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Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Introduction-Definition, Diagnosis, Cell of Origin

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Book cover Chronic Lymphocytic Leukemia

Part of the book series: Molecular and Translational Medicine ((MOLEMED))

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Abstract

This chapter begins by defining CLL as per the new WHO fourth edition revision and the “bread and butter” of this disease to include epidemiology; clinical features; morphology and phenotype of MBL, CLL, and SLL; the progression; and transformation. This chapter delves further and explains why and what makes the pseudo-follicles or proliferation centers (PCs) different from the normal germinal centers. The rationale behind the dim expression of surface immunoglobulin light chains or absence of FMC7 expression is explained. Some of the stories behind these molecules are charming. The initial definition and its relation to “lymphosarcoma” are expanded upon. The perspectives in CLL are changing since the 1960s. Is it really a low proliferative with low replication disease? How has its definition evolved since the 1960s–2016 ranging from the Rappaport system to the WHO 2016? Familiarity with these is important as we interact with clinicians and pathologists who are familiar with different classification systems. What is the cell of origin? Is it the naïve B cell, or is it the B cell that has passed through and differentiated in the germinal center? How is it treated? What is the role of CD20 antibodies? How has the CD20 antibody evolved over time, and what are its generations? CAR T therapy is cutting-edge individualized personalized medicine and is making its way into CLL. MRD is becoming significant in indolent lymphomas, and there are technologies available that can be pursued in clinical practice. In summary this chapter is a review of the pathology that is essential in day-to-day practice and also addresses the biology of disease that explain the day-to-day “CLL intrigues,” which would be nice to know but not always easily accessible in our busy day-to day lives.

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References

  1. Campo E, Swerdlow SH, Harris NL, Pileri S, Stein H, Jaffe ES. The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications. Blood. 2011;117(19):5019–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, Advani R, Ghielmini M, Salles GA, Zelenetz AD, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127(20):2375–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Eichhorst B, Dreyling M, Robak T, Montserrat E, Hallek M. Chronic lymphocytic leukemia: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2011;22(Suppl 6):vi50–4.

    PubMed  Google Scholar 

  4. Li Y, Wang Y, Wang Z, Yi D, Ma S. Racial differences in three major NHL subtypes: descriptive epidemiology. Cancer Epidemiol. 2015;39(1):8–13.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Berndt SI, Camp NJ, Skibola CF, Vijai J, Wang Z, Gu J, Nieters A, Kelly RS, Smedby KE, Monnereau A, et al. Meta-analysis of genome-wide association studies discovers multiple loci for chronic lymphocytic leukemia. Nat Commun. 2016;7:10933.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Baumann Kreuziger LM, Tarchand G, Morrison VA. The impact of Agent Orange exposure on presentation and prognosis of patients with chronic lymphocytic leukemia. Leuk Lymphoma. 2014;55(1):63–6.

    Article  CAS  PubMed  Google Scholar 

  7. Galton DA. The pathogenesis of chronic lymphocytic leukemia. Can Med Assoc J. 1966;94(19):1005–10.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Dameshek W. Chronic lymphocytic leukemia—an accumulative disease of immunolgically incompetent lymphocytes. Blood. 1967;29(Suppl 4):566–84.

    Google Scholar 

  9. Rai KR, Jain P. Chronic lymphocytic leukemia (CLL)-then and now. Am J Hematol. 2016;91(3):330–40.

    Article  CAS  PubMed  Google Scholar 

  10. Andreeff M, Darzynkiewicz Z, Sharpless TK, Clarkson BD, Melamed MR. Discrimination of human leukemia subtypes by flow cytometric analysis of cellular DNA and RNA. Blood. 1980;55(2):282–93.

    CAS  PubMed  Google Scholar 

  11. Caligaris-Cappio F, Hamblin TJ. B-cell chronic lymphocytic leukemia: a bird of a different feather. J Clin Oncol. 1999;17(1):399–408.

    Article  CAS  PubMed  Google Scholar 

  12. Damle RN, Temburni S, Calissano C, Yancopoulos S, Banapour T, Sison C, Allen SL, Rai KR, Chiorazzi N. CD38 expression labels an activated subset within chronic lymphocytic leukemia clones enriched in proliferating B cells. Blood. 2007;110(9):3352–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Consoli U, El-Tounsi I, Sandoval A, Snell V, Kleine HD, Brown W, Robinson JR, DiRaimondo F, Plunkett W, Andreeff M. Differential induction of apoptosis by fludarabine monophosphate in leukemic B and normal T cells in chronic lymphocytic leukemia. Blood. 1998;91(5):1742–8.

    CAS  PubMed  Google Scholar 

  14. Messmer BT, Messmer D, Allen SL, Kolitz JE, Kudalkar P, Cesar D, Murphy EJ, Koduru P, Ferrarini M, Zupo S, et al. In vivo measurements document the dynamic cellular kinetics of chronic lymphocytic leukemia B cells. J Clin Invest. 2005;115(3):755–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Chiorazzi N, Ferrarini M. Cellular origin(s) of chronic lymphocytic leukemia: cautionary notes and additional considerations and possibilities. Blood. 2011;117(6):1781–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Damle RN, Batliwalla FM, Ghiotto F, Valetto A, Albesiano E, Sison C, Allen SL, Kolitz J, Vinciguerra VP, Kudalkar P, et al. Telomere length and telomerase activity delineate distinctive replicative features of the B-CLL subgroups defined by immunoglobulin V gene mutations. Blood. 2004;103(2):375–82.

    Article  CAS  PubMed  Google Scholar 

  17. Herishanu Y, Perez-Galan P, Liu D, Biancotto A, Pittaluga S, Vire B, Gibellini F, Njuguna N, Lee E, Stennett L, et al. The lymph node microenvironment promotes B-cell receptor signaling, NF-kappaB activation, and tumor proliferation in chronic lymphocytic leukemia. Blood. 2011;117(2):563–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Swerdlow SH, Murray LJ, Habeshaw JA, Stansfeld AG. Lymphocytic lymphoma/B-chronic lymphocytic leukaemia—an immunohistopathological study of peripheral B lymphocyte neoplasia. Br J Cancer. 1984;50(5):587–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Granziero L, Ghia P, Circosta P, Gottardi D, Strola G, Geuna M, Montagna L, Piccoli P, Chilosi M, Caligaris-Cappio F. Survivin is expressed on CD40 stimulation and interfaces proliferation and apoptosis in B-cell chronic lymphocytic leukemia. Blood. 2001;97(9):2777–83.

