REFERENCES
2. Hallek M, Fischer K, Fingerle-Rowson G, Fink AM, Busch R, 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.
3. Fischer K, Cramer P, Busch R, Bottcher S, Bahlo J, 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;30:3209-16.
4. Goede V, Fischer K, Busch R, Engelke A, Eichhorst B, et al. Obinutuzumab plus chlorambucil in patients with cll and coexisting conditions. N Engl J Med 2014;370:1101-10.
5. Goede V, Fischer K, Dyer MJ, Müller L, Smolej L. Overall survival benefit of obinutuzumab over rituximab when combined with chlorambucil in patients with chronic lymphocytic leukemia and comorbidities: final survival analysis of the CLL11 study. 23rd Congress of the European Haematology Association; 2018.
6. Goede V, Fischer K, Engelke A, Schlag R, Lepretre S, et al. Obinutuzumab as frontline treatment of chronic lymphocytic leukemia: updated results of the CLL11 study. Leukemia 2015;29:1602.
7. Strati P, Keating MJ, O’Brien SM, Ferrajoli A, Burger J, et al. Outcomes of first-line treatment for chronic lymphocytic leukemia with 17p deletion. Haematologica 2014;99:1350-5.
8. Balducci L. ESH-SIOG international conference on haematological malignancies in the elderly. Expert Rev Hematol 2010;3:675-7.
9. Fischer K, Cramer P, Busch R, Stilgenbauer S, Bahlo J, 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.
10. Laurenti L, Innocenti I, Autore F, Ciolli S, Mauro FR, et al. Chlorambucil plus rituximab as front-line therapy for elderly and/or unfit chronic lymphocytic leukemia patients: Correlation with biologically-based risk stratification. Haematologica 2017;102:e352-e5.
11. Lin KI, Tam CS, Keating MJ, Wierda WG, O’Brien S, et al. Relevance of the immunoglobulin VH somatic mutation status in patients with chronic lymphocytic leukemia treated with fludarabine, cyclophosphamide, and rituximab (FCR) or related chemoimmunotherapy regimens. Blood 2009;113:3168-71.
12. 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.
13. Krober A, Seiler T, Benner A, Bullinger L, Bruckle E, et al. V(D) mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia. Blood 2002;100:1410-6.
14. O’Brien S, Furman RR, Coutre S, Flinn IW, Burger JA, et al. Single-agent ibrutinib in treatment-naive and relapsed/refractory chronic lymphocytic leukemia: A 5-year experience. Blood 2018;131:1910-9.
15. Roberts AW, Davids MS, Pagel JM, Kahl BS, Puvvada SD, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med 2016;374:311-22.
16. Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med 2014;370:997-1007.
17. Shanafelt TD, Wang XV, Kay NE, Hanson CA, O’Brien S, et al. Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med 2019;381:432-43.
18. Moreno C, Greil R, Demirkan F, Tedeschi A, Anz B, et al. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): A multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 2019;20:43-56.
19. Woyach JA, Ruppert AS, Heerema NA, Zhao W, Booth AM, et al. Ibrutinib regimens versus chemoimmunotherapy in older patients wituntreated CLL. N Engl J Med 2018;379:2517-28.
20. Fischer K, Al-Sawaf O, Bahlo J, Fink AM, Tandon M, et al. Effect of fixed-duration venetoclax plus obinutuzumab on progression-free survival, and rates and duration of minimal residual disease negativity in previously untreated patients with chronic lymphocytic leukemia and comorbidities. J Clin Oncol 2019;37:7502.
21. Fischer K, Al-Sawaf O, Bahlo J, Fink AM, Tandon M, et al. Venetoclax and obinutuzumab in patients with cll and coexisting conditions. N Engl J Med 2019;380:2225-36.
22. Seymour JF, Kipps TJ, Eichhorst B, Hillmen P, D’Rozario J, et al. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med 2018;378:1107-20.
23. Byrd JC, Brown JR, O’Brien S, Barrientos JC, Kay NE, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med 2014;371:213-23.
24. Seymour EK. Rapid transitions in the standard of care for chronic lymphocytic leukemia (CLL). Oncotarget 2019;10:2484-5.
25. Thompson PA, Tam CS, O’Brien SM, Wierda WG, Stingo F, et al. Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood 2016;127:303-9.
26. Chen Q, Jain N, Ayer T, Wierda WG, Flowers CR, et al. Economic burden of chronic lymphocytic leukemia in the era of oral targeted therapies in the United States. J Clin Oncol 2017;35:166-74.
27. Woyach JA, Furman RR, Liu TM, Ozer HG, Zapatka M, et al. Resistance mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib. N Engl J Med 2014;370:2286-94.
28. Blombery P, Anderson MA, Gong JN, Thijssen R, Birkinshaw RW, et al. Acquisition of the recurrent Gly101Val mutation in BCL2 confers resistance to venetoclax in patients with progressive chronic lymphocytic leukemia. Cancer Discov 2019;9:342-53.
30. Anderson MA, Tam C, Lew TE, Juneja S, Juneja M, et al. Clinicopathological features and outcomes of progression of CLL on the BCL2 inhibitor venetoclax. Blood 2017;129:3362-70.
31. Maddocks KJ, Ruppert AS, Lozanski G, Heerema NA, Zhao W, et al. Etiology of ibrutinib therapy discontinuation and outcomes in patients with chronic lymphocytic leukemia. JAMA Oncol 2015;1:80-7.
32. Souers AJ, Leverson JD, Boghaert ER, Ackler SL, Catron ND, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med 2013;19:202-8.
33. Moore VDG, Brown JR, Certo M, Love TM, Novina CD, et al. Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737. J Clin Invest 2007;117:112-21.
34. Robertson LE, Plunkett W, McConnell K, Keating MJ, McDonnell TJ. Bcl-2 expression in chronic lymphocytic leukemia and its correlation with the induction of apoptosis and clinical outcome. Leukemia 1996;10:456-9.
35. Van Delft MF, Wei AH, Mason KD, Vandenberg CJ, Chen L, et al. The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell 2006;10:389-99.
36. Anderson MA, Deng J, Seymour JF, Tam C, Kim SY, et al. The BCL2 selective inhibitor venetoclax induces rapid onset apoptosis of cll cells in patients via a TP53-independent mechanism. Blood 2016;127:3215-24.
37. Roberts AW, Seymour JF, Brown JR, Wierda WG, Kipps TJ, 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.
38. Stilgenbauer S, Eichhorst B, Schetelig J, Coutre S, Seymour JF, et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: A multicentre, open-label, phase 2 study. Lancet Oncol 2016;17:768-78.
39. Rawstron AC, Bottcher S, Letestu R, Villamor N, Fazi C, et al. Improving efficiency and sensitivity: European Research Initiative in CLL (ERIC) update on the international harmonised approach for flow cytometric residual disease monitoring in CLL. Leukemia 2013;27:142-9.
