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Small Lymphocytic Lymphoma/Chronic Lymphocytic Leukemia

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Lymphoma

Part of the book series: Current Clinical Oncology ((CCO,volume 43))

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Abstract

Small lymphocytic lymphoma (SLL)/chronic lymphocytic leukemia (CLL) is due to the accumulation of mature B cell with a distinctive immunophenotype. SLL/CLL is extremely heterogeneous from the biologic and clinical points of view, with different clinico-biologic forms of the disease being recognized. Management of patients with SLL/CLL is based on an individualized approach that takes into account both patient’s and disease’s characteristics. In the last decades, important progress has been made in the treatment of CLL/SLL, resulting in an important improvement in patients’ outlook. Although the cure of the disease is elusive, further progress in therapy based on treatments targeting disease-specific pathogenic pathways is already on the horizon.

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References

  1. Müller-Hermelink HK, Montserrat E, Catovsky D, Campo E, Harris NL, Stein H, et al. Chronic lymphocytic leukaemia/small lymphocytic lymphoma. In: Swerdlow SH, Campo E, Harris NL, editors. WHO classification of tumours of the haematopoietic and lymphoid tissues. Lyon: IARC Press; 2008. p. 188–90.

    Google Scholar 

  2. Altekruse SF KC, Krapcho M, Neyman N, et al., editors. SEER Clinical Statistics Review, 1975–2007. National Cancer Institute, Bethesda; 2010.

    Google Scholar 

  3. Sant M, Allemani C, Tereanu C, HAEMACARE Working Group, et al. Incidence of hematologic malignancies in Europe by morphologic subtype: results of the HAEMACARE project. Blood. 2010;116:3724–34.

    Article  PubMed  CAS  Google Scholar 

  4. Nishiyarna H, Mokuno J, lnoue T. Relative frequency and mortality rate of various types of leukemia in Japan. Jpn J Cancer Res. 1969;60:71–81.

    Google Scholar 

  5. Finch SC, Linet MS. Chronic leukaemias. Baillieres Clin Haematol. 1992;5:27–56.

    Article  PubMed  CAS  Google Scholar 

  6. Goldin LR, Slager SL, Caporaso NE. Familial chronic lymphocytic leukemia. Curr Opin Hematol. 2010;17:350–5.

    Article  PubMed  Google Scholar 

  7. Goldin LR, Sgambati M, Marti GE, et al. Anticipation in familial chronic lymphocytic leukemia. Am J Hum Genet. 1999;65:265–9.

    Article  PubMed  CAS  Google Scholar 

  8. Crowther-Swanepoel D, Houlston RS. Genetic variation and risk of chronic lymphocytic leukaemia. Semin Cancer Biol. 2010;20:363–9. Epub 2010 Sep 15.

    Article  PubMed  CAS  Google Scholar 

  9. Slager SL, Rabe KG, Achenbach SJ, et al. Genome-wide association study identifies a novel susceptibility locus at 6p21.3 among familial CLL. Blood. 2011;117:1911–6.

    Article  PubMed  CAS  Google Scholar 

  10. Chiorazzi N, Rai KR, Ferrarini M. Chronic lymphocytic leukemia. N Engl J Med. 2005;352:804–15.

    Article  PubMed  CAS  Google Scholar 

  11. Dighiero G, Hamblin T. Chronic lymphocytic leukaemia. Lancet. 2008;371:1017–29.

    Article  PubMed  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  13. Klein U, Dalla-Favera R. New insights into the pathogenesis of chronic lymphocytic leukemia. Semin Cancer Biol. 2010;20:377–83.

    Google Scholar 

  14. Zenz T, Mertens D, Küpper R, Döhner H, Stilgenbauer S. From pathogenesis to treatment of chronic lymphocytic leukemia. Nat Rev Cancer. 2010;10:36–50.

    Google Scholar 

  15. Stevenson FK, Krysov S, Davies AJ, Steele AJ, Packham G. B-cell receptor signaling in chronic lymphocytic leukemia. Blood. 2011;118:4313–20.

    Article  CAS  Google Scholar 

  16. Kikushige Y, Ishikawa F, Miyamoto T, et al. Self-renewing hematopoietic stem cell is the primary target in pathogenesis of human chronic lymphocytic leukemia. Cancer Cell. 2011;20:246–59.

    Article  PubMed  CAS  Google Scholar 

  17. Fazi C, Scarfò L, Pecciarini L, et al. General population low-count CLL-like MBL persist over time without clinical progression, though carrying the same cytogenetic abnormalities of CLL. Blood. 2011;118:6618–25.