    Article  CAS  PubMed  Google Scholar 

  20. Skarin AT, Dorfman DM. Non-Hodgkin's lymphomas: current classification and management. CA Cancer J Clin. 1997;47(6):351–72.

    Article  CAS  PubMed  Google Scholar 

  21. Johnstone AP. Chronic lymphocytic leukaemia and its relationship to normal B lymphopoiesis. Immunol Today. 1982;3(12):343–8.

    Article  CAS  PubMed  Google Scholar 

  22. Catovsky D, Cherchi M, Brookss D, Bradely J, Zola H. Heterogeneity of B-cell leukemias demonstrated by the monoclonal antibody FMC7. Blood. 1981;58(2):406–8.

    CAS  PubMed  Google Scholar 

  23. Damle RN, Wasil T, Fais F, Ghiotto F, Valetto A, Allen SL, Buchbinder A, Budman D, Dittmar K, Kolitz J, et al. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood. 1999;94(6):1840–7.

    CAS  PubMed  Google Scholar 

  24. Hamblin TJ, Orchard JA, Ibbotson RE, Davis Z, Thomas PW, Stevenson FK, Oscier DG. CD38 expression and immunoglobulin variable region mutations are independent prognostic variables in chronic lymphocytic leukemia, but CD38 expression may vary during the course of the disease. Blood. 2002;99(3):1023–9.

    Article  CAS  PubMed  Google Scholar 

  25. Tobin G, Thunberg U, Johnson A, Thorn I, Soderberg O, Hultdin M, Botling J, Enblad G, Sallstrom J, Sundstrom C, et al. Somatically mutated Ig V(H)3-21 genes characterize a new subset of chronic lymphocytic leukemia. Blood. 2002;99(6):2262–4.

    Article  CAS  PubMed  Google Scholar 

  26. Ghia EM, Jain S, Widhopf GF 2nd, Rassenti LZ, Keating MJ, Wierda WG, Gribben JG, Brown JR, Rai KR, Byrd JC, et al. Use of IGHV3-21 in chronic lymphocytic leukemia is associated with high-risk disease and reflects antigen-driven, post-germinal center leukemogenic selection. Blood. 2008;111(10):5101–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Klein U, Tu Y, Stolovitzky GA, Mattioli M, Cattoretti G, Husson H, Freedman A, Inghirami G, Cro L, Baldini L, et al. Gene expression profiling of B cell chronic lymphocytic leukemia reveals a homogeneous phenotype related to memory B cells. J Exp Med. 2001;194(11):1625–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Rosenwald A, Alizadeh AA, Widhopf G, Simon R, Davis RE, Yu X, Yang L, Pickeral OK, Rassenti LZ, Powell J, et al. Relation of gene expression phenotype to immunoglobulin mutation genotype in B cell chronic lymphocytic leukemia. J Exp Med. 2001;194(11):1639–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kipps TJ, Stevenson FK, CJ W, Croce CM, Packham G, Wierda WG, O'Brien S, Gribben J, Rai K. Chronic lymphocytic leukaemia. Nat Rev Dis Primers. 2017;3:16096.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Zent CS, Kay NE. Autoimmune complications in chronic lymphocytic leukaemia (CLL). Best Pract Res Clin Haematol. 2010;23(1):47–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kipps TJ, Carson DA. Autoantibodies in chronic lymphocytic leukemia and related systemic autoimmune diseases. Blood. 1993;81(10):2475–87.

    CAS  PubMed  Google Scholar 

  32. Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink HK, Vardiman J, Lister TA, Bloomfield CD. The World Health Organization classification of neoplasms of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting—Airlie House, Virginia, November, 1997. Hematol J. 2000;1(1):53–66.

    Article  CAS  PubMed  Google Scholar 

  33. Pangalis GA, Roussou PA, Kittas C, Mitsoulis-Mentzikoff C, Matsouka-Alexandridis P, Anagnostopoulos N, Rombos I, Fessas P. Patterns of bone marrow involvement in chronic lymphocytic leukemia and small lymphocytic (well differentiated) non-Hodgkin's lymphoma. Its clinical significance in relation to their differential diagnosis and prognosis. Cancer. 1984;54(4):702–8.

    Article  CAS  PubMed  Google Scholar 

  34. Han T, Barcos M, Emrich L, Ozer H, Gajera R, Gomez GA, Reese PA, Minowada J, Bloom ML, Sadamori N, et al. Bone marrow infiltration patterns and their prognostic significance in chronic lymphocytic leukemia: correlations with clinical, immunologic, phenotypic, and cytogenetic data. J Clin Oncol. 1984;2(6):562–70.

    Article  CAS  PubMed  Google Scholar 

  35. Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner H, Hillmen P, Keating MJ, Montserrat E, Rai KR, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008;111(12):5446–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Matutes E, Owusu-Ankomah K, Morilla R, Garcia Marco J, Houlihan A, Que TH, Catovsky D. The immunological profile of B-cell disorders and proposal of a scoring system for the diagnosis of CLL. Leukemia. 1994;8(10):1640–5.

    CAS  PubMed  Google Scholar 

  37. Zomas AP, Matutes E, Morilla R, Owusu-Ankomah K, Seon BK, Catovsky D. Expression of the immunoglobulin-associated protein B29 in B cell disorders with the monoclonal antibody SN8 (CD79b). Leukemia. 1996;10(12):1966–70.