40. Rawstron AC, Fazi C, Agathangelidis A, Villamor N, Letestu R, et al. A complementary role of multiparameter flow cytometry and high- throughput sequencing for minimal residual disease detection in chronic lymphocytic leukemia: an European Research Initiative on CLL study. Leukemia 2016;30:929-36.
41. Rawstron AC, Villamor N, Ritgen M, Bottcher S, Ghia P, et al. International standardized approach for flow cytometric residual disease monitoring in chronic lymphocytic leukaemia. Leukemia 2007;21:956-64.
42. Stilgenbauer S, Eichhorst B, Schetelig J, Hillmen P, Seymour JF, et al. Venetoclax for patients with chronic lymphocytic leukemia with 17p deletion: Results from the full population of a phase II pivotal trial. J Clin Oncol 2018;36:1973-80.
43. Brander DM, Seymour JF, Ma S, Anderson MA, Choi MY, et al. Durability of responses on continuous therapy and following drug cessation in deep responders with venetoclax and rituximab: long-term follow-up analysis of a Phase 1b study in patients with relapsed CLL. Blood 2019;134:3036.
44. Seymour JF, Ma S, Brander DM, Choi MY, Barrientos J, et al. Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: A phase 1b study. Lancet Oncol 2017;18:230-40.
45. Coutre S, Choi M, Furman RR, Eradat H, Heffner L, et al. Venetoclax for patients with chronic lymphocytic leukemia who progressed during or after idelalisib therapy. Blood 2018;131:1704-11.
46. Jones JA, Mato AR, Wierda WG, Davids MS, Choi M, et al. Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib: An interim analysis of a multicentre, open-label, phase 2 trial. Lancet Oncol 2018;19:65-75.
47. Flinn IW, Gribben JG, Dyer MJS, Wierda W, Maris MB, et al. Phase 1b study of venetoclax-obinutuzumab in previously untreated and relapsed/refractory chronic lymphocytic leukemia. Blood 2019;133:2765-75.
48. Seymour JF, Kipps TJ, Eichhorst B, Hillmen P, D’Rozario J, et al. Four-year analysis of MURANO study confirms sustained benefit of time-limited venetoclax-rituximab in relapsed/refractory chronic lymphocytic leukemia. Blood 2019;134:355.
49. Kater AP, Seymour JF, Hillmen P, Eichhorst B, Langerak AW, et al. Fixed duration of venetoclax-rituximab in relapsed/refractory chronic lymphocytic leukemia eradicates minimal residual disease and prolongs survival: Post-treatment follow-up of the MURANO phase III study. J Clin Oncol 2019;37:269-77.
50. Fischer K, Ritgen M, Al-Sawaf O, Robrecht S, Tandon M, et al. Quantitative analysis of minimal residual disease (MRD) shows high rates of undetectable MRD after fixed-duration chemotherapy-free treatment and serves as surrogate marker for progression-free survival: a prospective analysis of the randomized CLL14 Trial. Blood 2019;134:36.
51. Kipps TJ, Eradat H, Grosicki S, Catalano J, Cosolo W, et al. A phase 2 study of the BH3 mimetic BCL2 inhibitor navitoclax (ABT-263) with or without rituximab, in previously untreated B-cell chronic lymphocytic leukemia. Leuk Lymphoma 2015;56:2826-33.
52. Roberts AW, Advani RH, Kahl BS, Persky D, Sweetenham JW, et al. Phase 1 study of the safety, pharmacokinetics, and antitumour activity of the BCL 2 inhibitor navitoclax in combination with rituximab in patients with relapsed or refractory CD 20+ lymphoid malignancies. Br J Haematol 2015;170:669-78.
53. Böttcher S, Ritgen M, Fischer K, Stilgenbauer S, Busch RM, 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;30:980-8.
54. Kovacs G, Robrecht S, Fink AM, Bahlo J, Cramer P, 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;34:3758-65.
55. Kwok M, Rawstron AC, Varghese A, Evans PA, O’Connor SJ, et al. Minimal residual disease is an independent predictor for 10-year survival in CLL. Blood 2016;128:2770-3.
56. Lew TE, Anderson MA, Lin VS, Handunnetti SM, Came NA, et al. Undetectable peripheral blood mrd should be the goal of venetoclax in CLL, but attainment plateaus after 24 months. Blood Adv 2020;4:165-73.
57. Davids MS, Hallek M, Wierda W, Roberts AW, Stilgenbauer S, et al. Comprehensive safety analysis of venetoclax monotherapy for patients with relapsed/refractory chronic lymphocytic leukemia. Clin Cancer Res 2018;24:4371-9.
58. .
60. Davids MS, Roberts AW, Seymour JF, Gerecitano JF, Kahl BS, et al. Safety, efficacy and immune effects of venetoclax 400 mg daily in patients with relapsed chronic lymphocytic leukemia (CLL). J Clin Oncol 2017;34:7527.
61. Roberts AW, Ma S, Kipps TJ, Coutre SE, Davids MS, et al. Efficacy of venetoclax in relapsed chronic lymphocytic leukemia is influenced by disease and response variables. Blood 2019;134:111-22.
62. Del Poeta G, Biagi A, Chiarenza A, Laurenti L, Pozzo F, et al. Impaired nodal shrinkage and apoptosis lacking define the adverse independent clinical outcome of NOTCH1 mutated chronic lymphocytic leukemia patients in the age of targeted agents. Blood 2019;134:1744.
63. Blombery P. Mechanisms of intrinsic and acquired resistance to venetoclax in B-cell lymphoproliferative disease. Leuk Lymphoma 2019:1-6.
64. Adams JM, Cory S. The BCL-2 arbiters of apoptosis and their growing role as cancer targets. Cell Death Differ 2018;25:27-36.
65. Bojarczuk K, Sasi BK, Gobessi S, Innocenti I, Pozzato G, et al. BCR signaling inhibitors differ in their ability to overcome Mcl-1–mediated resistance of CLL B cells to ABT-199. Blood 2016;127:3192-201.
66. Davids MS, Deng J, Wiestner A, Lannutti BJ, Wang L, et al. Decreased mitochondrial apoptotic priming underlies stroma-mediated treatment resistance in chronic lymphocytic leukemia. Blood 2012;120:3501-9.
67. Thijssen R, Slinger E, Weller K, Geest CR, Beaumont T, et al. Resistance to ABT-199 induced by microenvironmental signals in chronic lymphocytic leukemia can be counteracted by CD20 antibodies or kinase inhibitors. Haematologica 2015;100:e302.
68. Hillmen P, Rawstron AC, Brock K, Munoz-Vicente S, Yates FJ, et al. Ibrutinib plus venetoclax in relapsed/refractory chronic lymphocytic leukemia: The clarity study. J Clin Oncol 2019;37:2722-9.
