Targeted therapies for CLL: Practical issues with the changing treatment paradigm

Blood Reviews

Volumn 30, Issue 3, 2016, Pages 233-244

  Jain, Nitin ^a   O'Brien, Susan ^b  

^a UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

Chronic lymphocytic leukemia; Ibrutinib; Idelalisib; Obinutuzumab; Targeted therapy

Indexed keywords

ACALABRUTINIB; ALEMTUZUMAB; ANTINEOPLASTIC AGENT; B LYMPHOCYTE RECEPTOR; BI 836826; BREAKPOINT CLUSTER REGION PROTEIN; CD20 ANTIBODY; CD37 ANTIBODY; CYCLOPHOSPHAMIDE; DUVELISIB; ENTOSPLETINIB; FLUDARABINE; FOSTAMATINIB; IBRUTINIB; IDELALISIB; IMGN 529; LENALIDOMIDE; MONOCLONAL ANTIBODY; OBINUTUZUMAB; OFATUMUMAB; ONO 4059; OTLERTUZUMAB; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN BCL 2; PROTEIN KINASE SYK; RITUXIMAB; SPEBRUTINIB; TGR 1202; UBLITUXIMAB; UNCLASSIFIED DRUG; UNINDEXED DRUG; TUMOR MARKER;

ANTINEOPLASTIC ACTIVITY; CANCER COMBINATION CHEMOTHERAPY; CANCER IMMUNOTHERAPY; CANCER SURVIVAL; CELL THERAPY; CHROMOSOME 17P; CHROMOSOME DELETION; CHRONIC LYMPHATIC LEUKEMIA; CLINICAL PRACTICE; CLINICAL TRIAL (TOPIC); DISEASE DURATION; DRUG EFFICACY; ENZYME INHIBITION; HUMAN; PATIENT CARE; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; PROTEIN FUNCTION; PROTEIN TARGETING; REVIEW; SIGNAL TRANSDUCTION; T LYMPHOCYTE; TREATMENT INDICATION; DISEASE MANAGEMENT; METABOLISM; MOLECULARLY TARGETED THERAPY; MULTIMODALITY CANCER THERAPY; TREATMENT OUTCOME;

ANTINEOPLASTIC AGENTS; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; BIOMARKERS, TUMOR; COMBINED MODALITY THERAPY; DISEASE MANAGEMENT; HUMANS; LEUKEMIA, LYMPHOCYTIC, CHRONIC, B-CELL; MOLECULAR TARGETED THERAPY; TREATMENT OUTCOME;

EID: 84953251975     PISSN: 0268960X     EISSN: 15321681     Source Type: Journal    
DOI: 10.1016/j.blre.2015.12.002     Document Type: Review

References (178)