    CAS  PubMed  Google Scholar 

  38. Pezzella F, Tse AG, Cordell JL, Pulford KA, Gatter KC, Mason DY. Expression of the bcl-2 oncogene protein is not specific for the 14;18 chromosomal translocation. Am J Pathol. 1990;137(2):225–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Brunetti L, Di Noto R, Abate G, Gorrese M, Gravetti A, Raia M, Scalia G, Pascariello C, Camera A, Del Vecchio L. CD200/OX2, a cell surface molecule with immuno-regulatory function, is consistently expressed on hairy cell leukaemia neoplastic cells. Br J Haematol. 2009;145(5):665–7.

    Article  CAS  PubMed  Google Scholar 

  40. Alapat D, Coviello-Malle J, Owens R, Qu P, Barlogie B, Shaughnessy JD, Lorsbach RB. Diagnostic usefulness and prognostic impact of CD200 expression in lymphoid malignancies and plasma cell myeloma. Am J Clin Pathol. 2012;137(1):93–100.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Sandes AF, de Lourdes Chauffaille M, Oliveira CR, Maekawa Y, Tamashiro N, Takao TT, Ritter EC, Rizzatti EG. CD200 has an important role in the differential diagnosis of mature B-cell neoplasms by multiparameter flow cytometry. Cytometry B Clin Cytom. 2014;86(2):98–105.

    Article  PubMed  Google Scholar 

  42. Masiakowski P, Carroll RD. A novel family of cell surface receptors with tyrosine kinase-like domain. J Biol Chem. 1992;267(36):26181–90.

    CAS  PubMed  Google Scholar 

  43. MacKeigan JP, Murphy LO, Blenis J. Sensitized RNAi screen of human kinases and phosphatases identifies new regulators of apoptosis and chemoresistance. Nat Cell Biol. 2005;7(6):591–600.

    Article  CAS  PubMed  Google Scholar 

  44. Baskar S, Kwong KY, Hofer T, Levy JM, Kennedy MG, Lee E, Staudt LM, Wilson WH, Wiestner A, Rader C. Unique cell surface expression of receptor tyrosine kinase ROR1 in human B-cell chronic lymphocytic leukemia. Clin Cancer Res. 2008;14(2):396–404.

    Article  CAS  PubMed  Google Scholar 

  45. Rawstron AC, Fazi C, Agathangelidis A, Villamor N, Letestu R, Nomdedeu J, Palacio C, Stehlikova O, Kreuzer KA, Liptrot S, et al. A complementary role of multiparameter flow cytometry and high-throughput sequencing for minimal residual disease detection in chronic lymphocytic leukemia: an European Research Initiative on CLL study. Leukemia. 2016;30(4):929–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Kohler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. 1975. J Immunol. 2005;174(5):2453–5.

    CAS  PubMed  Google Scholar 

  47. Brooks DA, Beckman IG, Bradley J, McNamara PJ, Thomas ME, Zola H. Human lymphocyte markers defined by antibodies derived from somatic cell hybrids. IV. A monoclonal antibody reacting specifically with a subpopulation of human B lymphocytes. J Immunol. 1981;126(4):1373–7.

    CAS  PubMed  Google Scholar 

  48. Zola H, Moore HA, Hohmann A, Hunter IK, Nikoloutsopoulos A, Bradley J. The antigen of mature human B cells detected by the monoclonal antibody FMC7: studies on the nature of the antigen and modulation of its expression. J Immunol. 1984;133(1):321–6.

    CAS  PubMed  Google Scholar 

  49. Polyak MJ, Ayer LM, Szczepek AJ, Deans JP. A cholesterol-dependent CD20 epitope detected by the FMC7 antibody. Leukemia. 2003;17(7):1384–9.

    Article  CAS  PubMed  Google Scholar 

  50. Serke S, Schwaner I, Yordanova M, Szczepek A, Huhn D. Monoclonal antibody FMC7 detects a conformational epitope on the CD20 molecule: evidence from phenotyping after rituxan therapy and transfectant cell analyses. Cytometry. 2001;46(2):98–104.

    Article  CAS  PubMed  Google Scholar 

  51. Tedder TF, Streuli M, Schlossman SF, Saito H. Isolation and structure of a cDNA encoding the B1 (CD20) cell-surface antigen of human B lymphocytes. Proc Natl Acad Sci U S A. 1988;85(1):208–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Bubien JK, Zhou LJ, Bell PD, Frizzell RA, Tedder TF. Transfection of the CD20 cell surface molecule into ectopic cell types generates a Ca2+ conductance found constitutively in B lymphocytes. J Cell Biol. 1993;121(5):1121–32.

    Article  CAS  PubMed  Google Scholar 

  53. Delgado J, Matutes E, Morilla AM, Morilla RM, Owusu-Ankomah KA, Rafiq-Mohammed F, del Giudice I, Catovsky D. Diagnostic significance of CD20 and FMC7 expression in B-cell disorders. Am J Clin Pathol. 2003;120(5):754–9.

    Article  CAS  PubMed  Google Scholar 

  54. Moreau EJ, Matutes E, A'Hern RP, Morilla AM, Morilla RM, Owusu-Ankomah KA, Seon BK, Catovsky D. Improvement of the chronic lymphocytic leukemia scoring system with the monoclonal antibody SN8 (CD79b). Am J Clin Pathol. 1997;108(4):378–82.

    Article  CAS  PubMed  Google Scholar 

  55. Marti GE, Rawstron AC, Ghia P, Hillmen P, Houlston RS, Kay N, Schleinitz TA, Caporaso N. Diagnostic criteria for monoclonal B-cell lymphocytosis. Br J Haematol. 2005;130(3):325–32.

    Article  PubMed  Google Scholar 

  56. Landgren O, Albitar M, Ma W, Abbasi F, Hayes RB, Ghia P, Marti GE, Caporaso NE. B-cell clones as early markers for chronic lymphocytic leukemia. N Engl J Med. 2009;360(7):659–67.

    Article  CAS  PubMed  Google Scholar 

  57. Cheson BD, Bennett JM, Grever M, Kay N, Keating MJ, O'Brien S, Rai KR. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood. 1996;87(12):4990–7.

