Chronic lymphocytic leukemia: 2017 update on diagnosis, risk stratification, and treatment

American Journal of Hematology

Volumn 92, Issue 9, 2017, Pages 946-965

  Hallek, Michael ^a  

^a UNIVERSITY OF COLOGNE   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

ACALABRUTINIB; ALEMTUZUMAB; ANTILEUKEMIC AGENT; BENDAMUSTINE; CD20 ANTIBODY; CYCLOPHOSPHAMIDE; CYTOSTATIC AGENT; FLAVOPIRIDOL; FLUDARABINE; IBRUTINIB; IDELALISIB; IMMUNOMODULATING AGENT; LENALIDOMIDE; MONOCLONAL ANTIBODY; OBINUTUZUMAB; OBLIMERSEN; OFATUMUMAB; PEMBROLIZUMAB; PURINE DERIVATIVE; RITUXIMAB; VENETOCLAX; ANTINEOPLASTIC AGENT; PROTEIN P53; PYRAZOLE DERIVATIVE; PYRIMIDINE DERIVATIVE; TP53 PROTEIN, HUMAN;

ARTICLE; CANCER CHEMOTHERAPY; CANCER COMBINATION CHEMOTHERAPY; CANCER DIAGNOSIS; CANCER IMMUNOTHERAPY; CANCER STAGING; CHRONIC LYMPHATIC LEUKEMIA; DRUG CONTRAINDICATION; HUMAN; IMMUNOPHENOTYPING; MINIMAL RESIDUAL DISEASE; MOLECULARLY TARGETED THERAPY; MONOCLONAL B CELL LYMPHOCYTOSIS; MULTICENTER STUDY (TOPIC); NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PRACTICE GUIDELINE; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); RISK ASSESSMENT; TREATMENT RESPONSE; CHROMOSOME 17; CHROMOSOME DELETION; GENETICS; LEUKEMIA, LYMPHOCYTIC, CHRONIC, B-CELL; PATHOLOGY; SMITH MAGENIS SYNDROME;

ANTIBODIES, MONOCLONAL; ANTIBODIES, MONOCLONAL, HUMANIZED; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; CHROMOSOME DELETION; CHROMOSOMES, HUMAN, PAIR 17; HUMANS; LEUKEMIA, LYMPHOCYTIC, CHRONIC, B-CELL; PYRAZOLES; PYRIMIDINES; RISK ASSESSMENT; RITUXIMAB; SMITH-MAGENIS SYNDROME; TUMOR SUPPRESSOR PROTEIN P53;

EID: 85026829845     PISSN: 03618609     EISSN: 10968652     Source Type: Journal    
DOI: 10.1002/ajh.24826     Document Type: Article

References (179)

1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2007. CA Cancer J Clin. 2007;57:43–66.
2. National Cancer Institute [Website]. Surveillance Epidemiology and End Results Cancer Statistics review. Available at: http://seercancergov/statfacts/html/clyl.html 2009. Last accessed March 29, 2010.
3. Molica S. Sex differences in incidence and outcome of chronic lymphocytic leukemia patients. Leuk Lymphoma. 2006;47:1477–1480.
4. Morton LM, Wang SS, Devesa SS, et al. Lymphoma incidence patterns by WHO subtype in the United States, 1992–2001. Blood. 2006;107:265–276.
5. Watson L, Wyld P, Catovsky D. Disease burden of chronic lymphocytic leukemia within the European Union. Eur J Haematol. 2008;81:253–258.
6. Mauro FR, Foa R, Giannarelli D, et al. Clinical characteristics and outcome of young chronic lymphocytic leukemia patients: a single institution study of 204 cases. Blood. 1999;94:448–454.
7. Rozman C, Montserrat E. Chronic lymphocytic leukemia. N Engl J Med. 1995;333:1052–1057.
8. 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;20:246–259.
9. Landau DA, Tausch E, Taylor-Weiner AN, et al. Mutations driving CLL and their evolution in progression and relapse. Nature. 2015;526:525–530.
10. 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;99:15524–15529.
11. 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.
12. Zenz T, Mertens D, Kuppers R, et al. From pathogenesis to treatment of chronic lymphocytic leukaemia. Nat Rev Cancer. 2010;10:37–50.
13. 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. 2011;44:47–52.
14. 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;89:2516–2522.
15. Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010;376:1164–1174.
16. Seiffert M, Dietrich S, Jethwa A, et al. Exploiting biological diversity and genomic aberrations in chronic lymphocytic leukemia. Leuk Lymphoma. 2012;53:1023–1031.
17. Zenz T, Vollmer D, Trbusek M, et al. TP53 mutation profile in chronic lymphocytic leukemia: evidence for a disease specific profile from a comprehensive analysis of 268 mutations. Leukemia. 2010;24:2072–2079.
18. Puente XS, Pinyol M, Quesada V, et al. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature. 2011;475:101–105.
19. Puente XS, Bea S, Valdes-Mas R, et al. Non-coding recurrent mutations in chronic lymphocytic leukaemia. Nature. 2015;526:519–524.
20. Jackson SP, Bartek J. The DNA-damage response in human biology and disease. Nature. 2009;461:1071–1078.
21. Tsukada N, Burger JA, Zvaifler NJ, et al. Distinctive features of “nurselike” cells that differentiate in the context of chronic lymphocytic leukemia. Blood. 2002;99:1030–1037.
22. Pedersen IM, Kitada S, Leoni LM, et al. Protection of CLL B cells by a follicular dendritic cell line is dependent on induction of Mcl-1. Blood. 2002;100:1795–1801.
23. Burger JA, Ghia P, Rosenwald A, et al. The microenvironment in mature B-cell malignancies: a target for new treatment strategies. Blood. 2009;114:3367–3375.
24. Chiorazzi N, Rai KR, Ferrarini M. Chronic lymphocytic leukemia. N Engl J Med. 2005;352:804–815.
25. Reinart N, Nguyen PH, Boucas J, et al. Delayed development of chronic lymphocytic leukemia in the absence of macrophage migration inhibitory factor. Blood. 2013;121:812–821.
26. Nguyen PH, Fedorchenko O, Rosen N, et al. LYN kinase in the tumor microenvironment is essential for the progression of chronic lymphocytic leukemia. Cancer Cell. 2016;30:610–622.
27. Fiorcari S, Maffei R, Audrito V, et al. Ibrutinib modifies the function of monocyte/macrophage population in chronic lymphocytic leukemia. Oncotarget. 2016;7:65968–65981.
28. Galletti G, Caligaris-Cappio F, Bertilaccio MT. B cells and macrophages pursue a common path toward the development and progression of chronic lymphocytic leukemia. Leukemia. 2016;30:2293–2301.
29. Herman SE, Mustafa RZ, Jones J, et al. Treatment with ibrutinib inhibits BTK- and VLA-4-dependent adhesion of chronic lymphocytic leukemia cells in vivo. Clin Cancer Res. 2015;21:4642–4651.
30. Maffei R, Fiorcari S, Martinelli S, et al. Targeting neoplastic B cells and harnessing microenvironment: the “double face” of ibrutinib and idelalisib. J Hematol Oncol. 2015;8:60
31. Hallek M. State-of-the-art treatment of chronic lymphocytic leukemia. Hematology. 2009;440–449.
32. Hallek M. Signaling the end of chronic lymphocytic leukemia: new frontline treatment strategies. Blood. 2013;122:3723–3734.
33. 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;111:5446–5456.
34. Müller-Hermelink HK, Montserrat E, Catovsky D, et al. Chronic lymphocytic leukemia/small lymphocytic lymphoma. In: Jaffe ES, Harris NL, Stein H, et al., ed. World Health Organization Classification of Tumours Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press; 2001:127–130.
35. Catovsky D, Ralfkiaer E, Müller-Hermelink HK. T-cell prolymphocytic leukaemia. In: Jaffe ES, Harris NL, Stein H, et al., ed. World Health Organization Classification of Tumours Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press; 2001:195–196.
36. Melo JV, Catovsky D, Galton DAG. The relationship between chronic lymphocytic leukaemia and prolymphocytic leukaemia. IV. Analysis of survival and prognostic features. Br J Haematol. 1986;63:377–387.
37. Rawstron AC, Bennett FL, O'connor SJ, et al. Monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia. N Engl J Med. 2008;359:575–583.
38. Moreau EJ, Matutes E, A'hern RP, et al. Improvement of the chronic lymphocytic leukemia scoring system with the monoclonal antibody SN8 (CD79b). Am J Clin Pathol. 1997;108:378–382.