1. Jain N., O'Brien S. Initial treatment of CLL: integrating biology and functional status. Blood 2015, 126:463-470.
2. Stevenson F.K., Caligaris-Cappio F. Chronic lymphocytic leukemia: revelations from the B-cell receptor. Blood 2004, 103:4389-4395.
3. ten Hacken E., Burger J.A. Microenvironment dependency in chronic lymphocytic leukemia: the basis for new targeted therapies. Pharmacol Ther 2014, 144:338-348.
4. Satterthwaite A.B., Witte O.N. The role of Bruton's tyrosine kinase in B-cell development and function: a genetic perspective. Immunol Rev 2000, 175:120-127.
5. Pan Z., Scheerens H., Li S.J., Schultz B.E., Sprengeler P.A., Burrill L.C., et al. Discovery of selective irreversible inhibitors for Bruton's tyrosine kinase. ChemMedChem 2007, 2:58-61.
6. Byrd J.C., Furman R.R., Coutre S.E., Flinn I.W., Burger J.A., Blum K.A., et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med 2013, 369:32-42.
7. Byrd J.C., Furman R.R., Coutre S.E., Burger J.A., Blum K.A., Coleman M., et al. Three-year follow-up of treatment-naive and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood 2015, 125:2497-2506.
8. Levade M., David E., Garcia C., Laurent P.A., Cadot S., Michallet A.S., et al. Ibrutinib treatment affects collagen and von Willebrand factor-dependent platelet functions. Blood 2014, 124:3991-3995.
9. Kamel S., Horton L., Ysebaert L., Levade M., Burbury K., Tan S., et al. Ibrutinib inhibits collagen-mediated but not ADP-mediated platelet aggregation. Leukemia 2015, 29:783-787.
10. Byrd J.C., Brown J.R., O'Brien S., Barrientos J.C., Kay N.E., Reddy N.M., et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med 2014, 371:213-223.
11. O'Brien S., Furman R.R., Coutre S.E., Sharman J.P., Burger J.A., Blum K.A., 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.
12. Ponader S., Chen S.S., Buggy J.J., Balakrishnan K., Gandhi V., Wierda W.G., et al. The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo. Blood 2012, 119:1182-1189.
13. Herman S.E., Niemann C.U., Farooqui M., Jones J., Mustafa R.Z., Lipsky A., et al. Ibrutinib-induced lymphocytosis in patients with chronic lymphocytic leukemia: correlative analyses from a phase II study. Leukemia 2014, 28:2188-2196.
14. Herman S.E., Mustafa R.Z., Gyamfi J.A., Pittaluga S., Chang S., Chang B., et al. Ibrutinib inhibits BCR and NF-kappaB signaling and reduces tumor proliferation in tissue-resident cells of patients with CLL. Blood 2014, 123:3286-3295.
15. Herman S.E., Mustafa R.Z., Jones J., Wong D.H., Farooqui M., Wiestner A. Treatment with ibrutinib inhibits BTK- and VLA-4-dependent adhesion of chronic lymphocytic leukemia cells in vivo. Clin Cancer Res 2015, 21:4642-4651.
16. Woyach J.A., Smucker K., Smith L.L., Lozanski A., Zhong Y., Ruppert A.S., et al. Prolonged lymphocytosis during ibrutinib therapy is associated with distinct molecular characteristics and does not indicate a suboptimal response to therapy. Blood 2014, 123:1810-1817.
17. Thompson P.A., Ferrajoli A., O'Brien S., Wierda W.G., Keating M.J., Burger J.A. Trisomy 12 is associated with an abbreviated redistribution lymphocytosis during treatment with the BTK inhibitor ibrutinib in patients with chronic lymphocytic leukaemia. Br J Haematol 2015, 170:125-128.
18. Cheson B.D., Byrd J.C., Rai K.R., Kay N.E., O'Brien S.M., Flinn I.W., et al. Novel targeted agents and the need to refine clinical end points in chronic lymphocytic leukemia. J Clin Oncol 2012, 30:2820-2822.
19. Woyach J.A., Furman R.R., Liu T.M., Ozer H.G., Zapatka M., Ruppert A.S., et al. Resistance mechanisms for the Bruton's tyrosine kinase inhibitor ibrutinib. N Engl J Med 2014, 370:2286-2294.
20. Maddocks K.J., Ruppert A.S., Lozanski G., Heerema N.A., Zhao W., Abruzzo L., et al. Etiology of ibrutinib therapy discontinuation and outcomes in patients with chronic lymphocytic leukemia. JAMA Oncol 2015, 1:80-87.
21. Cheng S., Guo A., Lu P., Ma J., Coleman M., Wang Y.L. Functional characterization of BTK(C481S) mutation that confers ibrutinib resistance: exploration of alternative kinase inhibitors. Leukemia 2015, 29:895-900.
22. Burger J.A., Keating M.J., Wierda W.G., Hartmann E., Hoellenriegel J., Rosin N.Y., 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.
23. Jaglowski S.M., Jones J.A., Nagar V., Flynn J.M., Andritsos L.A., Maddocks K.J., 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.
24. Sharman J., Farber C.M., Mahadevan D., Schreeder M.T., Brooks H.D., Kolibaba K.S., et al. Ublituximab (TG-1101), a novel glycoengineered anti-CD20 mAb, in combination with ibrutinib achieves 95% ORR in patients with high-risk relapsed/refractory CLL. 13th International Conference on Malignant Lymphoma (ICML) 2015, (Lugano, Switzerland).
25. Kohrt H.E., Sagiv-Barfi I., Rafiq S., Herman S.E., Butchar J.P., Cheney C., et al. Ibrutinib antagonizes rituximab-dependent NK cell-mediated cytotoxicity. Blood 2014, 123:1957-1960.