    CAS  PubMed  Google Scholar 

  58. Marti GE, Carter P, Abbasi F, Washington GC, Jain N, Zenger VE, Ishibe N, Goldin L, Fontaine L, Weissman N, et al. B-cell monoclonal lymphocytosis and B-cell abnormalities in the setting of familial B-cell chronic lymphocytic leukemia. Cytometry B Clin Cytom. 2003;52(1):1–12.

    Article  PubMed  Google Scholar 

  59. Rawstron AC, Yuille MR, Fuller J, Cullen M, Kennedy B, Richards SJ, Jack AS, Matutes E, Catovsky D, Hillmen P, et al. Inherited predisposition to CLL is detectable as subclinical monoclonal B-lymphocyte expansion. Blood. 2002;100(7):2289–90.

    Article  CAS  PubMed  Google Scholar 

  60. Shim YK, Vogt RF, Middleton D, Abbasi F, Slade B, Lee KY, Marti GE. Prevalence and natural history of monoclonal and polyclonal B-cell lymphocytosis in a residential adult population. Cytometry B Clin Cytom. 2007;72((5):344–53.

    Article  Google Scholar 

  61. Vogt RF, Shim YK, Middleton DC, Buffler PA, Campolucci SS, Lybarger JA, Marti GE. Monoclonal B-cell lymphocytosis as a biomarker in environmental health studies. Br J Haematol. 2007;139(5):690–700.

    Article  CAS  PubMed  Google Scholar 

  62. Ghia P, Prato G, Scielzo C, Stella S, Geuna M, Guida G, Caligaris-Cappio F. Monoclonal CD5+ and CD5- B-lymphocyte expansions are frequent in the peripheral blood of the elderly. Blood. 2004;103(6):2337–42.

    Article  CAS  PubMed  Google Scholar 

  63. Rachel JM, Zucker ML, Fox CM, Plapp FV, Menitove JE, Abbasi F, Marti GE. Monoclonal B-cell lymphocytosis in blood donors. Br J Haematol. 2007;139(5):832–6.

    Article  CAS  PubMed  Google Scholar 

  64. Rawstron AC, Shanafelt T, Lanasa MC, Landgren O, Hanson C, Orfao A, Hillmen P, Ghia P. Different biology and clinical outcome according to the absolute numbers of clonal B-cells in monoclonal B-cell lymphocytosis (MBL). Cytometry B Clin Cytom. 2010;78(Suppl 1):S19–23.

    Article  PubMed  Google Scholar 

  65. Shanafelt TD, Kay NE, Rabe KG, Call TG, Zent CS, Maddocks K, Jenkins G, Jelinek DF, Morice WG, Boysen J, et al. Brief report: natural history of individuals with clinically recognized monoclonal B-cell lymphocytosis compared with patients with Rai 0 chronic lymphocytic leukemia. J Clin Oncol. 2009;27(24):3959–63.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Rossi D, Sozzi E, Puma A, De Paoli L, Rasi S, Spina V, Gozzetti A, Tassi M, Cencini E, Raspadori D, et al. The prognosis of clinical monoclonal B cell lymphocytosis differs from prognosis of Rai 0 chronic lymphocytic leukaemia and is recapitulated by biological risk factors. Br J Haematol. 2009;146(1):64–75.

    Article  PubMed  Google Scholar 

  67. Mulligan CS, Thomas ME, Mulligan SP. Monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia. N Engl J Med. 2008;359(19):2065–6; author reply 2066.

    Article  CAS  PubMed  Google Scholar 

  68. Rawstron AC, Green MJ, Kuzmicki A, Kennedy B, Fenton JA, Evans PA, O'Connor SJ, Richards SJ, Morgan GJ, Jack AS, et al. Monoclonal B lymphocytes with the characteristics of “indolent” chronic lymphocytic leukemia are present in 3.5% of adults with normal blood counts. Blood. 2002;100(2):635–9.

    Article  CAS  PubMed  Google Scholar 

  69. Nieto WG, Almeida J, Romero A, Teodosio C, Lopez A, Henriques AF, Sanchez ML, Jara-Acevedo M, Rasillo A, Gonzalez M, et al. Increased frequency (12%) of circulating chronic lymphocytic leukemia-like B-cell clones in healthy subjects using a highly sensitive multicolor flow cytometry approach. Blood. 2009;114(1):33–7.

    Article  CAS  PubMed  Google Scholar 

  70. Almeida J, Nieto WG, Teodosio C, Pedreira CE, Lopez A, Fernandez-Navarro P, Nieto A, Rodriguez-Caballero A, Munoz-Criado S, Jara-Acevedo M, et al. CLL-like B-lymphocytes are systematically present at very low numbers in peripheral blood of healthy adults. Leukemia. 2011;25(4):718–22.

    Article  CAS  PubMed  Google Scholar 

  71. Scarfo L, Dagklis A, Scielzo C, Fazi C, Ghia P. CLL-like monoclonal B-cell lymphocytosis: are we all bound to have it? Semin Cancer Biol. 2010;20(6):384–90.

    Article  CAS  PubMed  Google Scholar 

  72. Fazi C, Scarfo L, Pecciarini L, Cottini F, Dagklis A, Janus A, Talarico A, Scielzo C, Sala C, Toniolo D, et al. General population low-count CLL-like MBL persists over time without clinical progression, although carrying the same cytogenetic abnormalities of CLL. Blood. 2011;118(25):6618–25.

    Article  CAS  PubMed  Google Scholar 

  73. Call TG, Norman AD, Hanson CA, Achenbach SJ, Kay NE, Zent CS, Ding W, Cerhan JR, Rabe KG, Vachon CM, et al. Incidence of chronic lymphocytic leukemia and high-count monoclonal B-cell lymphocytosis using the 2008 guidelines. Cancer. 2014;120(13):2000–5.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Morabito F, Mosca L, Cutrona G, Agnelli L, Tuana G, Ferracin M, Zagatti B, Lionetti M, Fabris S, Maura F, et al. Clinical monoclonal B lymphocytosis versus Rai 0 chronic lymphocytic leukemia: a comparison of cellular, cytogenetic, molecular, and clinical features. Clin Cancer Res. 2013;19(21):5890–900.