    Article  PubMed  CAS  Google Scholar 

  18. Calin GA, Dumitru CD, Shimizu M, et al. Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci USA. 2002;99:15524–9.

    Article  PubMed  CAS  Google Scholar 

  19. Calin GA, Croce CM. Chronic lymphocytic leukemia: interplay between non-coding RNAs and protein-­coding genes. Blood. 2009;114:4761–70.

    Article  PubMed  CAS  Google Scholar 

  20. Klein U, Lia M, Crespo M, et al. The DLEU2/miR-15a/16–1 cluster controls B cell proliferation and its deletion leads to chronic lymphocytic leukemia. Cancer Cell. 2010;17:28–40.

    Article  PubMed  CAS  Google Scholar 

  21. Messmer BT, Messmer D, Allen SL, et al. In vivo measurements document the dynamic cellular kinetics of chronic lymphocytic leukemia B cells. J Clin Invest. 2005;115:755–64.

    PubMed  CAS  Google Scholar 

  22. Damle RN, Wasil T, Fais F, et al. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood. 1999;94:1840–7.

    PubMed  CAS  Google Scholar 

  23. Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK. Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood. 1999;94:1848–54.

    PubMed  CAS  Google Scholar 

  24. Rosenwald A, Alizadeh AA, Widhopf G, et al. Relation of gene expression phenotype to immunoglobulin mutation genotype in B cell chronic lymphocytic leukaemia. J Exp Med. 2001;194:1639–47.

    Article  PubMed  CAS  Google Scholar 

  25. Weed RI. Exaggerated delayed hypersensitivity to mosquito bites in chronic lymphocytic leukemia. Blood. 1965;26:257–68.

    PubMed  CAS  Google Scholar 

  26. Ribera JM, Viñolas N, Urbano Ispizua A, et al. ‘Spontaneous’ complete remissions in chronic lymphocytic leukemia: report of three cases and review of the literature. Blood Cells. 1987;12:471–9.

    PubMed  CAS  Google Scholar 

  27. Del Giudice I, Chiaretti S, Tavolaro S, et al. Spontaneous regression of chronic lymphocytic leukemia: clinical and biologic features of 9 cases. Blood. 2009;16:638–46.

    Article  CAS  Google Scholar 

  28. Dohner H, Stilgenbauer S, Fischer K, Bentz M, Lichter P. Cytogenetic and molecular cytogenetic analysis of B cell chronic lymphocytic leukemia: specific chromosome aberrations identify prognostic subgroups of patients and point to loci for candidate genes. Leukemia. 1997;11:S19–24.

    PubMed  Google Scholar 

  29. Döhner H, Stilgenbauer S, James MR, et al. 11q deletions identify a new subset of B-cell chronic lymphocytic leukemia characterized by extensive nodal involvement and inferior prognosis. Blood. 1997;89:2516–22.

    PubMed  Google Scholar 

  30. Stilgenbauer S, Bullinger L, Benner A, et al. Incidence and clinical significance of 6q deletions in B cell chronic lymphocytic leukemia. Leukemia. 1999;13:1331–4.

    Article  PubMed  CAS  Google Scholar 

  31. Döhner H, Stilgenbauer S, Benner A, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000;343:1910–6.

    Article  PubMed  Google Scholar 

  32. Zenz T, Eichhorst B, Busch R, et al. TP53 mutation and survival in chronic lymphocytic leukemia. J Clin Oncol. 2010;28:4473–9.

    Article  PubMed  Google Scholar 

  33. Gonzalez D, Martinez P, Wade R, et al. Mutational status of the TP53 gene as a predictor of response and survival in patients with chronic lymphocytic ­leukemia: results from the LRF CLL4 trial. J Clin Oncol. 2011;29:2223–9.

    Article  PubMed  Google Scholar 

  34. Montserrat E, Moreno C. Genetic lesions in chronic lymphocytic leukemia: clinical implications. Curr Opin Oncol. 2009;21:609–14.

    Article  PubMed  Google Scholar 

  35. Zenz T, Mertens D, Döhner H, Stilgenbauer S. Importance of genetics in chronic lymphocytic leukemia. Blood Rev. 2011;25:131–7.

    Article  PubMed  CAS  Google Scholar 

  36. Rossi D, Cerri M, Deambrogi C, et al. The prognostic value of TP53 mutations in chronic lymphocytic leukemia is independent of del17p13: implications for overall survival and chemorefractoriness. Clin Cancer Res. 2009;15:995–1004.