69. Jain N, Keating M, Thompson P, Ferrajoli A, Burger J, et al. Ibrutinib and venetoclax for first-line treatment of CLL. N Engl J Med 2019;380:2095-103.
70. Tausch E, Close W, Dolnik A, Bloehdorn J, Chyla B, et al. Venetoclax resistance and acquired BCL2 mutations in chronic lymphocytic leukemia. Haematologica 2019;104:e434-e7.
71. Birkinshaw RW, Gong JN, Luo CS, Lio D, White CA, et al. Structures of BCL-2 in complex with venetoclax reveal the molecular basis of resistance mutations. Nat Commun 2019;10:2385.
72. Blombery P, Thompson ER, Nguyen T, Chen X, McBean M, et al. Detection of multiple recurrent novel BCL2 mutations co-occurring with BCL2 Gly101Val in patients with chronic lymphocytic leukemia on long term venetoclax. Blood 2019;134:171.
73. Blombery P, Birkinshaw RW, Nguyen T, Gong JN, Thompson ER, et al. Characterization of a novel venetoclax resistance mutation (BCL2 Phe104Ile) observed in follicular lymphoma. Br J Haematol 2019;186:e188-91.
74. Guieze R, Liu VM, Rosebrock D, Jourdain AA, Hernandez-Sanchez M, et al. Mitochondrial reprogramming underlies resistance to BCL-2 inhibition in lymphoid malignancies. Cancer Cell 2019;36:369-84 e13.
75. Herling CD, Abedpour N, Weiss J, Schmitt A, Jachimowicz RD, et al. Clonal dynamics towards the development of venetoclax resistance in chronic lymphocytic leukemia. Nat Commun 2018;9:727.
76. Brown JR, Davids MS, Chang J, Ma S, Biondo J, et al. Outcomes of ibrutinib therapy in ibr-naïve patients with chronic lymphocytic leukemia progressing after venetoclax. Blood 2019;134:4320.
77. Greil R, Fraser G, Leber B, Marks R, Quaresmini G, et al. Efficacy and safety of ibrutinib after venetoclax treatment in ibr-naïve patients with relapsed/refractory chronic lymphocytic leukemia : follow-up of patients from the MURANO study. Blood 2018;132:5548.
78. Mato A, Roeker L, Eyre T, Jacobs R, Hill B, et al. Efficacy of therapies following venetoclax discontinuation in CLL: focus on B-cell receptor signal transduction inhibitors and cellular therapies. Blood 2019;134:502.
79. Mato AR, Thompson M, Allan JN, Brander DM, Pagel JM, et al. Real-world outcomes and management strategies for venetoclax-treated chronic lymphocytic leukemia patients in the united states. Haematologica 2018;103:1511-7.
80. Lin VS, Lew TE, Handunnetti SM, Blombery P, Nguyen T, et al. BTK inhibitor therapy is effective in patients with CLL resistant to venetoclax. Blood 2020. [Epub ahead of print]
81. Roeker L, Brown JR, Dreger P, Lahoud O, Eyre T, et al. Allogeneic stem cell transplantation for chronic lymphocytic leukemia in the era of novel agents. Blood 2019;134:3321.
82. Honigberg LA, Smith AM, Sirisawad M, Verner E, Loury D, et al. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc Natl Acad Sci USA 2010;107:13075-80.
83. Craxton A, Jiang A, Kurosaki T, Clark EA. Syk and Bruton’s tyrosine kinase are required for B cell antigen receptor-mediated activation of the kinase Akt. J Biol Chem 1999;274:30644-50.
84. Herman SE, Gordon AL, Hertlein E, Ramanunni A, Zhang X, 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.
85. Petro JB, Khan WN. Phospholipase C-γ2 couples Bruton’s tyrosine kinase to the NF-κB signaling pathway in B lymphocytes. J Biol Chem 2001;276:1715-9.
86. Petro JB, Rahman SJ, Ballard DW, Khan WN. Bruton’s tyrosine kinase is required for activation of IκB kinase and nuclear factor κB in response to B cell receptor engagement. J Exp Med 2000;191:1745-54.
87. de Gorter DJ, Beuling EA, Kersseboom R, Middendorp S, van Gils JM, et al. Bruton’s tyrosine kinase and phospholipase Cgamma2 mediate chemokine-controlled B cell migration and homing. Immunity 2007;26:93-104.
88. Niemann CU, Herman SE, Maric I, Gomez-Rodriguez J, Biancotto A, 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 2016;22:1572-82.
89. Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med 2013;369:32-42.
90. Ahn IE, Farooqui MZH, Tian X, Valdez J, Sun C, et al. Depth and durability of response to ibrutinib in CLL: 5-year follow-up of a phase 2 study. Blood 2018;131:2357-66.
91. Farooqui MZ, Valdez J, Martyr S, Aue G, Saba N, et al. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: A phase 2, single-arm trial. Lancet Oncol 2015;16:169-76.
92. O’Brien S, Furman RR, Coutre SE, Sharman JP, Burger JA, et al. Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial. Lancet Oncol 2014;15:48-58.
93. Mato AR, Nabhan C, Thompson MC, Lamanna N, Brander DM, et al. Toxicities and outcomes of 616 ibrutinib-treated patients in the united states: A real-world analysis. Haematologica 2018;103:874-9.
94. Jones J, Mato A, Coutre S, Byrd JC, Furman RR, et al. Evaluation of 230 patients with relapsed/refractory deletion 17p chronic lymphocytic leukaemia treated with ibrutinib from 3 clinical trials. Br J Haematol 2018;182:504-12.
95. Brown JR, Hillmen P, O’Brien S, Barrientos JC, Reddy NM, et al. Extended follow-up and impact of high-risk prognostic factors from the phase 3 RESONATE study in patients with previously treated CLL/SLL. Leukemia 2018;32:83-91.
96. Munir T, Brown JR, O’Brien S, Barrientos JC, Barr PM, et al. Final analysis from resonate: Up to six years of follow-up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma. Am J Hematol 2019; doi: 10.1002/ajh.25638.
97. Barr PM, Robak T, Owen C, Tedeschi A, Bairey O, et al. Sustained efficacy and detailed clinical follow-up of first-line ibrutinib treatment in older patients with chronic lymphocytic leukemia: Extended phase 3 results from RESONATE-2. Haematologica 2018;103:1502-10.
98. Burger JA, Tedeschi A, Barr PM, Robak T, Owen C, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med 2015;373:2425-37.
99. O’Brien S, Jones JA, Coutre SE, Mato AR, Hillmen P, et al. Ibrutinib for patients with relapsed or refractory chronic lymphocytic leukaemia with 17p deletion (RESONATE-17): A phase 2, open-label, multicentre study. Lancet Oncol 2016;17:1409-18.