    Article  CAS  PubMed  Google Scholar 

  75. Santos FP, O'Brien S. Small lymphocytic lymphoma and chronic lymphocytic leukemia: are they the same disease? Cancer J. 2012;18(5):396–403.

    Article  CAS  PubMed  Google Scholar 

  76. Schmid C, Isaacson PG. Proliferation centres in B-cell malignant lymphoma, lymphocytic (B-CLL): an immunophenotypic study. Histopathology. 1994;24(5):445–51.

    Article  CAS  PubMed  Google Scholar 

  77. Shi YF, Li XH. [Immunohistochemical patterns of follicular dendritic cell meshwork and Ki-67 in small B-cell lymphomas]. Chin J Pathol. 2013;42(4):222–6.

    Google Scholar 

  78. Murray LJ, Swerdlow SH, Habeshaw JA. Distribution of B lymphocyte subsets in normal lymphoid tissue. Clin Exp Immunol. 1984;56(2):399–406.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Burger JA, Ghia P, Rosenwald A, Caligaris-Cappio F. The microenvironment in mature B-cell malignancies: a target for new treatment strategies. Blood. 2009;114(16):3367–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Castellino F, Huang AY, Altan-Bonnet G, Stoll S, Scheinecker C, Germain RN. Chemokines enhance immunity by guiding naive CD8+ T cells to sites of CD4+ T cell-dendritic cell interaction. Nature. 2006;440(7086):890–5.

    Article  CAS  PubMed  Google Scholar 

  81. Furman RR, Asgary Z, Mascarenhas JO, Liou HC, Schattner EJ. Modulation of NF-kappa B activity and apoptosis in chronic lymphocytic leukemia B cells. J Immunol. 2000;164(4):2200–6.

    Article  CAS  PubMed  Google Scholar 

  82. Teixeira Mendes LS, Peters N, Attygalle AD, Wotherspoon A. Cyclin D1 overexpression in proliferation centres of small lymphocytic lymphoma/chronic lymphocytic leukaemia. J Clin Pathol. 2017.

    Google Scholar 

  83. Ghia P, Strola G, Granziero L, Geuna M, Guida G, Sallusto F, Ruffing N, Montagna L, Piccoli P, Chilosi M, et al. Chronic lymphocytic leukemia B cells are endowed with the capacity to attract CD4+, CD40L+ T cells by producing CCL22. Eur J Immunol. 2002;32(5):1403–13.

    Article  CAS  PubMed  Google Scholar 

  84. Evans HL, Butler JJ, Youness EL. Malignant lymphoma, small lymphocytic type: a clinicopathologic study of 84 cases with suggested criteria for intermediate lymphocytic lymphoma. Cancer. 1978;41(4):1440–55.

    Article  CAS  PubMed  Google Scholar 

  85. Habeshaw JA, Lister TA, Stansfeld AG, Greaves MF. Correlation of transferrin receptor expression with histological class and outcome in non-Hodgkin lymphoma. Lancet. 1983;1(8323):498–501.

    Article  CAS  PubMed  Google Scholar 

  86. Ciccone M, Agostinelli C, Rigolin GM, Piccaluga PP, Cavazzini F, Righi S, Sista MT, Sofritti O, Rizzotto L, Sabattini E, et al. Proliferation centers in chronic lymphocytic leukemia: correlation with cytogenetic and clinicobiological features in consecutive patients analyzed on tissue microarrays. Leukemia. 2012;26(3):499–508.

    Article  CAS  PubMed  Google Scholar 

  87. Soma LA, Craig FE, Swerdlow SH. The proliferation center microenvironment and prognostic markers in chronic lymphocytic leukemia/small lymphocytic lymphoma. Hum Pathol. 2006;37(2):152–9.

    Article  CAS  PubMed  Google Scholar 

  88. Patten PE, Buggins AG, Richards J, Wotherspoon A, Salisbury J, Mufti GJ, Hamblin TJ, Devereux S. CD38 expression in chronic lymphocytic leukemia is regulated by the tumor microenvironment. Blood. 2008;111(10):5173–81.

    Article  CAS  PubMed  Google Scholar 

  89. Sarfati M, Chevret S, Chastang C, Biron G, Stryckmans P, Delespesse G, Binet JL, Merle-Beral H, Bron D. Prognostic importance of serum soluble CD23 level in chronic lymphocytic leukemia. Blood. 1996;88(11):4259–64.

    CAS  PubMed  Google Scholar 

  90. Lampert IA, Wotherspoon A, Van Noorden S, Hasserjian RP. High expression of CD23 in the proliferation centers of chronic lymphocytic leukemia in lymph nodes and spleen. Hum Pathol. 1999;30(6):648–54.

    Article  CAS  PubMed  Google Scholar 

  91. Chang JC, Harrington AM, Olteanu H, VanTuinen P, Kroft SH. Proliferation centers in bone marrows involved by chronic lymphocytic leukemia/small lymphocytic lymphoma: a clinicopathologic analysis. Ann Diagn Pathol. 2016;25:15–9.

    Article  PubMed  Google Scholar 

  92. Gine E, Martinez A, Villamor N, Lopez-Guillermo A, Camos M, Martinez D, Esteve J, Calvo X, Muntanola A, Abrisqueta P, et al. Expanded and highly active proliferation centers identify a histological subtype of chronic lymphocytic leukemia (“accelerated” chronic lymphocytic leukemia) with aggressive clinical behavior. Haematologica. 2010;95(9):1526–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Lampert I, Catovsky D, Marsh GW, Child JA, Galton DA. The histopathology of prolymphocytic leukaemia with particular reference to the spleen: a comparison with chronic lymphocytic leukaemia. Histopathology. 1980;4(1):3–19.

