请输入您要查询的百科知识：

　

词条 Chronic lymphocytic leukemia
释义

  1. Signs and symptoms

     Complications 

  2. Cause

  3. Diagnosis

     Clinical staging  Array-based karyotyping  Related diseases  Differential diagnosis 

  4. Treatment

     Decision to treat  Chemotherapy  Targeted therapy  Stem cell transplantation  Refractory CLL  During pregnancy 

  5. Prognosis

  6. Epidemiology

  7. Research directions

  8. See also

  9. References

  10. External links

{{Redirect|B-cell CLL|the gene family|B-cell CLL/lymphoma}}{{Infobox medical condition (new)
| name = Chronic lymphocytic leukemia
| synonyms = B-cell chronic lymphocytic leukemia (B-CLL)[1]
| image = Chronic_lymphocytic_leukemia.jpg
| caption = Peripheral blood smear showing CLL cells
| pronounce =
| field = Hematology and oncology
| symptoms = Early: None[2]
Later: Non-painful lymph nodes swelling, feeling tired, fever, weight loss[2]
| complications =
| onset = Older than 50[4]
| duration =
| types =
| causes =
| risks = Family history, Agent Orange, certain insecticides[2][6]
| diagnosis = Blood tests[7]
| differential = Mononucleosis, hairy cell leukemia, acute lymphocytic leukemia, persistent polyclonal B-cell lymphocytosis[7]
| prevention =
| treatment = Watchful waiting, chemotherapy, immunotherapy[6][7]
| medication =
| prognosis = Five-year survival ~83% (US)[4]
| frequency = 904,000 (2015)[12]
| deaths = 60,700 (2015)[13]
}}Chronic lymphocytic leukemia (CLL) is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell).[2] Early on there are typically no symptoms.[2] Later non-painful lymph nodes swelling, feeling tired, fever, or weight loss for no clear reason may occur.[2] Enlargement of the spleen and anemia may also occur.[2][6] It typically worsens gradually.[2]

Risk factors include having a family history of the disease.[2] Exposure to Agent Orange and certain insecticides might also be a risk.[6] CLL results in the buildup of B cell lymphocytes in the bone marrow, lymph nodes, and blood.[3] These cells do not function well and crowd out healthy blood cells.[2] CLL is divided into two main types: those with a mutated IGHV gene and those without.[3] Diagnosis is typically based on blood tests finding high numbers of mature lymphocytes and smudge cells.[4]

Management of early disease is generally with watchful waiting.[4] Infections should more readily be treated with antibiotics.[3] In those with significant symptoms, chemotherapy or immunotherapy may be used.[3] As of 2019 ibrutinib is often the initial medication recommended.[29] The medications fludarabine, cyclophosphamide, and rituximab were previously the initial treatment in those who are otherwise healthy.[5]

CLL affected about 904,000 people globally in 2015 and resulted in 60,700 deaths.[6][7] The disease most commonly occurs in people over the age of 50.[8] Males are affected more often than females.[8] It is much less common in people from Asia.[3] Five-year survival following diagnosis is approximately 83% in the United States.[8] It represents less than 1% of deaths from cancer.[7]

{{TOC limit|3}}

Signs and symptoms

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.

Complications

Complications include hypogammaglobulinemia leading to recurrent infection, warm autoimmune hemolytic anemia in 10–15% of patients, and marrow failure. Chronic lymphocytic leukemia may also transform into Richter's syndrome, the development of fast-growing diffuse large B cell lymphoma, prolymphocytic leukemia, Hodgkin's lymphoma, or acute leukemia in some patients. Its incidence is estimated to be around 5% in patients with CLL.[9]

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.[10]

Cause

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|date=August 2018}} 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.[11]

Diagnosis

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.[5] 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).[12]{{rp|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 differentiation 5 (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.[13]

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).[14] Discrimination between CLL and MCL can be improved by adding non-routine markers such as CD54[15] and CD200.[16] 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.[17]

Clinical staging

Staging, determining the extent of the disease, is done with the Rai staging system or the Binet classification (see details[18]) 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.[49]{{rp|1441}}