100. Jain P, Keating MJ, Wierda WG, Sivina M, Thompson PA, et al. Long-term follow-up of treatment with ibrutinib and rituximab in patients with high-risk chronic lymphocytic leukemia. Clin Cancer Res 2017;23:2154-8.
101. Burger JA, Keating MJ, Wierda WG, Hartmann E, Hoellenriegel J, 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;15:1090-9.
102. Jaglowski SM, Jones JA, Nagar V, Flynn JM, Andritsos LA, et al. Safety and activity of BTK inhibitor ibrutinib combined with ofatumumab in chronic lymphocytic leukemia: A phase 1b/2 study. Blood 2015;126:842-50.
103. Abrisqueta P, González-Barca E, Ferra CM, Herranz ER, Fernandez M, et al. Preliminary results of ibrutinib followed by ofatumumab consolidation in previously untreated patients with chronic lymphocytic leukemia: GELLC7 trials from the spanish group of CLL (GELLC). Blood 2019;134:4296.
104. Shanafelt TD, Wang V, Kay NE, Hanson CA, O’Brien SM, et al. ibrutinib and rituximab provides superior clinical outcome compared to FCR in younger patients with chronic lymphocytic leukemia : extended follow-up from the E1912 trial. Blood 2019;134:33.
105. Burger JA, Sivina M, Jain N, Kim E, Kadia T, et al. Randomized trial of ibrutinib vs ibrutinib plus rituximab in patients with chronic lymphocytic leukemia. Blood 2019;133:1011-9.
106. Borge M, Belen Almejun M, Podaza E, Colado A, Fernandez Grecco H, et al. Ibrutinib impairs the phagocytosis of rituximab-coated leukemic cells from chronic lymphocytic leukemia patients by human macrophages. Haematologica 2015;100:e140-2.
107. Da Roit F, Engelberts PJ, Taylor RP, Breij EC, Gritti G, et al. Ibrutinib interferes with the cell-mediated anti-tumor activities of therapeutic CD20 antibodies: Implications for combination therapy. Haematologica 2015;100:77-86.
108. Kohrt HE, Sagiv-Barfi I, Rafiq S, Herman SE, Butchar JP, et al. Ibrutinib antagonizes rituximab-dependent NK cell-mediated cytotoxicity. Blood 2014;123:1957-60.
109. Pavlasova G, Borsky M, Seda V, Cerna K, Osickova J, et al. Ibrutinib inhibits CD20 upregulation on CLL B cells mediated by the CXCR4/SDF-1 axis. Blood 2016;128:1609-13.
110. Golay J, Ubiali G, Introna M. The specific Bruton tyrosine kinase inhibitor acalabrutinib (ACP-196) shows favorable in vitro activity against chronic lymphocytic leukemia B cells with CD20 antibodies. Haematologica 2017;102:e400-3.
111. Woyach JA, Rogers KA, Bhat SA, Blachly JS, Jianfar M, et al. Acalabrutinib with obinutuzumab (Ob) in treatment-naive (TN) and relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): three-year follow-up. J Clin Oncol 2019;37:7500.
112. Byrd JC, Wierda WG, Schuh A, Devereux S, Chaves JM, et al. Acalabrutinib monotherapy in patients with relapsed/refractory chronic lymphocytic leukemia: updated results from the phase 1/2 ACE-CL-001 study. Blood 2017;130:498.
113. Sharman JP, Banerji V, Fogliatto LM, Herishanu Y, Munir T, et al. ELEVATE TN: Phase 3 study of acalabrutinib combined with obinutuzumab (O) or alone vs O plus chlorambucil in patients with treatment-naive chronic lymphocytic leukemia (CLL). Blood 2019;134:31.
114. Alduaij W, Ivanov A, Honeychurch J, Cheadle EJ, Potluri S, et al. Novel type II anti-CD20 monoclonal antibody (GA101) evokes homotypic adhesion and actin-dependent, lysosome-mediated cell death in B-cell malignancies. Blood 2011;117:4519-29.
115. Dalle S, Reslan L, Besseyre de Horts T, Herveau S, Herting F, et al. Preclinical studies on the mechanism of action and the anti-lymphoma activity of the novel anti-CD20 antibody GA101. Mol Cancer Ther 2011;10:178-85.
116. Herter S, Herting F, Mundigl O, Waldhauer I, Weinzierl T, et al. Preclinical activity of the type II CD20 antibody GA101 (obinutuzumab) compared with rituximab and ofatumumab in vitro and in xenograft models. Mol Cancer Ther 2013;12:2031-42.
117. Mössner E, Brünker P, Moser S, Püntener U, Schmidt C, 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;115:4393-402.
118. Patz M, Isaeva P, Forcob N, Muller B, Frenzel LP, 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.
119. Cramer P, von Tresckow J, Bahlo J, Robrecht S, Langerbeins P, et al. Bendamustine followed by obinutuzumab and venetoclax in chronic lymphocytic leukaemia (CLL2-BAG): Primary endpoint analysis of a multicentre, open-label, phase 2 trial. Lancet Oncol 2018;19:1215-28.
120. von Tresckow J, Cramer P, Bahlo J, Robrecht S, Langerbeins P, et al. CLL2-BIG: Sequential treatment with bendamustine, ibrutinib and obinutuzumab (GA101) in chronic lymphocytic leukemia. Leukemia 2019;33:1161-72.
121. Sun C, Tian X, Lee YS, Gunti S, Lipsky A, et al. Partial reconstitution of humoral immunity and fewer infections in patients with chronic lymphocytic leukemia treated with ibrutinib. Blood 2015;126:2213-9.
122. Long M, Beckwith K, Do P, Mundy BL, Gordon A, et al. Ibrutinib treatment improves T cell number and function in CLL patients. J Clin Invest 2017;127:3052-64.
123. Dubovsky JA, Beckwith KA, Natarajan G, Woyach JA, Jaglowski S, et al. Ibrutinib is an irreversible molecular inhibitor of ITK driving a TH1-selective pressure in T lymphocytes. Blood 2013;122:2539-49.
124. Fraietta JA, Beckwith KA, Patel PR, Ruella M, Zheng Z, et al. Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia. Blood 2016;127:1117-27.
125. Gauthier J, Hirayama AV, Hay KA, Li D, Lymp J, et al. Efficacy and toxicity of CD19-specific chimeric antigen receptor T-cells alone or in combination with ibrutinib for relapsed and/or refractory CLL. Biol Blood Marrow Transplant 2019;25:S9-10.
126. Gill SI, Vides V, Frey NV, Metzger S, O’Brien M, et al. Prospective clinical trial of anti-CD19 CAR T cells in combination with ibrutinib for the treatment of chronic lymphocytic leukemia shows a high response rate. Blood 2018;132:298.