39. Ginaldi L, De Martinis M, Matutes E, et al. Levels of expression of CD19 and CD20 in chronic B cell leukaemias. J Clin Pathol. 1998;51:364–369.
40. Catovsky D, Müller-Hermelink HK, Montserrat E, et al. B-cell prolymphocytic leukaemia. In: Jaffe ES, Harris NL, Stein H, et al., ed. World Health Organization Classification of Tumours Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press; 2001:131–132.
41. Rai KR, Sawitsky A, Cronkite EP, et al. Clinical staging of chronic lymphocytic leukemia. Blood. 1975;46:219–234.
42. Binet JL, Auquier A, Dighiero G, et al. A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer. 1981;48:198–204.
43. Rai KR. A critical analysis of staging in CLL. In: Gale RP, Rai KR, ed. Chronic Lymphocytic Leukemia: Recent Progress and Future Directions. New York: Alan R. Liss; 1987:253–264.
44. Pflug N, Bahlo J, Shanafelt TD, et al. Development of a comprehensive prognostic index for patients with chronic lymphocytic leukemia. Blood. 2014;124:49–62.
45. Cramer P, Hallek M. Prognostic factors in chronic lymphocytic leukemia-what do we need to know?. Nat Rev Clin Oncol. 2011;8:38–47.
46. Cortese D, Sutton LA, Cahill N, et al. On the way towards a 'CLL prognostic index': focus on TP53, BIRC3, SF3B1, NOTCH1 and MYD88 in a population-based cohort. Leukemia. 2014;28:710–713.
47. Shanafelt TD, Jenkins G, Call TG, et al. Validation of a new prognostic index for patients with chronic lymphocytic leukemia. Cancer. 2009;115:363–372.
48. Wierda WG, O'brien S, Wang X, et al. Prognostic nomogram and index for overall survival in previously untreated patients with chronic lymphocytic leukemia. Blood. 2007;109:4679–4685.
49. International C. L. L. I. P. I. working group. An international prognostic index for patients with chronic lymphocytic leukaemia (CLL-IPI): a meta-analysis of individual patient data. Lancet Oncol. 2016;17:779–790.
50. CLL trialists collaborative group. Chemotherapeutic options in chronic lymphocytic leukemia. J Natl Cancer Inst. 1999;91:861–868.
51. Montserrat E, Fontanillas M, Estape J, et al. Chronic lymphocytic leukemia treatment: an interim report of PETHEMA trials. Leuk Lymphoma. 1991;5:89–92.
52. Shustik C, Mick R, Silver R, et al. Treatment of early chronic lymphocytic leukemia: intermittent chlorambucil versus observation. Hematol Oncol. 1988;6:7–12.
53. Dighiero G, Maloum K, Desablens B, et al. Chlorambucil in indolent chronic lymphocytic leukemia. N Engl J Med. 1998;338:1506–1514.
54. Bottcher S, Hallek M, Ritgen M, et al. The role of minimal residual disease measurements in the therapy for CLL: is it ready for prime time? Hematol Oncol Clin North Am. 2013;27:267–288.
55. Bottcher S, Ritgen M, Fischer K, 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;30:980–988.
56. Kovacs G, Robrecht S, Fink AM, et al. Minimal residual disease assessment improves prediction of outcome in patients with chronic lymphocytic leukemia (CLL) who achieve partial response: comprehensive analysis of two phase III studies of the German CLL study group. J Clin Oncol. 2016;
57. Dreger P, Dohner 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;116:2438–2447.
58. Moreton P, Kennedy B, Lucas G, et al. Eradication of minimal residual disease in B-cell chronic lymphocytic leukemia after alemtuzumab therapy is associated with prolonged survival. J Clin Oncol. 2005;23:2971–2979.
59. Wendtner CM, Ritgen M, Schweighofer CD, et al. Consolidation with alemtuzumab in patients with chronic lymphocytic leukemia (CLL) in first remission–experience on safety and efficacy within a randomized multicenter phase III trial of the German CLL Study Group (GCLLSG). Leukemia. 2004;18:1093–1101.
60. Rawstron AC, Villamor N, Ritgen M, et al. International standardized approach for flow cytometric residual disease monitoring in chronic lymphocytic leukaemia. Leukemia. 2007;21:956–964.