    Article  CAS  PubMed  Google Scholar 

  94. Gibson SE, Swerdlow SH, Ferry JA, Surti U, Dal Cin P, Harris NL, Hasserjian RP. Reassessment of small lymphocytic lymphoma in the era of monoclonal B-cell lymphocytosis. Haematologica. 2011;96(8):1144–52.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Melo JV, Catovsky D, Gregory WM, Galton DA. The relationship between chronic lymphocytic leukaemia and prolymphocytic leukaemia. IV. Analysis of survival and prognostic features. Br J Haematol. 1987;65(1):23–9.

    Article  CAS  PubMed  Google Scholar 

  96. Vallespi T, Montserrat E, Sanz MA. Chronic lymphocytic leukaemia: prognostic value of lymphocyte morphological subtypes. A multivariate survival analysis in 146 patients. Br J Haematol. 1991;77(4):478–85.

    Article  CAS  PubMed  Google Scholar 

  97. Put N, Van Roosbroeck K, Konings P, Meeus P, Brusselmans C, Rack K, Gervais C, Nguyen-Khac F, Chapiro E, Radford-Weiss I, et al. Chronic lymphocytic leukemia and prolymphocytic leukemia with MYC translocations: a subgroup with an aggressive disease course. Ann Hematol. 2012;91(6):863–73.

    Article  CAS  PubMed  Google Scholar 

  98. Richter MN. Generalized reticular cell sarcoma of lymph nodes associated with lymphatic leukemia. Am J Pathol. 1928;4(4):285–292.287.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Lortholary P, Boiron M, Ripault P, Levy JP, Manus A, Bernard J. [Chronic lymphoid leukemia secondarily associated with a malignant reticulopathy: Richter’s syndrome]. Nouv Rev Fr Hemat. 1964;4:621–44.

    Google Scholar 

  100. Agbay RL, Jain N, Loghavi S, Medeiros LJ, Khoury JD. Histologic transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma. Am J Hematol. 2016;91(10):1036–43.

    Article  PubMed  Google Scholar 

  101. Papajik T, Myslivecek M, Urbanova R, Buriankova E, Kapitanova Z, Prochazka V, Turcsanyi P, Formanek R, Henzlova L, Flodr P, et al. 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography examination in patients with chronic lymphocytic leukemia may reveal Richter transformation. Leuk Lymphoma. 2014;55(2):314–9.

    Article  CAS  PubMed  Google Scholar 

  102. Parikh SA, Rabe KG, Call TG, Zent CS, Habermann TM, Ding W, Leis JF, Schwager SM, Hanson CA, Macon WR, et al. Diffuse large B-cell lymphoma (Richter syndrome) in patients with chronic lymphocytic leukaemia (CLL): a cohort study of newly diagnosed patients. Br J Haematol. 2013;162(6):774–82.

    Article  PubMed  PubMed Central  Google Scholar 

  103. Rossi D, Lobetti Bodoni C, Genuardi E, Monitillo L, Drandi D, Cerri M, Deambrogi C, Ricca I, Rocci A, Ferrero S, et al. Telomere length is an independent predictor of survival, treatment requirement and Richter’s syndrome transformation in chronic lymphocytic leukemia. Leukemia. 2009;23(6):1062–72.

    Article  CAS  PubMed  Google Scholar 

  104. Rossi D, Spina V, Cerri M, Rasi S, Deambrogi C, De Paoli L, Laurenti L, Maffei R, Forconi F, Bertoni F, et al. Stereotyped B-cell receptor is an independent risk factor of chronic lymphocytic leukemia transformation to Richter syndrome. Clin Cancer Res. 2009;15(13):4415–22.

    Article  CAS  PubMed  Google Scholar 

  105. Mao Z, Quintanilla-Martinez L, Raffeld M, Richter M, Krugmann J, Burek C, Hartmann E, Rudiger T, Jaffe ES, Muller-Hermelink HK, et al. IgVH mutational status and clonality analysis of Richter's transformation: diffuse large B-cell lymphoma and Hodgkin lymphoma in association with B-cell chronic lymphocytic leukemia (B-CLL) represent 2 different pathways of disease evolution. Am J Surg Pathol. 2007;31(10):1605–14.

    Article  PubMed  Google Scholar 

  106. Tsimberidou AM, O'Brien S, Kantarjian HM, Koller C, Hagemeister FB, Fayad L, Lerner S, Bueso-Ramos CE, Keating MJ. Hodgkin transformation of chronic lymphocytic leukemia: the M. D. Anderson Cancer Center experience. Cancer. 2006;107(6):1294–302.

    Article  CAS  PubMed  Google Scholar 

  107. Rubin D, Hudnall SD, Aisenberg A, Jacobson JO, Harris NL. Richter’s transformation of chronic lymphocytic leukemia with Hodgkin’s-like cells is associated with Epstein-Barr virus infection. Mod Pathol. 1994;7(1):91–8.

    CAS  PubMed  Google Scholar 

  108. Kanzler H, Kuppers R, Helmes S, Wacker HH, Chott A, Hansmann ML, Rajewsky K. Hodgkin and Reed-Sternberg-like cells in B-cell chronic lymphocytic leukemia represent the outgrowth of single germinal-center B-cell-derived clones: potential precursors of Hodgkin and Reed-Sternberg cells in Hodgkin’s disease. Blood. 2000;95(3):1023–31.

    CAS  PubMed  Google Scholar 

  109. Martinez D, Valera A, Perez NS, Sua Villegas LF, Gonzalez-Farre B, Sole C, Gine E, Lopez-Guillermo A, Roue G, Martinez S, et al. Plasmablastic transformation of low-grade B-cell lymphomas: report on 6 cases. Am J Surg Pathol. 2013;37(2):272–81.

    Article  PubMed  Google Scholar 

  110. Mohamed AN, Compean R, Dan ME, Smith MR, Al-Katib A. Clonal evolution of chronic lymphocytic leukemia to acute lymphoblastic leukemia. Cancer Genet Cytogenet. 1996;86(2):143–6.

    Article  CAS  PubMed  Google Scholar 

  111. Chakhachiro Z, Yin CC, Abruzzo LV, Aladily TN, Barron LL, Banks HE, Thomas DA, Keating M, Medeiros LJ, Huh YO. B-lymphoblastic leukemia in patients with chronic lymphocytic leukemia: a report of four cases. Am J Clin Pathol. 2015;144(2):333–40.

