Primer

Chronic lymphocytic leukaemia

  • Nature Reviews Disease Primers volume 3, Article number: 16096 (2017)
  • doi:10.1038/nrdp.2016.96
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Abstract

Chronic lymphocytic leukaemia (CLL) is a malignancy of CD5+ B cells that is characterized by the accumulation of small, mature-appearing lymphocytes in the blood, marrow and lymphoid tissues. Signalling via surface immunoglobulin, which constitutes the major part of the B cell receptor, and several genetic alterations play a part in CLL pathogenesis, in addition to interactions between CLL cells and other cell types, such as stromal cells, T cells and nurse-like cells in the lymph nodes. The clinical progression of CLL is heterogeneous and ranges from patients who require treatment soon after diagnosis to others who do not require therapy for many years, if at all. Several factors, including the immunoglobulin heavy-chain variable region gene (IGHV) mutational status, genomic changes, patient age and the presence of comorbidities, should be considered when defining the optimal management strategies, which include chemotherapy, chemoimmunotherapy and/or drugs targeting B cell receptor signalling or inhibitors of apoptosis, such as BCL-2. Research on the biology of CLL has profoundly enhanced our ability to identify patients who are at higher risk for disease progression and our capacity to treat patients with drugs that selectively target distinctive phenotypic or physiological features of CLL. How these and other advances have shaped our current understanding and treatment of patients with CLL is the subject of this Primer.

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References

  1. 1.

    , , , & Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 94, 1848–1854 (1999).

  2. 2.

    et al. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 94, 1840–1847 (1999). References 1 and 2 are landmark papers that describe two main subsets of patients with different disease progression tendencies based on IGHV mutation status of the immunoglobulins that are expressed by CLL cells.

  3. 3.

    et al. Somatically mutated Ig V(H)3-21 genes characterize a new subset of chronic lymphocytic leukemia. Blood 99, 2262–2264 (2002).

  4. 4.

    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 111, 5101–5108 (2008).

  5. 5.

    et al. Developmentally restricted immunoglobulin heavy chain variable region gene expressed at high frequency in chronic lymphocytic leukemia. Proc. Natl Acad. Sci. USA 86, 5913–5917 (1989). This paper describes the discovery that the immunoglobulin repertoire of CLL cells may be highly restricted, suggesting that the antibodies expressed by CLL cells are most likely selected based on their capacity to bind to some common self-antigens.

  6. 6.

    et al. Chronic lymphocytic leukemia B cells express restricted sets of mutated and unmutated antigen receptors. J. Clin. Invest. 102, 1515–1525 (1998).

  7. 7.

    et al. Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia: a molecular classification with implications for targeted therapies. Blood 119, 4467–4475 (2012).

  8. 8.

    et al. Chronic lymphocytic leukemia B cells of more than 1% of patients express virtually identical immunoglobulins. Blood 104, 2499–2504 (2004).

  9. 9.

    et al. Cell of origin associated classification of B-cell malignancies by gene signatures of the normal B-cell hierarchy. Leuk. Lymphoma 55, 1251–1260 (2014).

  10. 10.

    & Germinal centres and B cell lymphomagenesis. Nat. Rev. Immunol. 15, 172–184 (2015).

  11. 11.

    et al. Cancer treatment and survivorship statistics, 2012. CA Cancer J. Clin. 62, 220–241 (2012).

  12. 12.

    et al. The impact of race, ethnicity, age and sex on clinical outcome in chronic lymphocytic leukemia: a comprehensive Surveillance, Epidemiology, and End Results analysis in the modern era. Leuk. Lymphoma 55, 2778–2784 (2014).

  13. 13.

    , , , & Racial differences in three major NHL subtypes: descriptive epidemiology. Cancer Epidemiol. 39, 8–13 (2015).

  14. 14.

    , , & Survival for patients with chronic leukemias in the US and Britain: age-related disparities and changes in the early 21st century. Eur. J. Haematol. 94, 540–545 (2015).

  15. 15.

    & Familial predisposition and genetic risk factors for lymphoma. Blood 126, 2265–2273 (2015).

  16. 16.

    et al. Environmental and heritable factors in the causation of cancer — analyses of cohorts of twins from Sweden, Denmark, and Finland. N. Engl. J. Med. 343, 78–85 (2000).

  17. 17.

    et al. A genome-wide association study identifies six susceptibility loci for chronic lymphocytic leukemia. Nat. Genet. 40, 1204–1210 (2008).

  18. 18.

    et al. Genome-wide association study identifies a novel susceptibility locus at 6p21.3 among familial CLL. Blood 117, 1911–1916 (2011).

  19. 19.

    et al. Common variants at 2q37.3, 8q24.21, 15q21.3 and 16q24.1 influence chronic lymphocytic leukemia risk. Nat. Genet. 42, 132–136 (2010).

  20. 20.

    et al. Genome-wide association study identifies multiple risk loci for chronic lymphocytic leukemia. Nat. Genet. 45, 868–876 (2013).

  21. 21.

    et al. A genome-wide association study identifies multiple susceptibility loci for chronic lymphocytic leukemia. Nat. Genet. 46, 56–60 (2014).

  22. 22.

    et al. Meta-analysis of genome-wide association studies discovers multiple loci for chronic lymphocytic leukemia. Nat. Commun. 7, 10933 (2016).

  23. 23.

    , , , & A role for IRF4 in the development of CLL. Blood 122, 2848–2855 (2013).

  24. 24.