Rai staging system[19][20]
  • Stage 0: characterized by absolute lymphocytosis (>15,000/mm3) without adenopathy, hepatosplenomegaly, anemia, or thrombocytopenia
  • Stage I: characterized by absolute lymphocytosis with lymphadenopathy without hepatosplenomegaly, anemia, or thrombocytopenia
  • Stage II: characterized by absolute lymphocytosis with either hepatomegaly or splenomegaly with or without lymphadenopathy
  • Stage III: characterized by absolute lymphocytosis and anemia (hemoglobin <11 g/dL) with or without lymphadenopathy, hepatomegaly, or splenomegaly
  • Stage IV: characterized by absolute lymphocytosis and thrombocytopenia (<100,000/mm3) with or without lymphadenopathy, hepatomegaly, splenomegaly, or anemia
Binet classification[21]
  • Clinical stage A: characterized by no anemia or thrombocytopenia and fewer than three areas of lymphoid involvement (Rai stages 0, I, and II)
  • Clinical stage B: characterized by no anemia or thrombocytopenia with three or more areas of lymphoid involvement (Rai stages I and II)
  • Clinical stage C: characterized by anemia and/or thrombocytopenia regardless of the number of areas of lymphoid enlargement (Rai stages III and IV)

Array-based karyotyping

{{Main|Virtual karyotype}}

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.[22][23][24][25][26]

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 leukemias.[27][28]

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

Lymphoid disorders that can present as chronic leukemia and can be confused with typical B-cell chronic lymphoid leukemia[29]
Follicular lymphoma
Splenic marginal zone lymphoma
Nodal marginal zone 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.
  • 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.

Treatment

CLL treatment focuses on controlling the disease and its symptoms rather than on an outright cure. In those without or only minimal symptoms watchful waiting is generally appropriate.[29]

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).

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.[30]

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.[29][31]

The decision to start CLL treatment is taken when the person's symptoms or blood counts indicate that the disease has progressed to a point where it may affect 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.[18]

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.[32]

Chemotherapy

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:

  • FC (fludarabine with cyclophosphamide)[33]
  • FR (fludarabine with rituximab)[34]
  • FCR (fludarabine, cyclophosphamide, and rituximab)[35]
  • CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone)

Although the purine analogue fludarabine was shown to give superior response rates to chlorambucil as primary therapy,[36][37] 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.[38] 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.

Alkylating agents approved for CLL include bendamustine and cyclophosphamide.

Targeted therapy

Targeted therapy attacks cancer cells at a specific target, with the aim of not harming normal cells. Targeted drugs used in CLL include venetoclax (a Bcl-2 inhibitor), ibrutinib (a Bruton's tyrosine kinase inhibitor), idelalisib and duvelisib (inhibitors of some forms of the enzyme phosphoinositide 3-kinase), as well as monoclonal antibodies against CD20 (rituximab, ofatumumab and obinutuzumab) and CD52 (alemtuzumab).[39][40]

Stem cell transplantation

Autologous stem cell transplantation, using the recipient's own cells, is not curative.[49]{{rp|1458}} 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.[49]{{rp|1458}} An intermediate level, called reduced-intensity conditioning allogeneic stem cell transplantation, may be better tolerated by older or frail patients.[77][41]