127. Baptista MJ, Baskar S, Keyvanfar K, Gaglione EM, Ahn IE, et al. Patients with chronic lymphocytic leukemia treated with ibrutinib show expansion of T-cell clonotypes composed of antitumor cytotoxic CD8+ T-cells. Blood 2019;134:3030.
128. Bercusson A, Colley T, Shah A, Warris A, Armstrong-James D. Ibrutinib blocks Btk-dependent NF-kB and NFAT responses in human macrophages during Aspergillus fumigatus phagocytosis. Blood 2018;132:1985-8.
129. Ahn IE, Jerussi T, Farooqui M, Tian X, Wiestner A, et al. Atypical pneumocystis jirovecii pneumonia in previously untreated patients with CLL on single-agent ibrutinib. Blood 2016;128:1940-3.
130. Baron M, Zini JM, Challan Belval T, Vignon M, Denis B, et al. Fungal infections in patients treated with ibrutinib: Two unusual cases of invasive aspergillosis and cryptococcal meningoencephalitis. Leuk Lymphoma 2017;58:2981-2.
131. Chan TS, Au-Yeung R, Chim CS, Wong SC, Kwong YL. Disseminated fusarium infection after ibrutinib therapy in chronic lymphocytic leukaemia. Ann Hematol 2017;96:871-2.
132. Messina JA, Maziarz EK, Spec A, Kontoyiannis DP, Perfect JR. Disseminated cryptococcosis with brain involvement in patients with chronic lymphoid malignancies on ibrutinib. Open Forum Infect Dis 2017;4:ofw261.
133. Grommes C, Pastore A, Palaskas N, Tang SS, Campos C, et al. Ibrutinib unmasks critical role of Bruton tyrosine kinase in primary CNS lymphoma. Cancer Discov 2017;7:1018-29.
134. Lionakis MS, Dunleavy K, Roschewski M, Widemann BC, Butman JA, et al. Inhibition of B cell receptor signaling by ibrutinib in primary CNS lymphoma. Cancer Cell 2017;31:833-43 e5.
135. Ghez D, Calleja A, Protin C, Baron M, Ledoux MP, et al. Early-onset invasive aspergillosis and other fungal infections in patients treated with ibrutinib. Blood 2018;131:1955-9.
136. Varughese T, Taur Y, Cohen N, Palomba ML, Seo SK, et al. Serious infections in patients receiving ibrutinib for treatment of lymphoid cancer. Clin Infect Dis 2018;67:687-92.
137. Rogers KA, Mousa L, Zhao Q, Bhat SA, Byrd JC, et al. Incidence of opportunistic infections during ibrutinib treatment for B-cell malignancies. Leukemia 2019;33:2527-30.
138. Byrd JC, Harrington B, O’Brien S, Jones JA, Schuh A, et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med 2016;374:323-32.
139. Tam CS, Trotman J, Opat S, Burger JA, Cull G, et al. Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL. Blood 2019;134:851-9.
140. Aarup K, Enggaard L, Pedersen RS, Thomsen RH, Bergmann OJ, et al. Real-world outcomes for 205 Danish patients with chronic lymphocytic leukemia treated with ibrutinib. Blood 2019;134:1767.
141. Woyach JA, Ruppert AS, Guinn D, Lehman A, Blachly JS, et al. BTKC481S-mediated resistance to ibrutinib in chronic lymphocytic leukemia. J Clin Oncol 2017;35:1437-43.
142. Kamel S, Horton L, Ysebaert L, Levade M, Burbury K, et al. Ibrutinib inhibits collagen-mediated but not ADP-mediated platelet aggregation. Leukemia 2015;29:783.
143. Levade M, David E, Garcia C, Laurent PA, Cadot S, et al. Ibrutinib treatment affects collagen and von Willebrand factor-dependent platelet functions. Blood 2014;124:3991-5.
144. Shatzel JJ, Olson SR, Tao DL, McCarty OJT, Danilov AV, et al. Ibrutinib-associated bleeding: Pathogenesis, management and risk reduction strategies. J Thromb Haemost 2017;15:835-47.
145. Brown JR, Moslehi J, O’Brien S, Ghia P, Hillmen P, et al. Characterization of atrial fibrillation adverse events reported in ibrutinib randomized controlled registration trials. Haematologica 2017;102:1796-805.
146. McMullen JR, Boey EJ, Ooi JY, Seymour JF, Keating MJ, et al. Ibrutinib increases the risk of atrial fibrillation, potentially through inhibition of cardiac PI3K-AKT signaling. Blood 2014;124:3829-30.
147. Guha A, Derbala MH, Zhao Q, Wiczer TE, Woyach JA, et al. Ventricular arrhythmias following ibrutinib initiation for lymphoid malignancies. J Am Coll Cardiol 2018;72:697-8.
148. Lampson BL, Yu L, Glynn RJ, Barrientos JC, Jacobsen ED, et al. Ventricular arrhythmias and sudden death in patients taking ibrutinib. Blood 2017;129:2581-4.
149. Chanan-Khan A, Cramer P, Demirkan F, Fraser G, Silva RS, 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;17:200-11.
150. Byrd JC, Jones JA, Furman RR, Stephens DM, Devereux S, Brown JR, et al. Acalabrutinib, a second-generation Bruton tyrosine kinase (BTK) inhibitor, in previously untreated chronic lymphocytic leukemia. J Clin Oncol 2016;34:15.
151. Byrd JC, Woyach JA, Furman RR, Martin P, O’Brien SM, et al. Acalabrutinib in treatment-naive chronic lymphocytic leukemia: updated results from the phase 1/2 ACE-CL-001 study. Blood 2018;132:692.
152. Rogers KA, Thompson PA, Allan JN, Coleman M, Sharman JP, et al. Phase 2 study of acalabrutinib in ibrutinib intolerant patients with relapsed/refractory chronic lymphocytic leukemia. J Clin Oncol 2019;37:15.
153. Walter HS, Rule SA, Dyer MJ, Karlin L, Jones C, et al. A phase 1 clinical trial of the selective BTK inhibitor ONO/GS-4059 in relapsed and refractory mature B-cell malignancies. Blood 2016;127:411-9.
154. Walter HS, Jayne S, Rule SA, Cartron G, Morschhauser F, et al. Long-term follow-up of patients with CLL treated with the selective Bruton’s tyrosine kinase inhibitor ONO/GS-4059. Blood 2017;129:2808-10.
155. Cull G, Simpson D, Opat S, Burger J, Trotman J, et al. Treatment with the Bruton tyrosine kinase inhibitor zanubrutinib (BGB-3111) demonstrates high overall response rate and durable responses in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma: updated results from a phase 1/2 trial. Blood 2019;134:500.
156. Forum UC. Ibrutinib for relapsed/refractory chronic lymphocytic leukemia: A uk and ireland analysis of outcomes in 315 patients. Haematologica 2016;101:1563-72.