    , , & Interferon regulatory factor 4 attenuates notch signaling to suppress the development of chronic lymphocytic leukemia. Oncotarget 7, 41081–41094 (2016).

  25. 25.

    et al. Dysregulation of TNFalpha-induced necroptotic signaling in chronic lymphocytic leukemia: suppression of CYLD gene by LEF1. Leukemia 26, 1293–1300 (2012).

  26. 26.

    et al. A microRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. N. Engl. J. Med. 353, 1793–1801 (2005). This seminal study indicates that differences in the expression of certain miRNAs are associated with differences in clinical outcome, providing evidence that miRNA can influence disease progression in patients with CLL.

  27. 27.

    et al. Allele-specific loss and transcription of the miR-15a/16-1 cluster in chronic lymphocytic leukemia. Leukemia 29, 86–95 (2015).

  28. 28.

    et al. miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc. Natl Acad. Sci. USA 102, 13944–13949 (2005).

  29. 29.

    et al. ZAP-70 directly enhances IgM signaling in chronic lymphocytic leukemia. Blood 105, 2036–2041 (2005).

  30. 30.

    et al. Abnormal microRNA-16 locus with synteny to human 13q14 linked to CLL in NZB mice. Blood 109, 5079–5086 (2007).

  31. 31.

    et al. Genetic variation associated with longer telomere length increases risk of chronic lymphocytic leukemia. Cancer Epidemiol. Biomarkers Prev. 25, 1043–1049 (2016).

  32. 32.

    et al. A high rate of telomeric sister chromatid exchange occurs in chronic lymphocytic leukaemia B-cells. Br. J. Haematol. 174, 57–70 (2016).

  33. 33.

    , & The impact of Agent Orange exposure on presentation and prognosis of patients with chronic lymphocytic leukemia. Leuk. Lymphoma 55, 63–66 (2014).

  34. 34.

    et al. Insecticide exposure and farm history in relation to risk of lymphomas and leukemias in the Women's Health Initiative observational study cohort. Ann. Epidemiol. 25, 803–810 (2015).

  35. 35.

    et al. The incidence of leukemia, lymphoma and multiple myeloma among atomic bomb survivors: 1950–2001. Radiat. Res. 179, 361–382 (2013).

  36. 36.

    , , , & Ionizing radiation exposures in treatments of solid neoplasms are not associated with subsequent increased risks of chronic lymphocytic leukemia. Leuk. Res. 43, 9–12 (2016).

  37. 37.

    et al. No evidence of transmission of chronic lymphocytic leukemia through blood transfusion. Blood 126, 2059–2061 (2015).

  38. 38.

    et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N. Engl. J. Med. 343, 1910–1916 (2000).

  39. 39.

    et al. The DLEU2/miR-15a/16-1 cluster controls B cell proliferation and its deletion leads to chronic lymphocytic leukemia. Cancer Cell 17, 28–40 (2010).

  40. 40.

    , , , & From pathogenesis to treatment of chronic lymphocytic leukaemia. Nat. Rev. Cancer 10, 37–50 (2010).

  41. 41.

    et al. The Dohner fluorescence in situ hybridization prognostic classification of chronic lymphocytic leukaemia (CLL): the CLL Research Consortium experience. Br. J. Haematol. 173, 105–113 (2016).

  42. 42.

    et al. Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation. J. Exp. Med. 208, 1389–1401 (2011).

  43. 43.

    et al. A comprehensive catalogue of somatic mutations from a human cancer genome. Nature 463, 191–196 (2010).

  44. 44.

    et al. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature 475, 101–105 (2011).

  45. 45.

    et al. SF3B1 and other novel cancer genes in chronic lymphocytic leukemia. N. Engl. J. Med. 365, 2497–2506 (2011).

  46. 46.

    et al. Acquired initiating mutations in early hematopoietic cells of CLL patients. Cancer Discov. 4, 1088–1101 (2014).

  47. 47.

    et al. Somatic mutation as a mechanism of Wnt/beta-catenin pathway activation in CLL. Blood 124, 1089–1098 (2014).

  48. 48.

    et al. Transcriptome characterization by RNA sequencing identifies a major molecular and clinical subdivision in chronic lymphocytic leukemia. Genome Res. 24, 212–226 (2014).

  49. 49.

    et al. Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia. Nat. Genet. 44, 47–52 (2012).

  50. 50.

    et al. The impact of SF3B1 mutations in CLL on the DNA-damage response. Leukemia 29, 1133–1142 (2015).

  51. 51.

    et al. Mutations driving CLL and their evolution in progression and relapse. Nature 526, 525–530 (2015).

  52. 52.

    et al. Non-coding recurrent mutations in chronic lymphocytic leukaemia. Nature 526, 519–524 (2015). References 51 and 52 describe landmark studies on whole-exome sequencing of CLL cells obtained from a large cohort of patients, reporting new driver mutations in CLL.

  53. 53.

    et al. Whole-exome sequencing in relapsing chronic lymphocytic leukemia: clinical impact of recurrent RPS15 mutations. Blood 127, 1007–1016 (2016).

  54. 54.

    , , & The Pax-5 gene: a pluripotent regulator of B-cell differentiation and cancer disease. Cancer Res. 71, 7345–7350 (2011).

  55. 55.

    et al. NOTCH1 mutations identify a genetic subgroup of chronic lymphocytic leukemia patients with high risk of transformation and poor outcome. Leukemia 27, 1100–1106 (2013).