61. Schweighofer CD, Ritgen M, Eichhorst BF, et al. Consolidation with alemtuzumab improves progression-free survival in patients with chronic lymphocytic leukaemia (CLL) in first remission: long-term follow-up of a randomized phase III trial of the German CLL Study Group (GCLLSG). Br J Haematol. 2009;144:95–98.
62. Bosch F, Ferrer A, Lopez-Guillermo A, et al. Fludarabine, cyclophosphamide and mitoxantrone in the treatment of resistant or relapsed chronic lymphocytic leukaemia. Br J Haematol. 2002;119:976–984.
63. Montillo M, Cafro AM, Tedeschi A, et al. Safety and efficacy of subcutaneous Campath-1H for treating residual disease in patients with chronic lymphocytic leukemia responding to fludarabine. Haematologica. 2002;87:695–700; discussion 700.
64. O'Brien SM, Kantarjian HM, Thomas DA, et al. Alemtuzumab as treatment for residual disease after chemotherapy in patients with chronic lymphocytic leukemia. Cancer. 2003;98:2657–2663.
65. Kwok M, Rawstron AC, Varghese A, et al. Minimal residual disease is an independent predictor for 10-year survival in CLL. Blood. 2016;128:2770–2773.
66. Anaissie EJ, Kontoyiannis DP, O'brien S, et al. Infections in patients with chronic lymphocytic leukemia treated with fludarabine. Ann Intern Med. 1998;129:559–566.
67. Plunkett W, Gandhi V, Huang P, et al. Fludarabine: pharmacokinetics, mechanisms of action, and rationales for combination therapies. Semin Oncol. 1993;20:2–12.
68. Rai KR, Peterson BL, Appelbaum FR, et al. Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med. 2000;343:1750–1757.
69. Steurer M, Pall G, Richards S, et al. Purine antagonists for chronic lymphocytic leukaemia. Cochrane Database Syst Rev. 2006;3:CD004270
70. Johnson S, Smith AG, Loffler H, et al. Multicentre prospective randomised trial of fludarabine versus cyclophosphamide, doxorubicin, and prednisone (CAP) for treatment of advanced-stage chronic lymphocytic leukaemia. The French Cooperative Group on CLL [see comments]. Lancet. 1996;347:1432–1438.
71. Leporrier M, Chevret S, Cazin B, et al. Randomized comparison of fludarabine, CAP, and ChOP in 938 previously untreated stage B and C chronic lymphocytic leukemia patients. Blood. 2001;98:2319–2325.
72. Robak T, Blonski JZ, Kasznicki M, et al. Cladribine with prednisone versus chlorambucil with prednisone as first- line therapy in chronic lymphocytic leukemia: report of a prospective, randomized, multicenter trial. Blood. 2000;96:2723–2729.
73. Ozegowski W, Krebs D. ω-[Bis-(β-chloräthyl)-amino-benzimidazolyl-(2)]-propion- bzw. -buttersäuren als potentielle Cytostatika. J Prakt Chem B. 1963;20:178–186.
74. 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;27:4378–4384.
75. Niederle N, Megdenberg D, Balleisen L, et al. Bendamustine compared to fludarabine as second-line treatment in chronic lymphocytic leukemia. Ann Hematol. 2013;92:653–660.
76. Cragg MS, Walshe CA, Ivanov AO, et al. The biology of CD20 and its potential as a target for mAb therapy. Curr Dir Autoimmun. 2005;8:140–174.
77. Hagemeister F. Rituximab for the treatment of non-Hodgkin's lymphoma and chronic lymphocytic leukaemia. Drugs. 2010;70:261–272.
78. Bauer K, Rancea M, Roloff V, et al. Rituximab, ofatumumab and other monoclonal anti-CD20 antibodies for chronic lymphocytic leukaemia. Cochrane Database Syst Rev. 2012;11:CD008079
79. Cang S, Mukhi N, Wang K, et al. Novel CD20 monoclonal antibodies for lymphoma therapy. J Hematol Oncol. 2012;5:64
80. Maloney DG. Anti-CD20 antibody therapy for B-cell lymphomas. N Engl J Med. 2012;366:2008–2016.
81. Huhn D, von Schilling C, Wilhelm M, et al. Rituximab therapy of patients with B-cell chronic lymphocytic leukemia. Blood. 2001;98:1326–1331.