157. Iskierka-Jazdzewska E, Hus M, Giannopoulos K, Madro E, Holojda J, et al. Efficacy and toxicity of compassionate ibrutinib use in relapsed/refractory chronic lymphocytic leukemia in poland: Analysis of the polish adult leukemia group (PALG). Leuk Lymphoma 2017;58:2485-8.
158. Mato AR, Timlin C, Ujjani C, Skarbnik A, Howlett C, et al. Comparable outcomes in chronic lymphocytic leukaemia (CLL) patients treated with reduced-dose ibrutinib: Results from a multi-centre study. Br J Haematol 2018;181:259-61.
159. Chen LS, Bose P, Cruz ND, Jiang Y, Wu Q, et al. A pilot study of lower doses of ibrutinib in patients with chronic lymphocytic leukemia. Blood 2018;132:2249-59.
160. O’Brien SM, Jaglowski S, Byrd JC, Bannerji R, Blum KA, et al. Prognostic factors for complete response to ibrutinib in patients with chronic lymphocytic leukemia: A pooled analysis of 2 clinical trials. JAMA Oncol 2018;4:712-6.
161. Chiodin G, Dutton D, Martino EA, Drennan S, Tracy I, et al. High surface IgM levels associate with shorter response duration and bypass of the BTK blockade during ibrutinib therapy in CLL patients. Blood 2019;134:1752.
162. Ahn IE, Tian X, Albitar M, Herman SE, Cook EM, et al. Validation of clinical prognostic models and integration of genetic biomarkers of drug resistance in CLL patients treated with ibrutinib. Blood 2018;132:186.
163. Miller CR, Ruppert AS, Heerema NA, Maddocks KJ, Labanowska J, et al. Near-tetraploidy is associated with richter transformation in chronic lymphocytic leukemia patients receiving ibrutinib. Blood advances 2017;1:1584-8.
164. Thompson PA, O’Brien SM, Wierda WG, Ferrajoli A, Stingo F, 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 2015;121:3612-21.
165. Jones D, Woyach JA, Zhao W, Caruthers S, Tu H, et al. PLCG2 C2 domain mutations co-occur with BTK and PLCG2 resistance mutations in chronic lymphocytic leukemia undergoing ibrutinib treatment. Leukemia 2017;31:1645-7.
166. Ahn IE, Underbayev C, Albitar A, Herman SE, Tian X, et al. Clonal evolution leading to ibrutinib resistance in chronic lymphocytic leukemia. Blood 2017;129:1469-79.
167. Burger JA, Landau DA, Taylor-Weiner A, Bozic I, Zhang H, et al. Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to btk inhibition. Nat Commun 2016;7:11589.
168. Kadri S, Lee J, Fitzpatrick C, Galanina N, Sukhanova M, et al. Clonal evolution underlying leukemia progression and Richter transformation in patients with ibrutinib-relapsed CLL. Blood Adv 2017;1:715-27.
169. Kanagal-Shamanna R, Jain P, Patel KP, Routbort M, Bueso-Ramos C, et al. Targeted multigene deep sequencing of Bruton tyrosine kinase inhibitor-resistant chronic lymphocytic leukemia with disease progression and Richter transformation. Cancer 2019;125:559-74.
170. Landau DA, Sun C, Rosebrock D, Herman SEM, Fein J, et al. The evolutionary landscape of chronic lymphocytic leukemia treated with ibrutinib targeted therapy. Nat Commun 2017;8:2185.
171. Quinquenel A, Fornecker LM, Letestu R, Ysebaert L, Fleury C, et al. Prevalence of BTK and PLCG2 mutations in a real-life CLL cohort still on ibrutinib after 3 years: a FILO group study. Blood 2019;134:641-4.
172. Woyach J, Huang Y, Rogers KA, Bhat SA, Grever MR, et al. Resistance to acalabrutinib in CLL is mediated primarily by BTK mutations. Blood 2019;134:504.
173. Handunnetti S, Tang CPS, Nguyen T, Zhou X, Thompson ER, et al. BTK Leu528Trp - a potential secondary resistance mechanism specific for patients with chronic lymphocytic leukemia treated with the next generation BTK inhibitor zanubrutinib. Blood 2019;134:170.
174. Fama R, Bomben R, Rasi S, Dal Bo M, Ciardullo C, et al. Ibrutinib-naive chronic lymphocytic leukemia lacks Bruton tyrosine kinase mutations associated with treatment resistance. Blood 2014;124:3831-3.
175. Mato AR, Hill BT, Lamanna N, Barr PM, Ujjani CS, et al. Optimal sequencing of ibrutinib, idelalisib, and venetoclax in chronic lymphocytic leukemia: Results from a multicenter study of 683 patients. Ann Oncol 2017;28:1050-6.
176. Staber PB, Jurczak W, Brugger W, Chanan-Khan A, Greil R, et al. Primary analysis of anti-CD19 tafasitamab (MOR208) treatment in combination with idelalisib or venetoclax in R/R CLL patients who failed prior BTK inhibitor therapy (COSMOS Trial). Blood 2019;134:1754.
177. Porcu P, Flinn I, Kahl BS, Horwitz SM, Oki Y, et al. Clinical activity of duvelisib (IPI-145), a phosphoinositide-3-kinase-δ, γ inhibitor, in patients previously treated with ibrutinib. Blood 2014;124:3335.
178. Awan FT, Thirman MJ, Patel-Donnelly D, Assouline S, Rao AV, et al. Entospletinib monotherapy in patients with relapsed or refractory chronic lymphocytic leukemia previously treated with b-cell receptor inhibitors: Results of a phase 2 study. Leuk Lymphoma 2019;60:1972-7.
179. Aslan B, Mahendra M, Peoples MD, Marszalek JR, Vellano CP, et al. Vecabrutinib inhibits C481 mutated Bruton’s tyrosine kinase and its downstream signaling in vitro. Cancer Res 2019;79.
180. Fabian CA, Reiff SD, Guinn D, Neuman L, Fox JA, et al. SNS-062 demonstrates efficacy in chronic lymphocytic leukemia in vitro and inhibits C481S mutated bruton tyrosine kinase. Cancer Res 2017;77:1207.
181. Allan JN, Wierda WG, Patel K, O’Brien SM, Mato AR, et al. Preliminary safety, pharmacokinetic, and pharmacodynamic results from a phase 1b/2 dose-escalation and cohort-expansion study of the noncovalent, reversible Bruton’s tyrosine kinase inhibitor, Vecabrutinib, in B-lymphoid malignancies. Blood 2018;132:3141.
182. Brandhuber B, Gomez E, Smith S, Eary T, Spencer S, et al. LOXO-305, a next generation reversible BTK inhibitor, for overcoming acquired resistance to irreversible BTK inhibitors. Clin Lymphoma Myeloma Leuk 2018;18:S216.