  56. 56.

    et al. Presence of multiple recurrent mutations confers poor trial outcome of relapsed/refractory CLL. Blood 126, 2110–2117 (2015).

  57. 57.

    et al. Tumor evolutionary directed graphs and the history of chronic lymphocytic leukemia. eLife 3, e02869 (2014).

  58. 58.

    et al. Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition. Nat. Commun. 7, 11589 (2016).

  59. 59.

    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 99, 15524–15529 (2002). This is the seminal description of the involvement of miRNA in any human disease. This study describes the most common genetic lesion in CLL, namely, the deletion of two closely linked miRNAs, mir-15-1 and mir-16a, which are commonly downregulated in CLL.

  60. 60.

    et al. Association of a microRNA/TP53 feedback circuitry with pathogenesis and outcome of B-cell chronic lymphocytic leukemia. JAMA 305, 59–67 (2011).

  61. 61.

    & MicroRNAs and B cell receptor signaling in chronic lymphocytic leukemia. Leuk. Lymphoma 54, 1836–1839 (2013).

  62. 62.

    et al. TCL1 targeting miR-3676 is codeleted with tumor protein p53 in chronic lymphocytic leukemia. Proc. Natl Acad. Sci. USA 112, 2169–2174 (2015).

  63. 63.

    et al. Human chronic lymphocytic leukemia modeled in mouse by targeted TCL1 expression. Proc. Natl Acad. Sci. USA 99, 6955–6960 (2002).

  64. 64.

    et al. Pre-B cell proliferation and lymphoblastic leukemia/high-grade lymphoma in Eμ-miR155 transgenic mice. Proc. Natl Acad. Sci. USA 103, 7024–7029 (2006).

  65. 65.

    et al. MicroRNA-155 influences B-cell receptor signaling and associates with aggressive disease in chronic lymphocytic leukemia. Blood 124, 546–554 (2014).

  66. 66.

    et al. 450K-array analysis of chronic lymphocytic leukemia cells reveals global DNA methylation to be relatively stable over time and similar in resting and proliferative compartments. Leukemia 27, 150–158 (2013).

  67. 67.

    et al. Genomic hypomethylation in human chronic lymphocytic leukemia. Blood 80, 2074–2080 (1992).

  68. 68.

    et al. Charting a dynamic DNA methylation landscape of the human genome. Nature 500, 477–481 (2013).

  69. 69.

    et al. Epigenomic analysis detects widespread gene-body DNA hypomethylation in chronic lymphocytic leukemia. Nat. Genet. 44, 1236–1242 (2012). This paper describes an analysis of DNA methylation in CLL cases, showing that the two molecular subtypes of CLL have differing DNA methylomes that seem to represent epigenetic imprints from distinct normal B cell subpopulations.

  70. 70.

    et al. Locally disordered methylation forms the basis of intratumor methylome variation in chronic lymphocytic leukemia. Cancer Cell 26, 813–825 (2014).

  71. 71.

    et al. Evolution of DNA methylation is linked to genetic aberrations in chronic lymphocytic leukemia. Cancer Discov. 4, 348–361 (2014).

  72. 72.

    et al. Genome-wide DNA methylation analysis reveals novel epigenetic changes in chronic lymphocytic leukemia. Epigenetics 7, 567–578 (2012).

  73. 73.

    et al. A B-cell epigenetic signature defines three biologic subgroups of chronic lymphocytic leukemia with clinical impact. Leukemia 29, 598–605 (2015).

  74. 74.

    et al. Prognostic impact of epigenetic classification in chronic lymphocytic leukemia: the case of subset #2. Epigenetics 11, 449–455 (2016).

  75. 75.

    et al. DNA methylation dynamics during B cell maturation underlie a continuum of disease phenotypes in chronic lymphocytic leukemia. Nat. Genet. 48, 253–264 (2016).

  76. 76.

    , & In vivo ablation of surface immunoglobulin on mature B cells by inducible gene targeting results in rapid cell death. Cell 90, 1073–1083 (1997).

  77. 77.

    et al. The lymph node microenvironment promotes B-cell receptor signaling, NF-kappaB activation, and tumor proliferation in chronic lymphocytic leukemia. Blood 117, 563–574 (2011). This paper describes a study of gene expression profiles of CLL cells from the blood and lymphoid tissues (blood, marrow and lymph node) of the same patients with CLL, showing differences in gene expression for cells in the lymph node versus cells in the blood of the same patient. The lymph node was identified as the crucial site for BCR and NF-κB activation, and this was more evident in CLL cells that expressed unmutated IGHV.

  78. 78.

    et al. Reversible anergy of sIgM-mediated signaling in the two subsets of CLL defined by VH-gene mutational status. Blood 109, 4424–4431 (2007).

  79. 79.

    et al. Chronic lymphocytic leukaemia is driven by antigen-independent cell-autonomous signalling. Nature 489, 309–312 (2012).

  80. 80.

    & New strategies in chronic lymphocytic leukemia: shifting treatment paradigms. Clin. Cancer Res. 20, 5869–5874 (2014).

  81. 81.

    , & Molecular underpinning of B-cell anergy. Immunol. Rev. 237, 249–263 (2010).

  82. 82.

    , , , & Continuous inhibitory signaling by both SHP-1 and SHIP-1 pathways is required to maintain unresponsiveness of anergic B cells. J. Exp. Med. 213, 751–769 (2016).

  83. 83.

    et al. Monophosphorylation of CD79a and CD79b ITAM motifs initiates a SHIP-1 phosphatase-mediated inhibitory signaling cascade required for B cell anergy. Immunity 35, 746–756 (2011).