82. O'Brien S, Kantarijan H, Thomas D, et al. Rituximab dose-escalation trial in chronic lymphocytic leukaemia. J Clin Oncol. 2001;19:2165–2170.
83. Teeling JL, Mackus WJ, Wiegman LJ, et al. The biological activity of human CD20 monoclonal antibodies is linked to unique epitopes on CD20. J Immunol. 2006;177:362–371.
84. Wierda WG, Kipps TJ, Mayer J, et al. Ofatumumab as single-agent CD20 immunotherapy in fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol. 2010;28:1749–1755.
85. Patz M, Isaeva P, Forcob N, et al. Comparison of the in vitro effects of the anti-CD20 antibodies rituximab and GA101 on chronic lymphocytic leukaemia cells. Br J Haematol. 2011;152:295–306.
86. Mossner E, Brunker P, Moser S, 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;115:4393–4402.
87. Cartron G, de Guibert S, Dilhuydy MS, et al. Obinutuzumab (GA101) in relapsed/refractory chronic lymphocytic leukemia: final data from the phase 1/2 GAUGUIN study. Blood. 2014;124:2196–2202.
88. Österborg A, Dyer MJ, Bunjes D, et al. Phase II multicenter study of human CD52 antibody in previously treated chronic lymphocytic leucemia. European study group of CAMPATH-1H treatment in chronic lymphocytic leukemia. J Clin Oncol. 1997;15:1567–1574.
89. Rai KR, Freter CE, Mercier RJ, et al. Alemtuzumab in previously treated chronic lymphocytic leukemia patients who also had received fludarabine. J Clin Oncol. 2002;20:3891–3897.
90. 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;99:3554–3561.
91. Stilgenbauer S, Dohner H. Campath-1H-induced complete remission of chronic lymphocytic leukemia despite p53 gene mutation and resistance to chemotherapy. N Engl J Med. 2002;347:452–453.
92. Lozanski G, Heerema NA, Flinn IW, et al. Alemtuzumab is an effective therapy for chronic lymphocytic leukemia with p53 mutations and deletions. Blood. 2004;103:3278–3281.
93. Hillmen P, Skotnicki AB, Robak T, et al. Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia. J Clin Oncol. 2007;25:5616–5623.
94. Petlickovski A, Laurenti L, Li X, et al. Sustained signaling through the B-cell receptor induces Mcl-1 and promotes survival of chronic lymphocytic leukemia B cells. Blood. 2005;105:4820–4827.
95. Stevenson FK, Krysov S, Davies AJ, et al. B-cell receptor signaling in chronic lymphocytic leukemia. Blood. 2011;118:4313–4320.
96. Wiestner A. Emerging role of kinase-targeted strategies in chronic lymphocytic leukemia. Hematology. 2012;2012:88–96.
97. Okkenhaug K, Vanhaesebroeck B. PI3K in lymphocyte development, differentiation and activation. Nat Rev Immunol. 2003;3:317–330.
98. Hoellenriegel J, Meadows SA, Sivina M, et al. The phosphoinositide 3'-kinase delta inhibitor, CAL-101, inhibits B-cell receptor signaling and chemokine networks in chronic lymphocytic leukemia. Blood. 2011;118:3603–3612.
99. Brown JR, Byrd JC, Coutre SE, et al. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110delta, for relapsed/refractory chronic lymphocytic leukemia. Blood. 2014;123:3390–3397.
100. Herman SE, 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;117:6287–6296.
101. Advani RH, Buggy JJ, Sharman JP, et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol. 2013;31:88–94.
102. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369:32–42.
103. Byrd JC, Brown JR, O'brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371:213–223.
104. Woyach JA, Furman RR, Liu TM, et al. Resistance mechanisms for the Bruton's tyrosine kinase inhibitor ibrutinib. N Engl J Med. 2014;370:2286–2294.
105. Maddocks KJ, Ruppert AS, Lozanski G, et al. Etiology of ibrutinib therapy discontinuation and outcomes in patients with chronic lymphocytic leukemia. JAMA Oncol. 2015;1:80–87.
106. Woyach JA, Ruppert AS, Guinn D, et al. BTKC481S-mediated resistance to ibrutinib in chronic lymphocytic leukemia. J Clin Oncol. 2017;35:1437–1443.