    Article  PubMed  CAS  Google Scholar 

  37. Rinaldi A, Mian M, Kwee I, et al. Genome-wide DNA profiling better defines the prognosis of chronic lymphocytic leukaemia. Br J Haematol. 2011;154:590–9.

    Article  PubMed  Google Scholar 

  38. Sportoletti P, Baldoni S, Cavalli L, et al. NOTCH1 PEST domain mutation is an adverse prognostic factor in B-CLL. Br J Haematol. 2010;151:404–6.

    Article  PubMed  Google Scholar 

  39. Puente XS, Pinyol M, Quesada V, et al. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature. 2011;475:101–5.

    Article  PubMed  CAS  Google Scholar 

  40. Fabbri G, Rasi S, Rossi D, et al. Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation. J Exp Med. 2011;208:1389–401.

    Article  PubMed  CAS  Google Scholar 

  41. Rossi D, Bruscaggin A, Spina V, et al. Mutations of the SF3B1 splicing factor in chronic lymphocytic leukemia: association with progression and fludarabine-refractoriness. Blood. 2011;118:6904–8.

    Article  PubMed  CAS  Google Scholar 

  42. Rossi D, Radi S, Fabbri V, et al. Mutations of NOTCH1 are an independent predictor of survival in chronic lymphocytic leukemia. Blood. 2012;119:521–9.

    Google Scholar 

  43. Wang L, Lawrence MS, Wan Y, et al. SF3B1 and other novel cancer genes in chronic lymphocytic leukemia. N Engl J Med. 2011;365:2497–506.

    Article  PubMed  CAS  Google Scholar 

  44. Balatti V, Bottoni A, Palamarchuk A, et al. NOTCH1 mutations in CLL associated with trisomy 12. Blood. 2012;119:329–31.

    Article  PubMed  CAS  Google Scholar 

  45. Del Giudice G, Rossi D, Chiaretti S, et al. NOTCH1 mutations in +12 chronic lymphocytic leukemia (CLL) confer an unfavorable prognosis, induce a distinctive transcriptional profiling and refine the intermediate prognosis of +12 CLL. Haematologica. 2012;97:437–41.

    Google Scholar 

  46. Quesada V, Conde L, Villamor N, et al. Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia. Nat Genet. 2012;44:47–52.

    Article  CAS  Google Scholar 

  47. Dearden C. Disease-specific complications of chronic lymphocytic leukemia. Hematology Am Soc Educ Program Hematol. 2008:450–6.

    Google Scholar 

  48. Zent CS, Ding W, Schwager SM, et al. The prognostic significance of cytopenia in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL). Br J Haematol. 2008;141:615–21.

    Article  PubMed  Google Scholar 

  49. Moreno C, Hodgson K, Ferrer G, et al. Autoimmune cytopenia in chronic lymphocytic leukemia: prevalence, clinical associations, and prognostic significance. Blood. 2010;116:4771–6.

    Article  PubMed  CAS  Google Scholar 

  50. Hodgson K, Ferrer G, Montserrat E, Moreno C. Chronic lymphocytic leukemia and autoimmunity: systematic review. Haematologica. 2011;96:752–61.

    Article  PubMed  CAS  Google Scholar 

  51. Hodgson K, Ferrer G, Pereira A, Moreno C, Montserrat E. Autoimmune cytopenia in chronic lymphocytic leukaemia: diagnosis and treatment. Br J Haematol. 2011;154:14–22.

    Article  PubMed  Google Scholar 

  52. Robertson LE, Pugh W, O’Brien S, et al. Richter’s syndrome: a report on 39 patients. J Clin Oncol. 1993;11:1985–9.

    PubMed  CAS  Google Scholar 

  53. Rossi D, Spina V, Forconi F, et al. Molecular history of Richter syndrome: origin from a cell already present at the time of chronic lymphocytic leukemia diagnosis. Int J Cancer. 2012;130:3006–10.

    Google Scholar 

  54. Rossi D, Spina V, Deambrogi C, et al. The genetics of Richter syndrome reveals disease heterogeneity and predicts survival after transformation. Blood. 2011;117:3391–401.

    Article  PubMed  CAS  Google Scholar 

  55. Bruzzi JF, Macapinlac H, Tsimberidou AM, et al. Detection of Richter’s transformation of chronic lymphocytic leukemia by PET/CT. J Nucl Med. 2006;47:1267–73.