  84. 84.

    et al. The outcome of B-cell receptor signaling in chronic lymphocytic leukemia: proliferation or anergy. Haematologica 99, 1138–1148 (2014).

  85. 85.

    , , & B-cell anergy: from transgenic models to naturally occurring anergic B cells? Nat. Rev. Immunol. 7, 633–643 (2007).

  86. 86.

    et al. The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia. Blood 119, 2590–2594 (2012).

  87. 87.

    et al. Down-regulation of CXCR4 and CD62L in chronic lymphocytic leukemia cells is triggered by B-cell receptor ligation and associated with progressive disease. Cancer Res. 69, 6387–6395 (2009).

  88. 88.

    et al. B-cell antigen receptor signaling enhances chronic lymphocytic leukemia cell migration and survival: specific targeting with a novel spleen tyrosine kinase inhibitor, R406. Blood 114, 1029–1037 (2009).

  89. 89.

    et al. Elucidating the CXCL12/CXCR4 signaling network in chronic lymphocytic leukemia through phosphoproteomics analysis. PLoS ONE 5, e11716 (2010).

  90. 90.

    et al. BAFF and APRIL support chronic lymphocytic leukemia B-cell survival through activation of the canonical NF-kappaB pathway. Blood 109, 703–710 (2007).

  91. 91.

    et al. IL-4 enhances expression and function of surface IgM in CLL cells. Blood 127, 3015–3025 (2016).

  92. 92.

    et al. Activation of the Wnt signaling pathway in chronic lymphocytic leukemia. Proc. Natl Acad. Sci. USA 101, 3118–3123 (2004).

  93. 93.

    et al. Wnt5a induces ROR1/ROR2 heterooligomerization to enhance leukemia chemotaxis and proliferation. J. Clin. Invest. 126, 585–598 (2016).

  94. 94.

    et al. High-level ROR1 associates with accelerated disease-progression in chronic lymphocytic leukemia. Blood 128, 2931–2940 (2016).

  95. 95.

    , & Interactions between bone marrow stromal microenvironment and B-chronic lymphocytic leukemia cells: any role for Notch, Wnt and Hh signaling pathways? Cell Signal. 24, 1433–1443 (2012).

  96. 96.

    et al. Trisomy 12 and elevated GLI1 and PTCH1 transcript levels are biomarkers for Hedgehog-inhibitor responsiveness in CLL. Blood 119, 997–1007 (2012).

  97. 97.

    et al. Notch signaling sustains the expression of Mcl-1 and the activity of eIF4E to promote cell survival in CLL. Oncotarget 6, 16559–16572 (2015).

  98. 98.

    et al. Identification in CLL of circulating intraclonal subgroups with varying B-cell receptor expression and function. Blood 122, 2664–2672 (2013).

  99. 99.

    , & Chronic lymphocytic leukemia B cells express functional CXCR4 chemokine receptors that mediate spontaneous migration beneath bone marrow stromal cells. Blood 94, 3658–3667 (1999). This paper describes the finding that CLL cells express functional chemokine receptors, notably CXCR4, and can actively migrate and home to accessory cells in lymphoid tissue; these observations laid the foundation of our current view that CLL cells continuously re-circulate between blood and lymphoid tissue compartments.

  100. 100.

    et al. Blood-derived nurse-like cells protect chronic lymphocytic leukemia B cells from spontaneous apoptosis through stromal cell-derived factor-1. Blood 96, 2655–2663 (2000).

  101. 101.

    et al. Intraclonal complexity in chronic lymphocytic leukemia: fractions enriched in recently born/divided and older/quiescent cells. Mol. Med. 17, 1374–1382 (2011).

  102. 102.

    et al. Phenotypic heterogeneity in IGHV-mutated CLL patients has prognostic impact and identifies a subset with increased sensitivity to BTK and PI3Kdelta inhibition. Leukemia 29, 744–747 (2015).

  103. 103.

    et al. Disruption of in vivo chronic lymphocytic leukemia tumor–microenvironment interactions by ibrutinib — findings from an investigator-initiated phase II study. Clin. Cancer Res. 22, 1572–1582 (2016).

  104. 104.

    , & Regulatory T cells suppress systemic and mucosal immune activation to control intestinal inflammation. Immunol. Rev. 212, 256–271 (2006).

  105. 105.

    et al. Chronic lymphocytic leukemia and regulatory B cells share IL-10 competence and immunosuppressive function. Leukemia 27, 170–182 (2013).

  106. 106.

    , , & Multiple inhibitory ligands induce impaired T-cell immunologic synapse function in chronic lymphocytic leukemia that can be blocked with lenalidomide: establishing a reversible immune evasion mechanism in human cancer. Blood 120, 1412–1421 (2012).

  107. 107.

    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 111, 5446–5456 (2008).

  108. 108.

    & FMC7 is an epitope of CD20. Blood 111, 2492; author reply 2493–2494 (2008).

  109. 109.

    et al. Diagnostic usefulness and prognostic impact of CD200 expression in lymphoid malignancies and plasma cell myeloma. Am. J. Clin. Pathol. 137, 93–100 (2012).

  110. 110.

    et al. Antisera induced by infusions of autologous Ad-CD154-leukemia B cells identify ROR1 as an oncofetal antigen and receptor for Wnt5a. Proc. Natl Acad. Sci. USA 105, 3047–3052 (2008).

  111. 111.