107. Byrd JC, Harrington B, O'brien S, et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374:323–332.
108. Chao DT, Korsmeyer SJ. BCL-2 family: regulators of cell death. Annu Rev Immunol. 1998;16:395–419.
109. Tsujimoto Y, Finger LR, Yunis J, et al. Cloning of the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome translocation. Science. 1984;226:1097–1099.
110. Souers AJ, Leverson JD, Boghaert ER, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013;19:202–208.
111. Seymour JF, Davids MS, Pagel JM, et al. ABT-199 (GDC-0199) in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL): high complete- response rate and durable disease control. J Clin Oncol. 2014;32:abstr 7015.
112. Stilgenbauer S, Eichhorst B, Schetelig J, et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol. 2016;17:768–778.
113. Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374:311–322.
114. Sher T, Miller KC, Lawrence D, et al. Efficacy of lenalidomide in patients with chronic lymphocytic leukemia with high-risk cytogenetics. Leuk Lymphoma. 2010;51:85–88.
115. Moutouh-de Parseval LA, Weiss L, DeLap RJ, et al. Tumor lysis syndrome/tumor flare reaction in lenalidomide-treated chronic lymphocytic leukemia. J Clin Oncol. 2007;25:5047
116. Chanan-Khan A, Miller KC, Musial L, 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;24:5343–5349.
117. 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;111:5291–5297.
118. Chanan-Khan AA, Czuczman MS, Padmanabhan S, et al. Clinical efficacy of lenalidomide in fludarabine-refractory chronic lymphocytic leukemia patients. ASH Annu Meet Abstr. 2007;110:3108
119. Strati P, Keating MJ, Wierda WG, et al. Lenalidomide induces long-lasting responses in elderly patients with chronic lymphocytic leukemia. Blood. 2013;122:734–737.
120. Badoux XC, Keating MJ, Wen S, et al. Phase II study of lenalidomide and rituximab as salvage therapy for patients with relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2013;31:584–591.
121. Brown JR, Abramson J, Hochberg E, et al. A phase I study of lenalidomide in combination with fludarabine and rituximab in previously untreated CLL/SLL. Leukemia. 2010;24:1972–1975.
122. Flinn IW, Berdeja JG, Waselenko JK, et al. Preliminary results from a phase I/II study of fludarabine, rituximab, and lenalidomide in untreated patients with chronic lymphocytic leukemia (CLL). ASH Annu Meet Abstr. 2010;116:2461
123. Egle A, Steurer M, Melchardt T, et al. The REVLIRIT CLL5 AGMT study - a phase I/II trial combining fludarabine/rituximab with escalating doses of lenalidomide followed by rituximab/lenalidomide in untreated chronic lymphocytic leukemia (CLL): results of a planned interim analysis. ASH Annu Meet Abstr. 2009;114:3453
124. Maurer C, Pflug N, Bahlo J, et al. Bendamustine and rituximab in combination with lenalidomide in patients with chronic lymphocytic leukemia. Eur J Haematol. 2016;97:253–260.
125. Maddocks K, Wei L, Rozewski D, et al. Reduced occurrence of tumor flare with flavopiridol followed by combined flavopiridol and lenalidomide in patients with relapsed chronic lymphocytic leukemia (CLL). Am J Hematol. 2015;90:327–333.
126. Badoux X, O'brien S, Wierda WG, et al. Combination of ofatumumab and lenalidomide in patients with relapsed chronic lymphocytic leukemia: initial results of a phase II trial. ASH Annu Meet Abstr. 2010;116:2464
127. Fink A-M, Bahlo J, Robrecht S, et al. Lenalidomide maintenance after frontline therapy of high-risk chronic lymphocytic leukemia. Blood. 2017;129:3419–3427. doi:10.1182/blood-2017-02-765685. Epub 2017 Apr 19.
128. Ding W, LaPlant BR, Call TG, et al. Pembrolizumab in patients with chronic lymphocytic leukemia with Richter's transformation and relapsed CLL. Blood. 2017;129:3419–3427.
129. Porter DL, Levine BL, Kalos M, et al. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011;365:725–733.
130. Bellosillo B, Villamor N, Colomer D, et al. In vitro evaluation of fludarabine in combination with cyclophosphamide and/or mitoxantrone in B-cell chronic lymphocytic leukemia. Blood. 1999;94:2836–2843.