    PubMed  Google Scholar 

  56. Bockorny B, Codreanu I, Dasanu CA. Hodgkin lymphoma as Richter Transformation in chronic lymphocytic leukaemia: a retrospective analysis of world literature. Br J Haematol. 2012;156:50–66.

    Google Scholar 

  57. Hisada M, Biggar RJ, Greene MH, et al. Solid tumors after chronic lymphocytic leukemia. Blood. 2001;98:1979–81.

    Article  PubMed  CAS  Google Scholar 

  58. Tsimberidou AM, Wen S, McLaughlin P, et al. Other malignancies in chronic lymphocytic leukemia/small lymphocytic lymphoma. J Clin Oncol. 2009;27:904–10.

    Article  PubMed  Google Scholar 

  59. Morton LM, Curtis RE, Linet MS, et al. Second malignancy risks after non-Hodgkin’s lymphoma and chronic lymphocytic leukemia: differences by lymphoma subtype. J Clin Oncol. 2010;28:4935–44.

    Article  PubMed  Google Scholar 

  60. Royle JA, Baade PD, Joske D, et al. Second cancer incidence and cancer mortality among chronic lymphocytic leukaemia patients: a population-based study. Br J Cancer. 2011;105:1076–81.

    Article  PubMed  CAS  Google Scholar 

  61. Kaae J, Hansen AV, Biggar RJ, et al. Merkel cell carcinoma: incidence, mortality, and risk of other cancers. J Natl Cancer Inst. 2010;102:793–801.

    Article  PubMed  Google Scholar 

  62. Molica S. Infections in chronic lymphocytic leukemia: risk factors and impact on survival, and treatment. Leuk Lymphoma. 1994;13:203–14.

    Article  PubMed  CAS  Google Scholar 

  63. Morrison VA. Infectious complications of chronic lymphocytic leukaemia: pathogenesis, spectrum of infection, preventive approaches. Best Pract Res Clin Haematol. 2010;23:145–53.

    Article  PubMed  CAS  Google Scholar 

  64. Young JA. Epidemiology and management of infectious complications of contemporary management of chronic leukemias. Infect Disord Drug Targets. 2011;11:3–10.

    Article  PubMed  CAS  Google Scholar 

  65. Hallek M, Cheson BD, Catovsky D, 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;111:5446–56.

    Article  PubMed  CAS  Google Scholar 

  66. Rawstron AC, Bennett FL, O’Connor SJ, et al. Monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia. N Engl J Med. 2008;359:575–83.

    Article  PubMed  CAS  Google Scholar 

  67. Landgren O, Albitar M, Ma W, et al. B-cell clones as early markers for chronic lymphocytic leukemia. N Engl J Med. 2009;360:659–67.

    Article  PubMed  CAS  Google Scholar 

  68. Nieto WG, Almeida J, Romero A, Primary Health Care Group of Salamanca for the Study of MBL, 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;114:33–7.

    Article  PubMed  CAS  Google Scholar 

  69. Shanafelt TD, Ghia P, Lanasa MC, Landgren O, Rawstron AC. Monoclonal B-cell lymphocytosis (MBL): biology, natural history and clinical management. Leukemia. 2010;24:512–20.

    Article  PubMed  CAS  Google Scholar 

  70. Rai KR, Sawitsky A, Cronkite EP, et al. Clinical staging of chronic lymphocytic leukemia. Blood. 1975;46:219–34.

    PubMed  CAS  Google Scholar 

  71. Binet JL, Auquier A, Dighiero G, et al. A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer. 1981;48:198–206.

    Article  PubMed  CAS  Google Scholar 

  72. Catovsky D, Richards S, Matutes E, UK National Cancer Research Institute (NCRI) Haematological Oncology Clinical Studies Group; NCRI Chronic Lymphocytic Leukaemia Working Group, et al. Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial. Lancet. 2007;370:230–9.

    Article  PubMed  CAS  Google Scholar 

  73. Hallek M, Fischer K, Fingerle-Rowson G, International Group of Investigators; German Chronic Lymphocytic Leukaemia Study Group, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010;376:1164–74.

    Article  PubMed  CAS  Google Scholar 

  74. Keating MJ, O’Brien S, Albitar M, et al. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol. 2005;23:4079–88.

    Article  PubMed  CAS  Google Scholar 

  75. Moreno C, Montserrat E. New prognostic markers in chronic lymphocytic leukemia. Blood Rev. 2008;4:211–9.

    Article  CAS  Google Scholar 

  76. Cramer P, Hallek M. Prognostic factors in chronic lymphocytic leukemia-what do we need to know? Nat Rev Clin Oncol. 2011;8:38–47.