    B- and T-cell prolymphocytic leukemia: antibody approaches. Hematol. Am. Soc. Hematol. Educ. Program 2012, 645–651 (2012).

  112. 112.

    & Bone marrow biopsy in chronic lymphocytic leukaemia: a study of 208 cases. Haematologia (Budap.) 16, 73–79 (1983).

  113. 113.

    , , & Small lymphocytic lymphoma with perifollicular, marginal zone, or interfollicular distribution. Mod. Pathol. 13, 1161–1166 (2000).

  114. 114.

    et al. Clinical staging of chronic lymphocytic leukemia. Blood 46, 219–234 (1975).

  115. 115.

    et al. A clinical staging system for chronic lymphocytic leukemia: prognostic significance. Cancer 40, 855–864 (1977).

  116. 116.

    et al. Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia. Blood 121, 1403–1412 (2013).

  117. 117.

    et al. Development of a comprehensive prognostic index for patients with chronic lymphocytic leukemia. Blood 124, 49–62 (2014).

  118. 118.

    International CLL-IPI working group. An international prognostic index for patients with chronic lymphocytic leukaemia (CLL-IPI): a meta-analysis of individual patient data. Lancet Oncol. 17, 779–790 (2016).

  119. 119.

    et al. Prognostic nomogram and index for overall survival in previously untreated patients with chronic lymphocytic leukemia. Blood 109, 4679–4685 (2007).

  120. 120.

    et al. ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia. N. Engl. J. Med. 351, 893–901 (2004).

  121. 121.

    et al. ZAP-70 expression and prognosis in chronic lymphocytic leukaemia. Lancet 363, 105–111 (2004).

  122. 122.

    et al. CD49d is the strongest flow cytometry-based predictor of overall survival in chronic lymphocytic leukemia. J. Clin. Oncol. 32, 897–904 (2014).

  123. 123.

    et al. 11q deletions identify a new subset of B-cell chronic lymphocytic leukemia characterized by extensive nodal involvement and inferior prognosis. Blood 89, 2516–2522 (1997).

  124. 124.

    et al. Serum β2-microglobulin and serum thymidine kinase are independent predictors of progression-free survival in chronic lymphocytic leukemia and immunocytoma. Leuk. Lymphoma 22, 439–447 (1996).

  125. 125.

    et al. Major prognostic value of complex karyotype in addition to TP53 and IGHV mutational status in first-line chronic lymphocytic leukemia. Hematol. Oncol. (2016).

  126. 126.

    et al. Complex karyotype is a stronger predictor than del(17p) for an inferior outcome in relapsed or refractory chronic lymphocytic leukemia patients treated with ibrutinib-based regimens. Cancer 121, 3612–3621 (2015).

  127. 127.

    et al. Select high-risk genetic features predict earlier progression following chemoimmunotherapy with fludarabine and rituximab in chronic lymphocytic leukemia: justification for risk-adapted therapy. J. Clin. Oncol. 24, 437–443 (2006).

  128. 128.

    et al. Chronic lymphocytic leukaemia: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 26 (Suppl. 5), v78–v84 (2015).

  129. 129.

    et al. Appendix 6: chronic lymphocytic leukaemia: eUpdate published online September 2016 (). Ann. Oncol. 27 (Suppl. 5), v143–v144 (2016).

  130. 130.

    Therapy of chronic lymphocytic leukaemia with purine nucleoside analogues: facts and controversies. Drugs Aging 22, 983–1012 (2005).

  131. 131.

    & Bendamustine for treatment of chronic lymphocytic leukemia. Expert Opin. Pharmacother. 13, 1495–1505 (2012).

  132. 132.

    & Fludarabine: a review of the clear benefits and potential harms. Leuk. Res. 37, 986–994 (2013).

  133. 133.

    et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet 376, 1164–1174 (2010).

  134. 134.

    et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N. Engl. J. Med. 370, 1101–1110 (2014).

  135. 135.

    et al. Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukaemia (COMPLEMENT 1): a randomised, multicentre, open-label phase 3 trial. Lancet 385, 1873–1883 (2015).

  136. 136.

    et al. Ofatumumab as single-agent CD20 immunotherapy in fludarabine-refractory chronic lymphocytic leukemia. J. Clin. Oncol. 28, 1749–1755 (2010).

  137. 137.

    et al. Combination of bendamustine and rituximab as front-line therapy for patients with chronic lymphocytic leukaemia: multicenter, retrospective clinical practice experience with 279 cases outside of controlled clinical trials. Eur. J. Cancer 60, 154–165 (2016).

  138. 138.

    et al. Obinutuzumab plus fludarabine/cyclophosphamide or bendamustine in the initial therapy of CLL patients: the phase 1b GALTON trial. Blood 125, 2779–2785 (2015).

  139. 139.

    et al. First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol. 17, 928–942 (2016).

  140. 140.

    et al. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood 127, 208–215 (2016).

  141. 141.

    et al. Molecular prediction of durable remission after first-line fludarabine–cyclophosphamide–rituximab in chronic lymphocytic leukemia. Blood 126, 1921–1924 (2015).

  142. 142.

    et al. Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood 127, 303–309 (2016). This paper reports an important finding from the seminal clinical trial of fludarabine, cyclophosphamide and rituximab for the treatment of patients with CLL, demonstrating long-term disease-free survival following therapy for many patients who had CLL cells that express mutated IGHV. This study, along with references 139 and 140, shows that a large proportion of patients with CLL cells that express mutated IGHV potentially may be ‘cured’ by chemoimmunotherapy.