131. Hallek M, Eichhorst BF. Chemotherapy combination treatment regimens with fludarabine in chronic lymphocytic leukemia. Hematol J. 2004;5(Suppl 1):S20–S30.
132. Montillo M, Tedeschi A, O'brien S, et al. Phase II study of cladribine and cyclophosphamide in patients with chronic lymphocytic leukemia and prolymphocytic leukemia. Cancer. 2003;97:114–120.
133. Eichhorst BF, Busch R, Hopfinger G, et al. Fludarabine plus cyclophosphamide versus fludarabine alone in first line therapy of younger patients with chronic lymphocytic leukemia. Blood. 2006;107:885–891.
134. Flinn IW, Neuberg DS, Grever MR, et al. Phase III trial of fludarabine plus cyclophosphamide compared with fludarabine for patients with previously untreated chronic lymphocytic leukemia: US Intergroup Trial E2997. J Clin Oncol. 2007;25:793–798.
135. Catovsky D, Richards S, Matutes E, et al. Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial. Lancet. 2007;370:230–239.
136. Robak T, Blonski JZ, Gora-Tybor J, 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;108:473–479.
137. di Gaetano N, Xiao Y, Erba E, et al. Synergism between fludarabine and rituximab revealed in a follicular lymphoma cell line resistant to the cytotoxic activity of either drug alone. Br J Haematol. 2001;114:800–809.
138. Schulz H, Klein SH, Rehwald U, et al. Phase II study of a combined immunochemotherapy using rituximab and fludarabine in patients with chronic lymphocytic leukemia. Blood. 2002;100:3115–3120.
139. 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 (CALGB 9712). Blood. 2003;101:6–14.
140. Byrd JC, Rai K, Peterson BL, et al. Addition of rituximab to fludarabine may prolong progression-free survival and overall survival in patients with previously untreated chronic lymphocytic leukemia: an updated retrospective comparative analysis of CALGB 9712 and CALGB 9011. Blood. 2005;105:49–53.
141. 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;112:975–980.
142. Robak T, Dmoszynska A, Solal-Celigny 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;28:1756–1765.
143. Thompson PA, Tam CS, O'brien SM, et al. Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood. 2016;127:303–309.
144. Fischer K, Bahlo J, Fink AM, et al. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood. 2016;127:208–215.
145. Foon KA, Boyiadzis M, Land SR, et al. Chemoimmunotherapy with low-dose fludarabine and cyclophosphamide and high dose rituximab in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol. 2009;27:498–503.
146. 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;29:3559–3566.
147. Fischer K, Cramer P, Busch R, et al. Bendamustine in combination with rituximab for previously untreated patients with chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol. 2012;30:3209–3216.
148. Eichhorst B, Fink AM, Bahlo J, 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. 2016;17:928–942.
149. Parikh SA, Keating MJ, O'brien S, et al. Frontline chemoimmunotherapy with fludarabine, cyclophosphamide, alemtuzumab, and rituximab for high-risk chronic lymphocytic leukemia. Blood. 2011;118:2062–2068.
150. 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;27:4578–4584.
151. 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;30:1232–1240.
152. Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014;370:1101–1110.
153. Hillmen P, Gribben JG, Follows GA, et al. Rituximab plus chlorambucil in patients with CD20-positive B-cell chronic lymphocytic leukemia (CLL): final response analysis of an open-label phase II study. ASH Annu Meet Abstr. 2010;116:697
154. Foa R, Ciolli S, Di Raimondo F, et al. A phase II study of chlorambucil plus rituximab followed by maintenance versus observation in elderly patients with previously untreated chronic lymphocytic leukemia: results of the first interim analysis. ASH Annu Meet Abstr. 2010;116:2462
155. Goede V, Fischer K, Busch R, et al. Chemoimmunotherapy with GA101 plus chlorambucil in patients with chronic lymphocytic leukemia and comorbidity: results of the CLL11 (BO21004) safety run-in. Leukemia. 2013;27:1172–1174.
156. Hillmen P, Robak T, Janssens A, 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. 2015;385:1873–1883.
157. Kennedy B, Rawstron A, Carter C, et al. Campath-1H and fludarabine in combination are highly active in refractory chronic lymphocytic leukemia. Blood. 2002;99:2245–2247.