Refractory 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.[42] The monoclonal antibody alemtuzumab (directed against CD52) may be used in patients with refractory, bone marrow-based disease.| deadurl= no|date=January 1980 }}
19. ^{{cite book|editor1=Gale, Robert Peter|editor2=Rai, Kanti R.|title=Chronic lymphocytic leukemia : recent progress, future direction : proceedings of a Hyland Laboratories-UCLA symposium held in Napa, California, December 2–5, 1986|date=1987|publisher=Liss|location=New York|isbn=9780845126585}}
20. ^{{cite journal | authors = Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS | title = Clinical staging of chronic lymphocytic leukemia. | journal = Blood | volume = 46 | issue = 2 | pages = 219–34 | date = Aug 1975 | pmid = 1139039 }}
21. ^{{cite journal | authors = 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 | title = A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. | journal = Cancer | volume = 48 | issue = 1 | pages = 198–206 | date = Jul 1, 1981 | pmid = 7237385 | doi = 10.1002/1097-0142(19810701)48:1<198::aid-cncr2820480131>3.0.co;2-v }}
22. ^{{cite journal | authors = Lehmann S, Ogawa S, Raynaud SD, Sanada M, Nannya Y, Ticchioni M, Bastard C, Kawamata N, Koeffler HP | title = Molecular allelokaryotyping of early-stage, untreated chronic lymphocytic leukemia | journal = Cancer | volume = 112 | issue = 6 | pages = 1296–305 | date = March 2008 | pmid = 18246537 | doi = 10.1002/cncr.23270 }}
23. ^{{cite journal | authors = Sargent R, Jones D, Abruzzo LV, Yao H, Bonderover J, Cisneros M, Wierda WG, Keating MJ, Luthra R | title = Customized oligonucleotide array-based comparative genomic hybridization as a clinical assay for genomic profiling of chronic lymphocytic leukemia | journal = J Mol Diagn | volume = 11 | issue = 1 | pages = 25–34 | date = January 2009 | pmid = 19074592 | pmc = 2607562 | doi = 10.2353/jmoldx.2009.080037 | url = http://linkinghub.elsevier.com/retrieve/pii/S1525-1578(10)60205-X }}
24. ^{{cite journal | authors = Schwaenen C, Nessling M, Wessendorf S, Salvi T, Wrobel G, Radlwimmer B, Kestler HA, Haslinger C, Stilgenbauer S, Döhner H, Bentz M, Lichter P | title = Automated array-based genomic profiling in chronic lymphocytic leukemia: development of a clinical tool and discovery of recurrent genomic alterations | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 101 | issue = 4 | pages = 1039–44 | date = January 2004 | pmid = 14730057 | pmc = 327147 | doi = 10.1073/pnas.0304717101 }}
25. ^{{cite journal | authors = Pfeifer D, Pantic M, Skatulla I, Rawluk J, Kreutz C, Martens UM, Fisch P, Timmer J, Veelken H | 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 = 1202–10 | date = February 2007 | pmid = 17053054 | doi = 10.1182/blood-2006-07-034256 }}
26. ^{{cite journal | authors = 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 | title = Whole-genome scanning by array comparative genomic hybridization as a clinical tool for risk assessment in chronic lymphocytic leukemia | journal = J Mol Diagn | volume = 10 | issue = 5 | pages = 442–51 | date = September 2008 | pmid = 18687794 | pmc = 2518739 | doi = 10.2353/jmoldx.2008.080033 }}
27. ^{{cite web|url=http://www.accessmedicine.com/content.aspx?aid=2149838 |title=T Cell Prolymphocytic Leukemia |publisher=AccessMedicine |accessdate=2009-02-04 |deadurl=yes |archiveurl=https://web.archive.org/web/20110707080329/http://www.accessmedicine.com/content.aspx?aid=2149838 |archivedate=2011-07-07 |df= }}
28. ^{{cite journal | authors = Ascani S, Leoni P, Fraternali Orcioni G, Bearzi I, Piccioli M, Materazzi M, Zinzani PL, Gherlinzoni F, Falini B, Pileri SA | 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 = Ann. Oncol. | volume = 10 | issue = 6 | pages = 649–53 | date = June 1999 | pmid = 10442186 | doi = 10.1023/A:1008349422735 }}
29. ^Harison 18th ed., Pg-919, table 110.1
30. ^{{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 | archiveurl= https://web.archive.org/web/20071017143326/http://www.cancer.gov/cancertopics/pdq/treatment/CLL/HealthProfessional/page5| archivedate= 17 October 2007 | deadurl= no|date=January 1980}}