    Article  PubMed  CAS  Google Scholar 

  77. Crespo M, Bosch F, Villamor N, et al. ZAP-70 expression as a surrogate for immunoglobulivariable-region mutations in chronic lymphocytic leukemia. N Engl J Med. 2003;348:1764–75.

    Article  PubMed  CAS  Google Scholar 

  78. Wiestner A, Rosenwald A, Barry TS, et al. ZAP-70 expression identifies a chronic lymphocytic leukemia subtype with unmutated immunoglobulin genes, inferior clinical outcome, and distinct gene expression profile. Blood. 2003;101:4944–51.

    Article  PubMed  CAS  Google Scholar 

  79. Tobin G, Thunberg U, Johnson A. Somatically mutated Ig VH3–21 genes characterize a new subset of chronic lymphocytic leukemia. Blood. 2002;99:2262–4.

    Article  PubMed  CAS  Google Scholar 

  80. Byrd JC, Peterson BL, Morrison VA, et al. 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. Blood. 2003;101:6–14.

    Article  PubMed  CAS  Google Scholar 

  81. Rai KR, Peterson BL, Appelbaum FR, et al. Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med. 2000;343:1750–7.

    Article  PubMed  CAS  Google Scholar 

  82. 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(Supplement 6):vi50–4.

    Article  PubMed  Google Scholar 

  83. Tam CS, O’Brien S, Wierda W, et al. Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood. 2008;112:975–80.

    Article  PubMed  CAS  Google Scholar 

  84. Robak T, Dmoszynska A, Solal-Céligny P, et al. Rituximab plus fludarabine and cyclophosphamide prolongs progression-free survival compared with fludarabine and cyclophosphamide alone in previously treated chronic lymphocytic leukemia. J Clin Oncol. 2010;28:1756–65.

    Article  PubMed  CAS  Google Scholar 

  85. Abrisqueta P, Pereira A, Rozman C, et al. Improving survival in patients with chronic lymphocytic leukemia (1980–2008): the Hospital Clinic of Barcelona experience. Blood. 2009;114:2044–50.

    Article  PubMed  CAS  Google Scholar 

  86. Kristinsson SY, Dickman PW, Wilson WH, Caporaso N, Björkholm M, Landgren O. Improved survival in chronic lymphocytic leukemia in the past decade: a population-based study including 11,179 patients diagnosed between 1973–2003 in Sweden. Haematologica. 2009;94:1259–65.

    Article  PubMed  Google Scholar 

  87. Danese MD, Griffiths RI, Gleeson M, et al. An observational study of outcomes after initial infused therapy in Medicare patients diagnosed with chronic lymphocytic leukemia. Blood. 2011;117:3505–13.

    Article  PubMed  CAS  Google Scholar 

  88. Bosch F, Abrisqueta P, Villamor N, et al. Rituximab, fludarabine, cyclophosphamide, and mitoxantrone: a new, highly active chemoimmunotherapy regimen for chronic lymphocytic leukemia. J Clin Oncol. 2009;27:4578–84.

    Article  PubMed  CAS  Google Scholar 

  89. Faderl S, Wierda W, O’Brien S, Ferrajoli A, Lerner S, Keating MJ. Fludarabine, cyclophosphamide, mitoxantrone plus rituximab (FCM-R) in frontline CLL <70 years. Leuk Res. 2010;34:284–8.

    Article  PubMed  CAS  Google Scholar 

  90. Kay NE, Geyer SM, Call TG, et al. Combination chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab shows significant clinical activity with low accompanying toxicity in previously untreated B chronic lymphocytic leukemia. Blood. 2007;109:405–11.

    Article  PubMed  CAS  Google Scholar 

  91. Reynolds C, Di Bella N, Lyons RM, et al. A Phase III trial of fludarabine, cyclophosphamide, and rituximab vs. pentostatin, cyclophosphamide, and rituximab in B-cell chronic lymphocytic leukemia. Invest New Drugs. 2012;30:1232–40.

    Article  PubMed  CAS  Google Scholar 

  92. Robak T, Blonski JZ, Gora-Tybor J, Polish Leukemia Group (PALG CLL2), et al. Cladribine alone and in combination with cyclophosphamide or cyclophosphamide plus mitoxantrone in the treatment of progressive chronic lymphocytic leukemia: report of a prospective, multicenter, randomized trial of the Polish Adult Leukemia Group (PALG CLL2). Blood. 2006;108:473–9.