158. Elter T, Borchmann P, Schulz H, et al. Fludarabine in combination with alemtuzumab is effective and feasible in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: results of a phase II trial. J Clin Oncol. 2005;23:7024–7031.
159. Lepretre S, Aurran T, Mahe B, et al. Excess mortality after treatment with fludarabine and cyclophosphamide in combination with alemtuzumab in previously untreated patients with chronic lymphocytic leukemia in a randomized phase 3 trial. Blood. 2012;119:5104–5110.
160. Hallek M. FCA: forget chemoimmunotherapy with alemtuzumab?. Blood. 2012;119:5059–5060.
161. Elter T, Gercheva-Kyuchukova L, Pylylpenko H, et al. Fludarabine plus alemtuzumab versus fludarabine alone in patients with previously treated chronic lymphocytic leukaemia: a randomised phase 3 trial. Lancet Oncol. 2011;12:1204–1213.
162. Faderl S, Thomas DA, O'brien S, et al. Experience with alemtuzumab plus rituximab in patients with relapsed and refractory lymphoid malignancies. Blood. 2003;101:3413–3415.
163. Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370:997–1007.
164. Jones JA, Robak T, Brown JR, et al. Efficacy and safety of idelalisib in combination with ofatumumab for previously treated chronic lymphocytic leukaemia: an open-label, randomised phase 3 trial. Lancet Haematol. 2017;4:e114–e126.
165. Borge M, Belen Almejun M, Podaza E, et al. Ibrutinib impairs the phagocytosis of rituximab-coated leukemic cells from chronic lymphocytic leukemia patients by human macrophages. Haematologica. 2015;100:e140–e142.
166. Kohrt HE, Sagiv-Barfi I, Rafiq S, et al. Ibrutinib antagonizes rituximab-dependent NK cell-mediated cytotoxicity. Blood. 2014;123:1957–1960.
167. Burger JA, Keating MJ, Wierda WG, et al. Safety and activity of ibrutinib plus rituximab for patients with high-risk chronic lymphocytic leukaemia: a single-arm, phase 2 study. Lancet Oncol. 2014;15:1090–1099.
168. Jain P, Keating MJ, Wierda WG, et al. Long-term follow-up of treatment with ibrutinib and rituximab in patients with high-risk chronic lymphocytic leukemia. Clin Cancer Res. 2017;23:2154–2158.
169. Chanan-Khan A, Cramer P, Demirkan F, et al. Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study. Lancet Oncol. 2016;17:200–211.
170. Jaglowski SM, Jones JA, Nagar V, et al. Safety and activity of BTK inhibitor ibrutinib combined with ofatumumab in chronic lymphocytic leukemia: a phase 1b/2 study. Blood. 2015;126:842–850.
171. O'Brien S, Moore JO, Boyd TE, et al. 5-Year survival in patients with relapsed or refractory chronic lymphocytic leukemia in a randomized, phase III trial of fludarabine plus cyclophosphamide with or without oblimersen. J Clin Oncol. 2009.
172. O'Brien S, Moore JO, Boyd TE, et al. Randomized phase III trial of fludarabine plus cyclophosphamide with or without oblimersen sodium (Bcl-2 antisense) in patients with relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2007;25:1114–1120.
173. Seymour JF, Ma S, Brander DM, et al. Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study. Lancet Oncol. 2017;18:230–240.
174. Fischer K, Al-Sawaf O, Fink AM, et al. Venetoclax and obinutuzumab in chronic lymphocytic leukemia. Blood. 2017;129:2702–2705.
175. Extermann M, Overcash J, Lyman GH, et al. Comorbidity and functional status are independent in older patients. J Clin Oncol. 1998;16:1582–1587.
176. Dreger P, Schetelig J, Andersen N, et al. Managing high-risk CLL during transition to a new treatment era: stem cell transplantation or novel agents?. Blood. 2014;124:3841–3849.
177. Hallek M. Chronic lymphocytic leukemia: 2013 update on diagnosis, risk stratification and treatment. Am J Hematol. 2013;88:803–816.
178. Hallek M. Chronic lymphocytic leukemia: 2015 Update on diagnosis, risk stratification, and treatment. Am J Hematol. 2015;90:446–460.
179. Jain P, Keating M, Wierda W, et al. Outcomes of patients with chronic lymphocytic leukemia after discontinuing ibrutinib. Blood. 2015;125:2062–2067.