183. Mato A, Flinn IW, Pagel JM, Brown JR, Cheah CY, et al. Results from a first-in-human, proof-of-concept phase 1 trial in pretreated B-Cell malignancies for LOXO-305, a next-generation, highly selective, non-covalent BTK inhibitor. Blood 2019;134:501.
184. Naeem AS, Nguy WI, Tyekucheva S, Fernandes SM, Rai V, et al. LOXO-305: Targeting C481S Bruton tyrosine kinase in patients with ibrutinib-resistant CLL. Blood 2019;134:478.
185. Johnson AR, Kohli PB, Katewa A, Gogol E, Belmont LD, et al. Battling BTK mutants with noncovalent inhibitors that overcome Cys481 and Thr474 mutations. ACS Chem Biol 2016;11:2897-907.
186. Lee SK, Xing J, Catlett IM, Adamczyk R, Griffies A, et al. Safety, pharmacokinetics, and pharmacodynamics of BMS-986142, a novel reversible BTK inhibitor, in healthy participants. Eur J Clin Pharmacol 2017;73:689-98.
187. Reiff SD, Mantel R, Smith LL, Greene JT, Muhowski EM, et al. The BTK inhibitor ARQ 531 targets ibrutinib-resistant CLL and Richter transformation. Cancer Discov 2018;8:1300-15.
188. Smith PF, Krishnarajah J, Nunn PA, Hill RJ, Karr D, et al. A Phase I trial of PRN1008, a novel reversible covalent inhibitor of Bruton’s tyrosine kinase, in healthy volunteers. Br J Clin Pharmacol 2017;83:2367-76.
189. Woyach J, Stephens DM, Flinn IW, Bhat SA, Savage R, et al. Final results of phase 1, dose escalation study evaluating ARQ 531 in patients with relapsed or refractory B-cell lymphoid malignancies. Blood 2019;134:4298.
190. Lannutti BJ, Meadows SA, Herman SE, Kashishian A, Steiner B, et al. CAL-101, a p110delta selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood 2011;117:591-4.
191. Brown JR, Byrd JC, Coutre SE, Benson DM, Flinn IW, et al. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110delta, for relapsed/refractory chronic lymphocytic leukemia. Blood 2014;123:3390-7.
192. Herman SE, Gordon AL, Wagner AJ, Heerema NA, Zhao W, 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.
193. Zelenetz AD, Lamanna N, Kipps TJ, Coutre SE, O’Brien S, et al. A phase 2 study of idelalisib monotherapy in previously untreated patients ≥ 65 years with chronic lymphocytic leukemia or small lymphocytic lymphoma. Blood 2014;124:1986.
194. De Vos S, Leonard JP, Barrientos JC, Schreeder MT, Flinn IW, et al. A phase 1 study of the selective PI3Kδ inhibitor idelalisib (GS-1101) in combination with therapeutic anti-CD20 antibodies (rituximab or ofatumumab) in patients with relapsed or refractory chronic lymphocytic leukemia. Blood 2013;122:4180.
195. Furman RR, de Vos S, Barrientos JC, Schreeder MT, Flinn IW, et al. Long-term follow-up of a phase 1 study of idelalisib (ZYDELIG®) in combination with anti-CD20 antibodies (rituximab or ofatumumab) in patients with relapsed or refractory chronic lymphocytic leukemia. Blood 2014;124:5653.
196. Ghia P, Pluta A, Wach M, Lysak D, Kozak T, et al. Acalabrutinib versus investigator’s choice of idelalisib plus rituximab or bendamustine plus rituximab in relapsed or refractory CLL: the randomised, controlled, phase 3 ASCEND trial. SSRN 2019; doi: 10.1002/hon.54_2629.
197. Ali K, Soond DR, Pineiro R, Hagemann T, Pearce W, et al. Inactivation of PI3K p110delta breaks regulatory T-cell-mediated immune tolerance to cancer. Nature 2014;510:407-11.
198. Patton DT, Garden OA, Pearce WP, Clough LE, Monk CR, et al. Cutting edge: The phosphoinositide 3-kinase p110δ is critical for the function of CD4+ CD25+ FOXP3+ regulatory T cells. J Immunol 2006;177:6598-602.
199. Gadi D, Kasar S, Griffith A, Chiu PY, Tyekucheva S, et al. Imbalance in T cell subsets triggers the autoimmune toxicity of PI3K inhibitors in CLL. Blood 2019;134:1745.
200. O’Brien S, Lamanna N, Kipps TJ, Flinn IW, Zelenetz AD, et al. Update on a phase 2 study of idelalisib in combination with rituximab in treatment-naïve patients ≥ 65 years with chronic lymphocytic leukemia or small lymphocytic lymphoma. Blood 2014;124:1994.
201. Lampson BL, Kim HT, Davids MS, Abramson JS, Freedman AS, et al. Efficacy results of a phase 2 trial of first-line idelalisib plus ofatumumab in chronic lymphocytic leukemia. Blood Adv 2019;3:1167-74.
202. Coutre SE, Flinn IW, de Vos S, Barrientos JC, Schreeder MT, et al. Idelalisib in combination with rituximab or bendamustine or both in patients with relapsed/refractory chronic lymphocytic leukemia. HemaSphere 2018;2:e39.
203. Sharman JP, Coutre SE, Furman RR, Cheson BD, Pagel JM, et al. Second interim analysis of a phase 3 study of idelalisib (ZYDELIG®) plus rituximab for relapsed chronic lymphocytic leukemia: efficacy analysis in patient subpopulations with del (17p) and other adverse prognostic factors. Blood 2014;124:330.
204. Jones JA, Robak T, Brown JR, Awan FT, Badoux X, 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-e26.
205. Jones JA, Robak T, Wach M, Brown JR, Menter AR, et al. Updated results of a Phase III randomized, controlled study of idelalisib in combination with ofatumumab for previously treated chronic lymphocytic leukemia. J Clin Oncol 2016;34:7515.
206. Lampson BL, Kasar SN, Matos TR, Morgan EA, Rassenti L, et al. Idelalisib given front-line for treatment of chronic lymphocytic leukemia causes frequent immune-mediated hepatotoxicity. Blood 2016;128:195-203.
207. Coutre S, Barrientos JC, Brown JR, De Vos S, Furman RR, et al. Safety of idelalisib in B-cell malignancies: Integrated analysis of eight clinical trials. J Clin Oncol 2015;33:e18030.
208. Cheah CY, Nastoupil LJ, Neelapu SS, Forbes SG, Oki Y, et al. Lenalidomide, idelalisib, and rituximab are unacceptably toxic in patients with relapsed/refractory indolent lymphoma. Blood 2015;125:3357-9.
209. Barr PM, Saylors GB, Spurgeon SE, Cheson BD, Greenwald DR, et al. Phase 2 study of idelalisib and entospletinib: Pneumonitis limits combination therapy in relapsed refractory CLL and NHL. Blood 2016;127:2411-5.