    Article  PubMed  CAS  Google Scholar 

  93. Robak T, Jamroziak K, Gora-Tybor J, et al. Comparison of cladribine plus cyclophosphamide with fludarabine plus cyclophosphamide as first-line therapy for chronic lymphocytic leukemia: a phase III randomized study by the Polish Adult Leukemia Group (PALG-CLL3 Study). J Clin Oncol. 2010;28:1863–9.

    Article  PubMed  CAS  Google Scholar 

  94. Montillo M, Tedeschi A, Petrizzi VB, et al. An open-label, pilot study of fludarabine, cyclophosphamide, and alemtuzumab (FCC) in relapsed/refractory patients with B-cell chronic lymphocytic leukemia. Blood. 2011;118:4079–85.

    Article  PubMed  CAS  Google Scholar 

  95. Tam CS, Keating MJ. Chemoimmunotherapy for chronic lymphocytic leukemia. Nat Rev Clin Oncol. 2010;7:521–32.

    Article  PubMed  CAS  Google Scholar 

  96. Montserrat E. Treatment of chronic lymphocytic leukemia: achieving minimal residual disease—negative status as a goal [editorial]. J Clin Oncol. 2005;23:2884–5.

    Article  PubMed  Google Scholar 

  97. Smith MR, Neuberg D, Flin IW. Incidence of therapy-related myeloid neoplasia after initial therapy for chronic lymphocytic leukemia with fludarabine-cyclophosphamide versus fludarabine: long-term follow-up of US Intergroup Study E2997. Blood. 2011;118:3525–7.

    Article  PubMed  CAS  Google Scholar 

  98. D’Souza A, Wilson J, Mukherjee S, Jaiyesimi I. Progressive multifocal leukoencephalopathy in chronic lymphocytic leukemia: a report of three cases and review of the literature. Clin Lymphoma Myeloma Leuk. 2010;10(1):E1–9.

    Article  PubMed  Google Scholar 

  99. Eichhorst BF, Busch R, Stilgenbauer S, et al., German CLL Study Group (GCLLSG). First-line therapy with fludarabine compared with chlorambucil does not result in a major benefit for elderly patients with advanced chronic lymphocytic leukemia. Blood. 2009;114:3382–91.

    Article  PubMed  CAS  Google Scholar 

  100. Knauf WU, Lissichkov T, Aldaoud A, et al. Phase III randomized study of bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol. 2009;27:4378–84.

    Article  PubMed  CAS  Google Scholar 

  101. Dreger P, Corradini P, Kimby E, et al., Chronic Leukemia Working Party of the EBMT. Indications for allogeneic stem cell transplantation in chronic lymphocytic leukemia: the EBMT transplant consensus. Leukemia. 2007;21:12–7.

    Article  PubMed  CAS  Google Scholar 

  102. Montserrat E, Moreno C, Esteve J, Urbano-Ispizua A, Gine E, Bosch F. How I treat refractory CLL. Blood. 2006;107:1276–83.

    Article  PubMed  CAS  Google Scholar 

  103. Moreno C, Villamor N, Colomer D, et al. Allogeneic stem-cell transplantation may overcome the adverse prognosis of unmutated VH gene in patients with chronic lymphocytic leukemia. J Clin Oncol. 2005;23:3433–8.

    Article  PubMed  Google Scholar 

  104. Caballero D, Garcia-Marco JA, Martino R, et al. Allogeneic transplant with reduced intensity conditioning regimens may overcome the poor prognosis of B-cell chronic lymphocytic leukemia with unmutated immunoglobulin variable heavy-chain gene and chromosomal abnormalities (11q- and 17p-). Clin Cancer Res. 2005;11:7757–63.

    Article  PubMed  CAS  Google Scholar 

  105. Schetelig J, Thiede C, Bornhauser M, et al. Evidence of a graft-versus-leukemia effect in chronic lymphocytic leukemia after reduced-intensity conditioning and allogeneic stem-cell transplantation: the Cooperative German Transplant Study Group. J Clin Oncol. 2003;21:2747–53.

    Article  PubMed  CAS  Google Scholar 

  106. Schetelig J, van Biezen A, Brand R, et al. Allogeneic hematopoietic stem-cell transplantation for chronic lymphocytic leukemia with 17p deletion: a retrospective European Group for Blood and Marrow Transplantation Analysis. J Clin Oncol. 2008;26:5094–100.