  143. 143.

    et al. The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo. Blood 119, 1182–1189 (2012).

  144. 144.

    et al. Heightened BTK-dependent cell proliferation in unmutated chronic lymphocytic leukemia confers increased sensitivity to ibrutinib. Oncotarget 7, 4598–4610 (2016).

  145. 145.

    et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N. Engl. J. Med. 371, 213–223 (2014). This paper reports on the randomized study of ibrutinib versus ofatumumab in patients with relapse CLL, showing that ibrutinib can be highly effective in the treatment of patients, including those with high-risk features, such as del(17p). The results of this study resulted in regulatory agency approval of ibrutinib for the treatment of patients with relapsed CLL or as initial therapy of patients with CLL cells with del(17p).

  146. 146.

    et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N. Engl. J. Med. 373, 2425–2437 (2015). This paper reports on the randomized study of ibrutinib versus chlorambucil in the initial therapy of patients with CLL that showed that ibrutinib was more effective than chemotherapy in the treatment of patients, resulting in the regulatory agency approval of ibrutinib for the initial treatment of patients with CLL.

  147. 147.

    et al. Resistance mechanisms for the Bruton's tyrosine kinase inhibitor ibrutinib. N. Engl. J. Med. 370, 2286–2294 (2014). This paper reports on genetic studies of CLL cells from patients who developed resistance to ibrutinib, showing that a large subset of such patients had mutations in BTK, which encodes the enzyme inhibited by ibrutinib. As such, this study demonstrates that inhibition of BTK is responsible for the clinical activity of ibrutinib.

  148. 148.

    et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N. Engl. J. Med. 374, 323–332 (2016).

  149. 149.

    et al. A phase 1 clinical trial of the selective BTK inhibitor ONO/GS-4059 in relapsed and refractory mature B-cell malignancies. Blood 127, 411–419 (2016).

  150. 150.

    , , & Second-generation inhibitors of Bruton tyrosine kinase. J. Hematol. Oncol. 9, 80 (2016).

  151. 151.

    & Pharmacological targeting of PI3K isoforms as a therapeutic strategy in chronic lymphocytic leukaemia. Leuk. Res. Rep. 4, 60–63 (2015).

  152. 152.

    et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N. Engl. J. Med. 370, 997–1007 (2014).

  153. 153.

    et al. Idelalisib given front-line for treatment of chronic lymphocytic leukemia causes frequent immune-mediated hepatotoxicity. Blood 128, 195–203 (2016).

  154. 154.

    et al. Management of adverse events associated with idelalisib treatment: expert panel opinion. Leuk. Lymphoma 56, 2779–2786 (2015).

  155. 155.

    & Prophylaxis against hepatitis B reactivation among patients with lymphoma receiving rituximab. Expert Rev. Anti Infect. Ther. 12, 151–154 (2014).

  156. 156.

    et al. Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood 115, 2578–2585 (2010).

  157. 157.

    et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat. Med. 19, 202–208 (2013).

  158. 158.

    et al. Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737. J. Clin. Invest. 117, 112–121 (2007).

  159. 159.

    et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N. Engl. J. Med. 374, 311–322 (2016). This paper reports on seminal clinical studies of venetoclax, a BCL-2 inhibitor, showing that this drug can be highly effective in the treatment of patients with CLL, resulting in the initial regulatory agency approval of venetoclax for the treatment of patients with relapsed CLL with del(17p).

  160. 160.

    et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol. 17, 768–778 (2016).

  161. 161.

    et al. Pharmacological and protein profiling suggests venetoclax (ABT-199) as optimal partner with ibrutinib in chronic lymphocytic leukemia. Clin. Cancer Res. 21, 3705–3715 (2015).

  162. 162.

    et al. Resistance to ABT-199 induced by microenvironmental signals in chronic lymphocytic leukemia can be counteracted by CD20 antibodies or kinase inhibitors. Haematologica 100, e302–e306 (2015).

  163. 163.

    & Eliminating minimal residual disease as a therapeutic end point: working toward cure for patients with CLL. Blood 127, 279–286 (2016).

  164. 164.

    , , , & Rituximab in combination with high-dose methylprednisolone for the treatment of fludarabine refractory high-risk chronic lymphocytic leukemia. Leukemia 22, 2048–2053 (2008).

  165. 165.

    et al. Lenalidomide induces complete and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia. Blood 111, 5291–5297 (2008).

  166. 166.

    et al. Lenalidomide and rituximab for the initial treatment of patients with chronic lymphocytic leukemia: a multicenter clinical-translational study from the chronic lymphocytic leukemia research consortium. J. Clin. Oncol. 32, 2067–2073 (2014).

  167. 167.

    Patterns of resistance to B cell-receptor pathway antagonists in chronic lymphocytic leukemia and strategies for management. Hematol. Am. Soc. Hematol. Educ. Program 2015, 355–360 (2015).

  168. 168.

    et al. Rituximab maintenance versus observation alone in patients with chronic lymphocytic leukaemia who respond to first-line or second-line rituximab-containing chemoimmunotherapy: final results of the AGMT CLL-8a Mabtenance randomised trial. Lancet Haematol. 3, e317–e329 (2016).

  169. 169.

    et al. Quality of life in chronic lymphocytic leukemia: an international survey of 1482 patients. Br. J. Haematol. 139, 255–264 (2007).

  170. 170.

    & Perturbation of the normal immune system in patients with CLL. Blood 126, 573–581 (2015).