    Article  CAS  PubMed  Google Scholar 

  112. Hallek M. Chronic lymphocytic leukemia: 2017 update on diagnosis, risk stratification, and treatment. Am J Hematol. 2017;92(9):946–65.

    Article  CAS  PubMed  Google Scholar 

  113. Cragg MS, Walshe CA, Ivanov AO, Glennie MJ. The biology of CD20 and its potential as a target for mAb therapy. Curr Dir Autoimmun. 2005;8:140–74.

    Article  CAS  PubMed  Google Scholar 

  114. Walshe CA, Beers SA, French RR, Chan CH, Johnson PW, Packham GK, Glennie MJ, Cragg MS. Induction of cytosolic calcium flux by CD20 is dependent upon B cell antigen receptor signaling. J Biol Chem. 2008;283(25):16971–84.

    Article  CAS  PubMed  Google Scholar 

  115. Li H, Ayer LM, Lytton J, Deans JP. Store-operated cation entry mediated by CD20 in membrane rafts. J Biol Chem. 2003;278(43):42427–34.

    Article  CAS  PubMed  Google Scholar 

  116. Tedder TF, Forsgren A, Boyd AW, Nadler LM, Schlossman SF. Antibodies reactive with the B1 molecule inhibit cell cycle progression but not activation of human B lymphocytes. Eur J Immunol. 1986;16(8):881–7.

    Article  CAS  PubMed  Google Scholar 

  117. Maloney DG, Liles TM, Czerwinski DK, Waldichuk C, Rosenberg J, Grillo-Lopez A, Levy R. Phase I clinical trial using escalating single-dose infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma. Blood. 1994;84(8):2457–66.

    CAS  PubMed  Google Scholar 

  118. Feugier P. A review of rituximab, the first anti-CD20 monoclonal antibody used in the treatment of B non-Hodgkin's lymphomas. Future Oncol. 2015;11(9):1327–42.

    Article  CAS  PubMed  Google Scholar 

  119. Bachy E, Salles G. Are we nearing an era of chemotherapy-free management of indolent lymphoma? Clin Cancer Res. 2014;20(20):5226–39.

    Article  CAS  PubMed  Google Scholar 

  120. Alduaij W, Illidge TM. The future of anti-CD20 monoclonal antibodies: are we making progress? Blood. 2011;117(11):2993–3001.

    Article  CAS  PubMed  Google Scholar 

  121. Taylor RP, Lindorfer MA. Fcgamma-receptor-mediated trogocytosis impacts mAb-based therapies: historical precedence and recent developments. Blood. 2015;125(5):762–6.

    Article  CAS  PubMed  Google Scholar 

  122. Tobinai K, Klein C, Oya N, Fingerle-Rowson G. A review of obinutuzumab (GA101), a novel type II anti-CD20 monoclonal antibody, for the treatment of patients with B-cell malignancies. Adv Ther. 2017;34(2):324–56.

    Article  CAS  PubMed  Google Scholar 

  123. Mossner E, Brunker P, Moser S, Puntener U, Schmidt C, Herter S, Grau R, Gerdes C, Nopora A, van Puijenbroek E, et al. Increasing the efficacy of CD20 antibody therapy through the engineering of a new type II anti-CD20 antibody with enhanced direct and immune effector cell-mediated B-cell cytotoxicity. Blood. 2010;115(22):4393–402.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Goede V, Fischer K, Busch R, Engelke A, Eichhorst B, Wendtner CM, Chagorova T, de la Serna J, Dilhuydy MS, Illmer T, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014;370(12):1101–10.

    Article  CAS  PubMed  Google Scholar 

  125. Zhang B. Ofatumumab. MAbs. 2009;1(4):326–31.

    Article  PubMed  PubMed Central  Google Scholar 

  126. Barth MJ, Czuczman MS. Ofatumumab: a novel, fully human anti-CD20 monoclonal antibody for the treatment of chronic lymphocytic leukemia. Future Oncol. 2013;9(12):1829–39.

    Article  CAS  PubMed  Google Scholar 

  127. Sato S, Steeber DA, Jansen PJ, Tedder TF. CD19 expression levels regulate B lymphocyte development: human CD19 restores normal function in mice lacking endogenous CD19. J Immunol. 1997;158(10):4662–9.

    CAS  PubMed  Google Scholar 

  128. Sato S, Miller AS, Howard MC, Tedder TF. Regulation of B lymphocyte development and activation by the CD19/CD21/CD81/Leu 13 complex requires the cytoplasmic domain of CD19. J Immunol. 1997;159(7):3278–87.

    CAS  PubMed  Google Scholar 

  129. Sato S, Steeber DA, Tedder TF. The CD19 signal transduction molecule is a response regulator of B-lymphocyte differentiation. Proc Natl Acad Sci U S A. 1995;92(25):11558–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Engel P, Zhou LJ, Ord DC, Sato S, Koller B, Tedder TF. Abnormal B lymphocyte development, activation, and differentiation in mice that lack or overexpress the CD19 signal transduction molecule. Immunity. 1995;3(1):39–50.

    Article  CAS  PubMed  Google Scholar 

  131. Otero DC, Anzelon AN, Rickert RC. CD19 function in early and late B cell development: I. Maintenance of follicular and marginal zone B cells requires CD19-dependent survival signals. J Immunol. 2003;170(1):73–83.

    Article  CAS  PubMed  Google Scholar 

  132. Yang W, Agrawal N, Patel J, Edinger A, Osei E, Thut D, Powers J, Meyerson H. Diminished expression of CD19 in B-cell lymphomas. Cytometry B Clin Cytom. 2005;63((1):28–35.