    Article  PubMed  Google Scholar 

  107. Sorror ML, Storer BE, Sandmaier BM, et al. Five-year follow up of patients with advanced chronic lymphocytic leukemia treated with allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning. J Clin Oncol. 2008;26:4912–20.

    Article  PubMed  Google Scholar 

  108. Dreger P, Döhner H, Ritgen M, et al. Allogeneic stem cell transplantation provides durable disease control in poor-risk chronic lymphocytic leukemia: long-term clinical and MRD results of the German CLL Study Group CLL3X trial. Blood. 2010;116:2438–47.

    Article  PubMed  CAS  Google Scholar 

  109. Gribben JG, Hosing C, Maloney DG. Stem cell transplantation for indolent lymphoma and chronic lymphocytic leukemia. Biol Blood Marrow Transplant. 2011;17(1 Suppl):S63–70.

    Article  PubMed  Google Scholar 

  110. Keating MJ, Flinn I, Jain V, et al. Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study. Blood. 2002;99:3554–61.

    Article  PubMed  CAS  Google Scholar 

  111. Hillmen P, Skotnicki AB, Robak T, et al. Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia. J Clin Oncol. 2007;25:5616–23.

    Article  PubMed  CAS  Google Scholar 

  112. Osterborg A, Foà R, Bezares RF, et al. Management guidelines for the use of alemtuzumab in chronic lymphocytic leukemia. Leukemia. 2009;23:1980–8.

    Article  PubMed  CAS  Google Scholar 

  113. Castro JE, Sandoval-Sus JD, Bole J, Rassenti L, Kipps TJ. Rituximab in combination with high dose methylprednisolone for the treatment of fludarabine refractory high-risk chronic lymphocytic leukemia. Leukemia. 2008;22:2048–53.

    Article  PubMed  CAS  Google Scholar 

  114. Keating MJ, Wierda WG, Tam CS, et al. Long term outcome following treatment failure of FCR chemoimmunotherapy as initial therapy for chronic lymphocytic leukemia [abstract]. Blood (ASH Annu Meet Abstr). 2009;114:Abstract 2381.

    Google Scholar 

  115. Badoux XC, Keating M, Wang X, et al. Fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy is highly effective treatment for relapsed patients with CLL. Blood. 2011;117:3016–24.

    Article  PubMed  CAS  Google Scholar 

  116. Delgado J, Briones J, Sierra J. Emerging therapies for patients with advanced chronic lymphocytic leukaemia. Blood Rev. 2009;23:217–24.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  118. Gribben JG, O’Brien S. Update on therapy of chronic lymphocytic leukemia. J Clin Oncol. 2011;29:544–50.

    Article  PubMed  Google Scholar 

  119. Coiffier B, Lepretre S, Pedersen LM, et al. Safety and efficacy of ofatumumab, a fully human monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: a phase 1–2 study. Blood. 2008;111:1094–100.

    Article  PubMed  CAS  Google Scholar 

  120. Wierda WG, Kipps TJ, Mayer J, et al. Hx-CD20–406 Study Investigators. Ofatumumab as single-agent CD20 immunotherapy in fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol. 2010;28:1749–55.

    Article  PubMed  CAS  Google Scholar 

  121. Lemery SJ, Zhang J, Rothmann MD, et al. U.S. Food and Drug Administration approval: ofatumumab for the treatment of patients with chronic lymphocytic leukemia refractory to fludarabine and alemtuzumab. Clin Cancer Res. 2010;16:4331–8.

    Article  PubMed  CAS  Google Scholar 

  122. Gravanis I, Ersbøll J, Skovlund E, Abadie E, Marti M, Pignatti F. The European Medicines Agency review of ofatumumab (Arzerra®) for the treatment of chronic lymphocytic leukemia in patients refractory to fludarabine and alemtuzumab: summary of the scientific assessment of the European medicines agency committee for medicinal products for human use. Oncologist. 2010;15:1335–43.

    Article  PubMed  CAS  Google Scholar 

  123. Wierda WG, Kipps TJ, Dürig J, on behalf of the 407 Study Investigators, et al. Chemoimmunotherapy with O-FC in previously untreated patients with chronic lymphocytic leukemia. Blood. 2011;117:6450–8.

    Article  PubMed  CAS  Google Scholar 

  124. Wierda WG, Padmanabhan S, Chaib GW, Gupta IV, Lisby S, Osterborg A, et al. Ofatumumab is active in patients with fludarabine-refractory CLL irrespective of prior rituximab: results from the phase 2 international study. Blood. 2011;118:5126–9.