31. ^{{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}}
32. ^{{cite journal | authors = Cheson BD, Bennett JM, Grever M, Kay N, Keating MJ, O'Brien S, Rai KR | 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 }}
33. ^{{cite journal | authors = 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 | 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 = 885–91 | year = 2006 | pmid = 16219797 | doi = 10.1182/blood-2005-06-2395 }}
34. ^{{cite journal | authors = Byrd JC, Peterson BL, Morrison VA, Park K, Jacobson R, Hoke E, Vardiman JW, Rai K, Schiffer CA, Larson RA | 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 }}
35. ^{{cite journal | authors = 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 | 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 }}
36. ^{{cite journal | authors = Rai KR, Peterson BL, Appelbaum FR, Kolitz J, Elias L, Shepherd L, Hines J, Threatte GA, Larson RA, Cheson BD, Schiffer CA | 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 = 10.1056/NEJM200012143432402 }}
37. ^{{cite journal | authors = 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 | volume = 3 | issue = 3 | pages = CD004270 | year = 2006 | pmid = 16856041 | doi = 10.1002/14651858.CD004270.pub2 | editor1-last = Steurer | editor1-first = Michael }}
38. ^{{cite journal | authors = 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 | 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 = 1164–74 | year = 2010 | pmid = 20888994 | doi = 10.1016/S0140-6736(10)61381-5 }}
39. ^{{cite journal |last1=Khan |first1=M |last2=Siddiqi |first2=T |title=Targeted Therapies in CLL: Monotherapy Versus Combination Approaches. |journal=Current hematologic malignancy reports |date=December 2018 |volume=13 |issue=6 |pages=525-533 |doi=10.1007/s11899-018-0481-7 |pmid=30535947}}
40. ^1 2 3 {{cite web |title=Chronic Lymphocytic Leukemia Treatment |url=https://www.cancer.gov/types/leukemia/hp/cll-treatment-pdq |website=National Cancer Institute |accessdate=19 February 2019 |language=en |date=1 January 1980}}
41. ^{{cite journal | authors = 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 | 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 = 841–8 | year = 2003 | pmid = 12750695 | doi = 10.1038/sj.leu.2402905 }}
42. ^{{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 | archiveurl= https://web.archive.org/web/20071017143330/http://www.cancer.gov/cancertopics/pdq/treatment/CLL/HealthProfessional/page6| archivedate= 17 October 2007 | deadurl= no|date=January 1980}}
43. ^{{cite journal | authors = 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 | volume = 99 | issue = 10 | pages = 3554–61 | year = 2002 | pmid = 11986207 | doi = 10.1182/blood.V99.10.3554 }}
44. ^1 {{cite journal | authors = Shapira T, Pereg D, Lishner M | title = How I treat acute and chronic leukemia in pregnancy | journal = Blood Rev. | volume = 22 | issue = 5 | pages = 247–59 | date = September 2008 | pmid = 18472198 | doi = 10.1016/j.blre.2008.03.006 }}
45. ^{{cite journal | authors = 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 | 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 = 1062–72 | date = June 2009 | pmid = 19340005 | doi = 10.1038/leu.2008.399 }}
46. ^{{cite web |url=http://www.cancer.gov/cancertopics/pdq/treatment/CLL/healthprofessional/page1 |title=General Information About Chronic Lymphocytic Leukemia |author=National Cancer Institute |accessdate=2007-09-04 |deadurl= no|date=January 1980 }}
47. ^{{cite web|title=Chronic lymphocytic leukaemia (CLL) statistics|url=http://www.cancerresearchuk.org/cancer-info/cancerstats/types/leukaemia-cll/|website=Cancer Research UK|accessdate=27 October 2014}}
48. ^{{cite journal | authors = Rawstron AC, Green MJ, Kuzmicki A, Kennedy B, Fenton JA, Evans PA, O'Connor SJ, Richards SJ, Morgan GJ, Jack AS, Hillmen P | 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 = 635–9 | date = July 2002 | pmid = 12091358 | doi = 10.1182/blood.V100.2.635 }}
49. ^1 2 3 4 {{Cite book | last=Kaushansky | first=K |author2=Lichtman, M |author3=Beutler, E |author4=Kipps, T |author5=Prchal, J |author6= Seligsohn, U. |title=Williams Hematology | publisher=McGraw-Hill | year=2010 | chapter= |edition=8th |isbn= 978-0071621519}}