    Article  Google Scholar 

  133. Awan FT, Lapalombella R, Trotta R, Butchar JP, Yu B, Benson DM Jr, Roda JM, Cheney C, Mo X, Lehman A, et al. CD19 targeting of chronic lymphocytic leukemia with a novel Fc-domain-engineered monoclonal antibody. Blood. 2010;115(6):1204–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Lazar GA, Dang W, Karki S, Vafa O, Peng JS, Hyun L, Chan C, Chung HS, Eivazi A, Yoder SC, et al. Engineered antibody Fc variants with enhanced effector function. Proc Natl Acad Sci U S A. 2006;103(11):4005–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Szili D, Cserhalmi M, Banko Z, Nagy G, Szymkowski DE, Sarmay G. Suppression of innate and adaptive B cell activation pathways by antibody coengagement of FcgammaRIIb and CD19. MAbs. 2014;6(4):991–9.

    Article  PubMed  PubMed Central  Google Scholar 

  136. Portell CA, Wenzell CM, Advani AS. Clinical and pharmacologic aspects of blinatumomab in the treatment of B-cell acute lymphoblastic leukemia. Clin Pharmacol. 2013;5(Suppl 1):5–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Golay J, D'Amico A, Borleri G, Bonzi M, Valgardsdottir R, Alzani R, Cribioli S, Albanese C, Pesenti E, Finazzi MC, et al. A novel method using blinatumomab for efficient, clinical-grade expansion of polyclonal T cells for adoptive immunotherapy. J Immunol. 2014;193(9):4739–47.

    Article  CAS  PubMed  Google Scholar 

  138. Herbst R, Wang Y, Gallagher S, Mittereder N, Kuta E, Damschroder M, Woods R, Rowe DC, Cheng L, Cook K, et al. B-cell depletion in vitro and in vivo with an afucosylated anti-CD19 antibody. J Pharmacol Exp Ther. 2010;335(1):213–22.

    Article  CAS  PubMed  Google Scholar 

  139. Robak P, Smolewski P, Robak T. Emerging immunological drugs for chronic lymphocytic leukemia. Expert Opin Emerg Drugs. 2015;20(3):423–47.

    Article  CAS  PubMed  Google Scholar 

  140. Gross G, Waks T, Eshhar Z. Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc Natl Acad Sci U S A. 1989;86(24):10024–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Eshhar Z. The T-body approach: redirecting T cells with antibody specificity. Handb Exp Pharmacol. 2008;181:329–42.

    Article  CAS  Google Scholar 

  142. Curran KJ, Pegram HJ, Brentjens RJ. Chimeric antigen receptors for T cell immunotherapy: current understanding and future directions. J Gene Med. 2012;14(6):405–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Sadelain M, Brentjens R, Riviere I. The basic principles of chimeric antigen receptor design. Cancer Discov. 2013;3(4):388–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Fraietta JA, Schwab RD, Maus MV. Improving therapy of chronic lymphocytic leukemia with chimeric antigen receptor T cells. Semin Oncol. 2016;43(2):291–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Jackson HJ, Rafiq S, Brentjens RJ. Driving CAR T-cells forward. Nat Rev Clin Oncol. 2016;13(6):370–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Davila ML, Brentjens R, Wang X, Riviere I, Sadelain M. How do CARs work?: early insights from recent clinical studies targeting CD19. Oncoimmunology. 2012;1(9):1577–83.

    Article  PubMed  PubMed Central  Google Scholar 

  147. Zhang T, Cao L, Xie J, Shi N, Zhang Z, Luo Z, Yue D, Zhang Z, Wang L, Han W, et al. Efficiency of CD19 chimeric antigen receptor-modified T cells for treatment of B cell malignancies in phase I clinical trials: a meta-analysis. Oncotarget. 2015;6(32):33961–71.

    PubMed  PubMed Central  Google Scholar 

  148. Bottcher S, Ritgen M, Fischer K, Stilgenbauer S, Busch RM, Fingerle-Rowson G, Fink AM, Buhler A, Zenz T, Wenger MK, et al. Minimal residual disease quantification is an independent predictor of progression-free and overall survival in chronic lymphocytic leukemia: a multivariate analysis from the randomized GCLLSG CLL8 trial. J Clin Oncol. 2012;30(9):980–8.

    Article  PubMed  Google Scholar 

  149. Bottcher S, Stilgenbauer S, Busch R, Bruggemann M, Raff T, Pott C, Fischer K, Fingerle-Rowson G, Dohner H, Hallek M, et al. Standardized MRD flow and ASO IGH RQ-PCR for MRD quantification in CLL patients after rituximab-containing immunochemotherapy: a comparative analysis. Leukemia. 2009;23(11):2007–17.

    Article  CAS  PubMed  Google Scholar 

  150. Rawstron AC, Bottcher S, Letestu R, Villamor N, Fazi C, Kartsios H, de Tute RM, Shingles J, Ritgen M, Moreno C, et al. Improving efficiency and sensitivity: European Research Initiative in CLL (ERIC) update on the international harmonised approach for flow cytometric residual disease monitoring in CLL. Leukemia. 2013;27(1):142–9.

    Article  CAS  PubMed  Google Scholar 

  151. van der Velden VH, Cazzaniga G, Schrauder A, Hancock J, Bader P, Panzer-Grumayer ER, Flohr T, Sutton R, Cave H, Madsen HO, et al. Analysis of minimal residual disease by Ig/TCR gene rearrangements: guidelines for interpretation of real-time quantitative PCR data. Leukemia. 2007;21(4):604–11.

    Article  PubMed  CAS  Google Scholar 

  152. Montserrat E, Bauman T, Delgado J. Present and future of personalized medicine in CLL. Best Pract Res Clin Haematol. 2016;29(1):100–10.

    Article  PubMed  Google Scholar 

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  1. Department of Pathology, Dartmouth Hitchcock Medical Center and Geisel School of Medicine at Dartmouth 1 Medical Center Drive, Lebanon, 03756, New Hampshire, USA

    Prabhjot Kaur (Associate Professor of Pathology)

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Kaur, P. (2018). Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Introduction-Definition, Diagnosis, Cell of Origin. In: Chronic Lymphocytic Leukemia . Molecular and Translational Medicine. Humana Press, Cham. https://doi.org/10.1007/978-3-319-70603-0_1

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