Hillmen P, Byrd J, Albitar M, Brettman L, Santabarbara P, Wacker B, Rai KR (2002). "Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study". Blood. 99 (10): 3554–61. doi:10.1182/blood.V99.10.3554. PMID11986207.CS1 maint: Uses authors parameter (link)
^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 (June 2009). "Telomere length is an independent predictor of survival, treatment requirement and Richter's syndrome transformation in chronic lymphocytic leukemia". Leukemia. 23 (6): 1062–72. doi:10.1038/leu.2008.399. PMID19340005.CS1 maint: Uses authors parameter (link)
^Rawstron AC, Green MJ, Kuzmicki A, Kennedy B, Fenton JA, Evans PA, O'Connor SJ, Richards SJ, Morgan GJ, Jack AS, Hillmen P (July 2002). "Monoclonal B lymphocytes with the characteristics of "indolent" chronic lymphocytic leukemia are present in 3.5% of adults with normal blood counts". Blood. 100 (2): 635–9. doi:10.1182/blood.V100.2.635. PMID12091358.CS1 maint: Uses authors parameter (link)
^Turgeon, Mary Louise (2005). Clinical hematology: theory and procedures. Hagerstown, MD: Lippincott Williams & Wilkins. p. 283. ISBN978-0-7817-5007-3. Frequency of lymphoid neoplasms. (Source: Modified from WHO Blue Book on Tumour of Hematopoietic and Lymphoid Tissues. 2001, p. 2001.)CS1 maint: Uses authors parameter (link)