50. ^1 {{cite journal | authors = 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 }}
51. ^{{cite book | authors = Turgeon, Mary Louise | 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.) }}
52. ^1 {{cite journal | authors = Gribben JG | title = Stem cell transplantation in chronic lymphocytic leukemia | journal = Biol. Blood Marrow Transplant. | volume = 15 | issue = 1 Suppl | pages = 53–8 | date = January 2008 | pmid = 19147079 | pmc = 2668540 | doi = 10.1016/j.bbmt.2008.10.022 }}
53. ^{{cite news | last = Auer | first = Holly | title = Genetically Modified "Serial Killer" T Cells Obliterate Tumors in Patients with Chronic Lymphocytic Leukemia, Penn Researchers Report | url = http://www.uphs.upenn.edu/news/News_Releases/2011/08/t-cells/ | publisher = University of Pennsylvania School of Medicine | date = August 10, 2011 | accessdate = August 12, 2011}}
54. ^{{cite journal | authors = Porter DL, Levine BL, Kalos M, Bagg A, June CH | title = Chimeric Antigen Receptor–Modified T Cells in Chronic Lymphoid Leukemia | journal = N. Engl. J. Med. | volume = 365 | issue = 8 | pages = 725–33 | year = 2011 | pmid = 21830940 | pmc = 3387277 | doi = 10.1056/NEJMoa1103849 }}
55. ^{{cite journal | authors = Kalos M, Levine BL, Porter DL, Katz S, Grupp SA, Bagg A, June CH | title = T Cells with Chimeric Antigen Receptors Have Potent Antitumor Effects and Can Establish Memory in Patients with Advanced Leukemia | journal = Sci. Transl. Med. | volume = 3 | issue = 95 | pages = 95ra73 | year = 2011 | pmid = 21832238 | pmc = 3393096 | doi = 10.1126/scitranslmed.3002842 }}
56. ^1 {{cite news | last = Palca | first = Joe | title = Gene Therapy Advance Trains Immune System To Fight Leukemia | url = https://www.npr.org/blogs/health/2011/08/11/139536661/gene-therapy-breakthrough-trains-immune-system-to-fight-leukemia | publisher = NPR | date = August 11, 2011 | accessdate = August 12, 2011}}
57. ^{{cite news | last = Bazell | first = Robert | title = New leukemia treatment exceeds 'wildest expectations' | url = http://www.msnbc.msn.com/id/44090512/ | publisher = MSNBC | date = August 10, 2011 | accessdate = August 12, 2011}}
58. ^{{cite news | last = DeNoon | first = Daniel J. | title = Gene Therapy Cures Adult Leukemia | url = http://www.webmd.com/cancer/news/20110810/gene-therapy-cures-adult-leukemia | publisher = WebMD | date = August 10, 2011 | accessdate = August 12, 2011}}
59. ^{{cite news | last = Beasly | first = Deena | title = Gene therapy shown to destroy leukemia tumors | url = https://www.reuters.com/article/2011/08/10/us-leukemia-genetherapy-idUSTRE7795NT20110810 | agency = Reuters | date = August 10, 2011 | accessdate = August 12, 2011}}
60. ^{{cite journal | authors = ten Hacken E, Burger JA | title = Microenvironment dependency in Chronic Lymphocytic Leukemia: The basis for new targeted therapies | journal = Pharmacol. Ther. | volume = 144 | issue = 3 | pages = 338–48 | year = 2014 | pmid = 25050922 | doi = 10.1016/j.pharmthera.2014.07.003 }}
61. ^{{Cite journal | url=http://www.bloodjournal.org/content/130/Suppl_1/428 | title=Initial Results of Ibrutinib Plus Venetoclax in Relapsed, Refractory CLL (Bloodwise TAP CLARITY Study): High Rates of Overall Response, Complete Remission and MRD Eradication after 6 Months of Combination Therapy| journal=Blood| volume=130| issue=Suppl 1| pages=428| date=2017-12-07| last1=Forconi| first1=Francesco| last2=Fox| first2=Christopher P.| last3=Bloor| first3=Adrian| last4=Devereux| first4=Stephen| last5=Gribben| first5=John G.| last6=Pettitt| first6=Andrew| last7=Schuh| first7=Anna| last8=McCaig| first8=Alison| last9=MacDonald| first9=Donald| last10=Fegan| first10=Christopher| last11=Bishop| first11=Rebecca| last12=Yates| first12=Francesca| last13=Vicente| first13=Samuel Munoz| last14=Brock| first14=Kristian| last15=Rawstron| first15=Andy| last16=Munir| first16=Talha| last17=Hillmen| first17=Peter}}

External links

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