  171. 171.

    [No authors listed.] Intravenous immunoglobulin for the prevention of infection in chronic lymphocytic leukemia. A Randomized, Controlled Clinical Trial Cooperative Group for the study of immunoglobulin in chronic lymphocytic leukemia. N. Engl. J. Med. 319, 902–907 (1988).

  172. 172.

    , , , & Intravenous versus subcutaneous immunoglobulin replacement in secondary hypogammaglobulinemia. Clin. Immunol. 166–167, 103–104 (2016).

  173. 173.

    et al. Antibody deficiency secondary to chronic lymphocytic leukemia: should patients be treated with prophylactic replacement immunoglobulin? J. Clin. Immunol. 34, 277–282 (2014).

  174. 174.

    et al. Autoimmune cytopenias in chronic lymphocytic leukemia. Am. J. Hematol. 89, 1055–1062 (2014).

  175. 175.

    , , , & Autoimmune cytopenia in chronic lymphocytic leukaemia: diagnosis and treatment. Br. J. Haematol. 154, 14–22 (2011).

  176. 176.

    et al. Mycophenolate mofetil therapy for severe immune thrombocytopenia. Br. J. Haematol. 171, 625–630 (2015).

  177. 177.

    , , , & Solid tumors after chronic lymphocytic leukemia. Blood 98, 1979–1981 (2001).

  178. 178.

    , & Merkel cell carcinoma, chronic lymphocytic leukemia and other lymphoproliferative disorders: an old bond with possible new viral ties. Ann. Oncol. 22, 250–256 (2011).

  179. 179.

    , , & Second malignancies in B-cell chronic lymphocytic leukaemia: possible association with human papilloma virus. Br. J. Haematol. 149, 388–390 (2010).

  180. 180.

    et al. Effect of first-line treatment on second primary malignancies and Richter's transformation in patients with CLL. Leukemia 30, 2019–2025 (2016).

  181. 181.

    , & Hodgkin lymphoma as Richter transformation in chronic lymphocytic leukaemia: a retrospective analysis of world literature. Br. J. Haematol. 156, 50–66 (2012).

  182. 182.

    & Richter syndrome: pathogenesis and management. Semin. Oncol. 43, 311–319 (2016).

  183. 183.

    et al. Stereotyped B-cell receptor is an independent risk factor of chronic lymphocytic leukemia transformation to Richter syndrome. Clin. Cancer Res. 15, 4415–4422 (2009).

  184. 184.

    et al. Diagnostic and prognostic role of PET/CT in patients with chronic lymphocytic leukemia and progressive disease. Leukemia 29, 1360–1365 (2015).

  185. 185.

    et al. Outcomes for patients with chronic lymphocytic leukemia and acute leukemia or myelodysplastic syndrome. Leukemia 30, 325–330 (2016).

  186. 186.

    et al. Results of a phase II study of lenalidomide and rituximab for refractory/relapsed chronic lymphocytic leukemia. Leuk. Res. 47, 78–83 (2016).

  187. 187.

    et al. Lenalidomide inhibits the proliferation of CLL cells via a cereblon/p21WAF1/Cip1-dependent mechanism independent of functional p53. Blood 124, 1637–1644 (2014).

  188. 188.

    et al. Chronic lymphocytic leukemia T cells show impaired immunological synapse formation that can be reversed with an immunomodulating drug. J. Clin. Invest. 118, 2427–2437 (2008).

  189. 189.

    et al. Lenalidomide as initial therapy of elderly patients with chronic lymphocytic leukemia. Blood 118, 3489–3498 (2011).

  190. 190.

    , & Treating chronic lymphocytic leukemia with thalidomide and lenalidomide. Expert Opin. Pharmacother. 12, 2857–2864 (2011).

  191. 191.

    US National Library of Medicine. ClinicalTrials.gov (2015).

  192. 192.

    et al. Phase II study of lenalidomide and rituximab as salvage therapy for patients with relapsed or refractory chronic lymphocytic leukemia. J. Clin. Oncol. 31, 584–591 (2013).

  193. 193.

    et al. Ofatumumab and lenalidomide for patients with relapsed or refractory chronic lymphocytic leukemia: correlation between responses and immune characteristics. Clin. Cancer Res. 22, 2359–2367 (2016).

  194. 194.

    et al. Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS. Nature 523, 183–188 (2015).

  195. 195.

    et al. Nonmyeloablative allogeneic stem cell transplantation in relapsed/refractory chronic lymphocytic leukemia: long-term follow-up, prognostic factors, and effect of human leukocyte histocompatibility antigen subtype on outcome. Cancer 117, 4679–4688 (2011).

  196. 196.

    et al. TP53, SF3B1, and NOTCH1 mutations and outcome of allotransplantation for chronic lymphocytic leukemia: six-year follow-up of the GCLLSG CLL3X trial. Blood 121, 3284–3288 (2013).

  197. 197.

    et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci. Transl Med. 7, 303ra139 (2015).

  198. 198.

    et al. Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia. Blood 127, 1117–1127 (2016).

  199. 199.

    et al. Receptor affinity and extracellular domain modifications affect tumor recognition by ROR1-specific chimeric antigen receptor T cells. Clin. Cancer Res. 19, 3153–3164 (2013).

  200. 200.

    et al. Sleeping beauty transposition of chimeric antigen receptors targeting receptor tyrosine kinase-like orphan receptor-1 (ROR1) into diverse memory t-cell populations. PLoS ONE 10, e0128151 (2015).