    Article  PubMed  CAS  Google Scholar 

  125. Bergmann MA, Goebeler ME, Herold M, et al. Efficacy of bendamustine in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase I/II study of the German CLL Study Group. Haematologica. 2005;90:1357–64.

    PubMed  CAS  Google Scholar 

  126. Cheson BD, Rummel MJ. Bendamustine: rebirth of an old drug. J Clin Oncol. 2009;27:122.

    Google Scholar 

  127. Fischer K, Cramer P, Busch R, et al. Bendamustine combined with rituximab in patients with relapsed and/or refractory chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol. 2011;29:3559–66.

    Article  PubMed  CAS  Google Scholar 

  128. Iannitto E, Morabito F, Mancuso S, Gentile M, et al. Bendamustine with or without rituximab in the treatment of relapsed chronic lymphocytic leukaemia: an Italian retrospective study. Br J Haematol. 2011;153:351–7.

    Article  PubMed  CAS  Google Scholar 

  129. Chanan-Khan A, Miller KC, Musial L, Lawrence D, Padmanabhan S, Takeshita K, et al. Clinical efficacy of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase II study. J Clin Oncol. 2006;24:5343–9.

    Article  PubMed  CAS  Google Scholar 

  130. Ferrajoli A, Lee BN, Schlette EJ, et al. Lenalidomide induces complete and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia. Blood. 2008;111:5291–7.

    Article  PubMed  CAS  Google Scholar 

  131. Chen CI, Bergsagel PL, Paul H, et al. Single-agent lenalidomide in the treatment of previously untreated chronic lymphocytic leukemia. J Clin Oncol. 2011;29:1175–81.

    Article  PubMed  CAS  Google Scholar 

  132. Badoux C, Keating MJ, Wen S, et al. Lenalidomide as initial therapy of elderly patients with chronic lymphocytic leukemia. Blood. 2011;118:3489–98.

    Article  PubMed  CAS  Google Scholar 

  133. Bologna L, Gotti E, Manganini M, et al. Mechanism of action of type II, glycoengineered, anti-CD20 monoclonal antibody GA101 in B-chronic lymphocytic leukemia whole blood assays in comparison with rituximab and alemtuzumab. J Immunol. 2011;186:3762–9.

    Article  PubMed  CAS  Google Scholar 

  134. Phelps MA, Lin TS, Johnson AJ, et al. Clinical response and pharmacokinetics from a phase 1 study of an active dosing schedule of flavopiridol in relapsed chronic lymphocytic leukemia. Blood. 2009;113:2637–45.

    Article  PubMed  CAS  Google Scholar 

  135. Lin TS, Ruppert AS, Johnson AJ, et al. Phase II study of flavopiridol in relapsed chronic lymphocytic leukemia demonstrating high response rates in genetically high-risk disease. J Clin Oncol. 2009;27:6012–8.

    Article  PubMed  CAS  Google Scholar 

  136. Herman SEM, Gordon AL, Hertlein E, et al. Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. Blood. 2011;117:6287–96.

    Article  PubMed  CAS  Google Scholar 

  137. Lannutti BJ, Meadows SA, Herman SEM, et al. CAL-101, a p110δ selective phosphatidylinositol-3- kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood. 2011;117:591–4.

    Article  PubMed  CAS  Google Scholar 

  138. Herman SEM, Gordon AL, Wagner AJ, et al. Phosphatidylinositol 3-kinase-δ inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals. Blood. 2010;116:2078–88.

    Article  PubMed  CAS  Google Scholar 

  139. O’Brien S, Burger JA, Coutre SE, et al. The BTK inhibitor PCI-32765 is highly active and tolerable in patients with poor-risk CLL: interim results from a phase Ib/II study. Ann Oncol (ICML Meet Abstr) 2011;22(Suppl 4):122.

    Google Scholar 

  140. Roberts AW, Seymour JF, Brown JR, et al. Substantial susceptibility of chronic lymphocytic leukemia to BCL2 inhibition: Results of a phase I study of navitoclax in patients with relapsed or refractory disease. J Clin Oncol. 2012;30:488–96.

    Google Scholar 

  141. Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor–modified T Cells in chronic lymphoid leukemia. N Engl J Med. 2011;365:725–33.

    Article  PubMed  CAS  Google Scholar 

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Montserrat, E. (2013). Small Lymphocytic Lymphoma/Chronic Lymphocytic Leukemia. In: Younes, A., Coiffier, B. (eds) Lymphoma. Current Clinical Oncology, vol 43. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-62703-408-1_4

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