210. Ghia P, Ljungström V, Tausch E, Agathangelidis A, Scheffold A, et al. Whole-exome sequencing revealed no recurrent mutations within the PI3K pathway in relapsed chronic lymphocytic leukemia patients progressing under idelalisib treatment. Blood 2016;128:2770.
211. Scheffold A, Jebaraj BMC, Tausch E, Yahiaoui A, Dolnik A, et al. In vivo modeling of resistance to PI3Kδ inhibitor treatment using EµTCL1-Tg tumor transfer model. Blood 2016;128:190.
212. Flinn IW, O’Brien S, Kahl B, Patel M, Oki Y, et al. Duvelisib, a novel oral dual inhibitor of PI3K-δ, γ, is clinically active in advanced hematologic malignancies. Blood 2018;131:877-87.
213. De Henau O, Rausch M, Winkler D, Campesato LF, Liu C, et al. Overcoming resistance to checkpoint blockade therapy by targeting PI3K gamma in myeloid cells. Nature 2016;539:443-7.
214. Kaneda MM, Messer KS, Ralainirina N, Li H, Leem CJ, et al. PI3Kγ is a molecular switch that controls immune suppression. Nature 2016;539:437.
215. Reif K, Okkenhaug K, Sasaki T, Penninger JM, Vanhaesebroeck B, et al. Cutting edge: Differential roles for phosphoinositide 3-kinases, p110gamma and p110delta, in lymphocyte chemotaxis and homing. J Immunol 2004;173:2236-40.
216. Balakrishnan K, Peluso M, Fu M, Rosin NY, Burger JA, et al. The phosphoinositide-3-kinase (PI3K)-delta and gamma inhibitor, IPI-145 (duvelisib), overcomes signals from the PI3K/AKT/S6 pathway and promotes apoptosis in CLL. Leukemia 2015;29:1811-22.
217. Flinn IW, Hillmen P, Montillo M, Nagy Z, Illes A, et al. The phase 3 DUO trial: Duvelisib vs ofatumumab in relapsed and refractory CLL/sll. Blood 2018;132:2446-55.
218. Burris HA III, Flinn IW, Patel MR, Fenske TS, Deng C, et al. Umbralisib, a novel PI3Kδ and casein kinase-1ε inhibitor, in relapsed or refractory chronic lymphocytic leukaemia and lymphoma: An open-label, phase 1, dose-escalation, first-in-human study. Lancet Oncol 2018;19:486-96.
219. Barr PM, Hill BT, Ma S, Baran AM, Bui A, et al. A phase 1/2 study of umbralisib ublituximab and venetoclax in patients with relapsed or refractory chronic lymphocytic leukemia. Blood 2019;134:360.
220. Mato AR, Schuster SJ, Lamanna N, Flinn I, Barrientos JC, et al. A phase 2 study to assess the safety and efficacy of umbralisib (TGR 1202) in pts with CLL who are intolerant to prior BTK or PI3Kδ inhibitor therapy. J Clin Oncol 2018;36:7530.
221. Nastoupil LJ, Lunning MA, Vose JM, Schreeder MT, Siddiqi T, et al. Tolerability and activity of ublituximab, umbralisib, and ibrutinib in patients with chronic lymphocytic leukaemia and non-hodgkin lymphoma: A phase 1 dose escalation and expansion trial. Lancet Haematol 2019;6:e100-e9.
222. Zelenetz AD, Barrientos JC, Brown JR, Coiffier B, Delgado J, et al. Idelalisib or placebo in combination with bendamustine and rituximab in patients with relapsed or refractory chronic lymphocytic leukaemia: Interim results from a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol 2017;18:297-311.
223. Fraser G, Cramer P, Demirkan F, Silva RS, Grosicki S, et al. Updated results from the phase 3 HELIOS study of ibrutinib, bendamustine, and rituximab in relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma. Leukemia 2019;33:969-80.
224. Davids MS, Fisher D, Tyekucheva S, Haesook K, McDonough M, et al. .
225. Davids MS, Brander DM, Kim HT, Tyekucheva S, Bsat J, et al. Ibrutinib plus fludarabine, cyclophosphamide, and rituximab as initial treatment for younger patients with chronic lymphocytic leukaemia: a single-arm, multicentre, phase 2 trial. Lancet Haematol 2019;6:e419-28.
226. Thompson PA, Peterson CB, Strati P, Jorgensen J, Keating MJ, et al. Serial minimal residual disease (MRD) monitoring during first-line FCR treatment for CLL may direct individualized therapeutic strategies. Leukemia 2018;32:2388-98.
227. Hilal T, Betcher JA, Leis JF. Economic impact of oral therapies for chronic lymphocytic leukemia-the burden of novelty. Curr Hematol Malig Rep 2018;13:237-43.
228. Tam CS, Siddiqi T, Allan JN, Kipps TJ, Flinn IW, et al. Ibrutinib plus venetoclax for first-line treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma: results from the MRD cohort of the phase 2 CAPTIVATE study. Blood 2019;134.
229. Lampson BL, Tyekucheva S, Crombie JL, Lim AI, Merryman RW, et al. Preliminary safety and efficacy results from a phase 2 study of acalabrutinib, venetoclax and obinutuzumab in patients with previously untreated chronic lymphocytic leukemia. Blood 2019;134:32.
230. Jain N, Keating M, Thompson P, Ferrajoli A, Burger J, et al. Combined ibrutinib and venetoclax for first-line treatment for patients with chronic lymphocytic leukemia. Blood 2019;134:34.
231. Jain N, Keating M, Thompson P, Burger J, Ferrajoli A, et al. Combined ibrutinib and venetoclax in patients with relapsed/refractory chronic lymphocytic leukemia. Blood 2019;134:359.
232. Rogers KA, Huang Y, Ruppert AS, Awan FT, Heerema NA, et al. Phase 1b study of obinutuzumab, ibrutinib, and venetoclax in relapsed and refractory chronic lymphocytic leukemia. Blood 2018;132:1568-72.
233. Rogers KA, Huang Y, Ruppert AS, Awan FT, Hoffman C, et al. Phase 2 study of combination obinutuzumab, ibrutinib, and venetoclax in treatment-naive and relapsed/refractory chronic lymphocytic leukemia. Blood 2018;132:693.
234. Niemann C, Dubois J, Kersting S, Enggaard L, Veldhuis GJ, et al. Venetoclax and ibrutinib for patients with relapsed/refractory chronic lymphocytic leukemia - 15-month safety, response and MRD evaluation: third interim analysis from the Phase II Vision HO141 trial. Blood 2019;134:4292.
235. Thompson P, Keating M, Jain N, Ferrajoli A, Kadia T, et al. Venetoclax added to ibrutinib in high-risk CLL achieves a high rate of undetectable minimal residual disease. Blood 2019;134:358.