  201. 201.

    & Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell 161, 205–214 (2015).

  202. 202.

    et al. PD-L1 checkpoint blockade prevents immune dysfunction and leukemia development in a mouse model of chronic lymphocytic leukemia. Blood 126, 203–211 (2015).

  203. 203.

    et al. Cirmtuzumab inhibits Wnt5a-induced Rac1-activation in chronic lymphocytic leukemia treated with ibrutinib. Leukemia (2016).

  204. 204.

    & Monoclonal B-cell lymphocytosis and early-stage chronic lymphocytic leukemia: diagnosis, natural history, and risk stratification. Blood 126, 454–462 (2015).

  205. 205.

    , , , & Monoclonal B-cell lymphocytosis (MBL): biology, natural history and clinical management. Leukemia 24, 512–520 (2010).

  206. 206.

    et al. Monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia. N. Engl. J. Med. 359, 575–583 (2008).

  207. 207.

    , , & Common clonal origin of chronic lymphocytic leukemia and high-grade lymphoma of Richter's syndrome. Blood 82, 3141–3147 (1993).

  208. 208.

    , , & Epstein–Barr virus-positive diffuse large B cell lymphoma arising from a chronic lymphocytic leukemia: overlapping features with classical Hodgkin lymphoma. Pathol. Int. 66, 393–397 (2016).

  209. 209.

    et al. Two main genetic pathways lead to the transformation of chronic lymphocytic leukemia to Richter syndrome. Blood 122, 2673–2682 (2013).

  210. 210.

    et al. The genetics of Richter syndrome reveals disease heterogeneity and predicts survival after transformation. Blood 117, 3391–3401 (2011).

  211. 211.

    et al. Genetic lesions associated with chronic lymphocytic leukemia transformation to Richter syndrome. J. Exp. Med. 210, 2273–2288 (2013).

  212. 212.

    , & Driving CAR T-cells forward. Nat. Rev. Clin. Oncol. 13, 370–383 (2016).

  213. 213.

    & Chronic lymphocytic leukemia: molecular heterogeneity revealed by high-throughput genomics. Genome Med. 5, 47 (2013).

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Acknowledgements

The authors thank H.-Y. Wang and E. Broome, Department of Pathology, University of California San Diego, for their contributions to Figures 5–7. The authors also thank A. Greaves, University of California San Diego, for help in figure development. This Primer is supported by the US NIH PO1-CA81534 for the CLL Research Consortium; members include K.R., W.G.W., T.J.K., C.M.C., C.J.W. and J.G. The authors also acknowledge support to F.K.S. and G.P. from Bloodwise, Kay Kendall Leukaemia Fund, Cancer Research UK, the Southampton Experimental Cancer Medicine Centre, and the Southampton Cancer Research UK Centre (F.K.S. and G.P.). The authors also acknowledge support from the Leukemia & Lymphoma Society (LLS) Specialized Center of Research Program (SCOR) grant (T.J.K.), 1R01HL116452, 1R01CA182461, CLL Global Reseach Foundation (W.G.W.), the Blood Cancer Research Fund (T.J.K.), and U10CA180861.

Author information

Affiliations

  1. Division of Hematology-Oncology, Department of Medicine, Moores Cancer Centre, University of California, San Diego, 3855 Health Sciences Drive M/C 0820, La Jolla, California 92093, USA.

    • Thomas J. Kipps
  2. Southampton Cancer Research UK Centre, Cancer Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK.

    • Freda K. Stevenson
    •  & Graham Packham
  3. Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Catherine J. Wu
  4. Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus, Ohio, USA.

    • Carlo M. Croce
  5. Department of Hematology, MD Anderson Cancer Centre, Houston, Texas, USA.

    • William G. Wierda
  6. Division of Hematology, Department of Medicine, University of California, Irvine, California, USA.

    • Susan O'Brien
  7. Department of Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.

    • John Gribben
  8. CLL Research and Treatment Program, Feinstein Institute for Medical Research, Northwell Health, New Hyde Park, New York, USA.

    • Kanti Rai

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Contributions

Introduction (T.J.K.); Epidemiology (T.J.K.); Mechanisms/pathophysiology (T.J.K., C.M.C., C.J.W., G.P. and F.K.S.); Diagnosis, screening and prevention (K.R., W.G.W. and T.J.K.); Management (W.G.W., S.O., J.G. and T.J.K.); Quality of life (J.G. and T.J.K.); Outlook (T.J.K.); Overview of Primer (T.J.K.).

Competing interests

J.G. has received honoraria for advisory boards from Roche, Genentech, AbbVie, Janssen, Pharmacyclics, Acerta, Gilead, TG Therapeutics and Unum. S.O. has acted as a consultant for Amgen and Celgene, is a scientific advisory board member for CLL Global Research Foundation and has received research support from Acerta, TG Therapeutics, Regeneron, Gilead, Pharmacyclics and ProNAi. K.R. is a member of the medical advisory board for Celgene, Roche/Genetech, Pharmacyclics and Gilead. T.J.K. has received honoraria for Ad boards, meetings, presentations and/or consulting from Gilead, Pharmacyclics, Celgene, Roche and AbbVie, and has received research funding from AbbVie and Celgene. C.J.W. is a co-founder and a member of the scientific advisory board of Neon Therapeutics. W.G.W., G.P., C.M.C. and F.K.S. declare no competing interests.

Corresponding author

Correspondence to Thomas J. Kipps.

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