26. Da Roit F., Engelberts P.J., Taylor R.P., Breij E.C., Gritti G., Rambaldi A., et al. Ibrutinib interferes with the cell-mediated anti-tumor activities of therapeutic CD20 antibodies: implications for combination therapy. Haematologica 2015, 100:77-86.
27. Duong M.N., Matera E.L., Mathe D., Evesque A., Valsesia-Wittmann S., Clemenceau B., et al. Effect of kinase inhibitors on the therapeutic properties of monoclonal antibodies. MAbs 2015, 7:192-198.
28. Borge M., Belen Almejun M., Podaza E., Colado A., Fernandez Grecco H., Cabrejo M., et al. Ibrutinib impairs the phagocytosis of rituximab-coated leukemic cells from chronic lymphocytic leukemia patients by human macrophages. Haematologica 2015, 100:e140-e142.
29. Brown J.R., Barrientos J.C., Barr P.M., Flinn I.W., Burger J.A., Tran A., et al. The Bruton tyrosine kinase inhibitor ibrutinib with chemoimmunotherapy in patients with chronic lymphocytic leukemia. Blood 2015, 125:2915-2922.
30. Chanan-Khan A.A., Cramer P., Demirkan F., Fraser G., Silva R.S., Pylypenko H., et al. Ibrutinib combined with bendamustine and rituximab (BR) in previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): First results from a randomized, double-blind, placebo-controlled, phase III study. American Society of Clinical Oncology Annual Meeting 2015, LBA7005.
31. Covey T., Barf T., Gulrajani M., Krantz F., van Lith B., Bibikova E., et al. ACP-196: a novel covalent Bruton's tyrosine kinase (Btk) inhibitor with improved selectivity and in vivo target coverage in chronic lymphocytic leukemia (CLL) patients. American Association of Cancer Research Annual Meeting 2015, 2596a.
32. Niemann C.U., Montraveta A., Herman S.E., Ingallinera T., Barf T., Colomer D., et al. The novel Bruton's tyrosine kinase inhibitor ACP-196 shows in vivo efficacy against human chronic lymphocytic leukemia cells xenografted to the NSG mouse model. American Association of Cancer Research Annual Meeting 2014, 2624a.
33. Fegan C., Bagshawe J., Salles G., Karlin L., Rule S., Shah N., et al. The Bruton's tyrosine kinase (BTK) inhibitor ONO-4059: promising single agent activity and well tolerated in patients with high risk chronic lymphocytic leukaemia (CLL). American Society of Hematology Annual Meeting 2014, 3328a.
34. Brown J.R., Harb W.A., Hill B.T., Gabrilove J., Sharman J.P., Schreeder M.T., et al. Phase 1 study of single agent CC-292, a highly selective Bruton's tyrosine kinase (BTK) inhibitor, In relapsed/refractory chronic lymphocytic leukemia (CLL). American Society of Hematology Annual Meeting 2013, 1630a.
35. Herman S.E., Gordon A.L., Wagner A.J., Heerema N.A., Zhao W., Flynn J.M., et al. Phosphatidylinositol 3-kinase-delta inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals. Blood 2010, 116:2078-2088.
36. Brown J.R., Byrd J.C., Coutre S.E., Benson D.M., Flinn I.W., Wagner-Johnston N.D., et al. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110delta, for relapsed/refractory chronic lymphocytic leukemia. Blood 2014, 123:3390-3397.
37. Furman R.R., Sharman J.P., Coutre S.E., Cheson B.D., Pagel J.M., Hillmen P., et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med 2014, 370:997-1007.
38. Zelenetz A.D., Lamanna N., Kipps T.J., Coutre S.E., O'Brien S., Aiello M., et al. A phase 2 study of idelalisib monotherapy in previously untreated patients ≥ 65 years with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Blood 2014, 124:1986a.
39. O'Brien S., Lamanna N., Kipps T.J., Flinn I.W., Zelenetz A.D., Burger J.A., et al. Update on a phase 2 study of idelalisib in combination with rituximab in treatment-naïve patients ≥ 65 years with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Blood 2014, 124:1994a.
40. Okkenhaug K., Bilancio A., Farjot G., Priddle H., Sancho S., Peskett E., et al. Impaired B and T cell antigen receptor signaling in p110delta PI 3-kinase mutant mice. Science 2002, 297:1031-1034.
41. Ali K., Soond D.R., Pineiro R., Hagemann T., Pearce W., Lim E.L., et al. Inactivation of PI(3)K p110delta breaks regulatory T-cell-mediated immune tolerance to cancer. Nature 2014, 510:407-411.
42. Patton D.T., Garden O.A., Pearce W.P., Clough L.E., Monk C.R., Leung E., et al. Cutting edge: the phosphoinositide 3-kinase p110 delta is critical for the function of CD4 + CD25 + Foxp3 + regulatory T cells. J Immunol 2006, 177:6598-6602.
43. Cheah C.Y., Nastoupil L.J., Neelapu S.S., Forbes S.G., Oki Y., Fowler N.H. Lenalidomide, idelalisib, and rituximab are unacceptably toxic in patients with relapsed/refractory indolent lymphoma. Blood 2015, 125:3357-3359.
44. Smith S.M., Pitcher B., Jung S.-H., Bartlett N.L., Wagner-Johnston N., Park S.I., et al. Unexpected and serious toxicity observed with combined idelalisib, lenalidomide and rituximab in relapsed/refractory b cell lymphomas: alliance A051201 and A051202. American Society of Hematology Annual Meeting 2014, 3091a.
45. O'Brien S., Patel M., Kahl B.S., Horwitz S.M., Foss F.M., Porcu P., et al. Duvelisib (IPI-145), a PI3K-δ,γ inhibitor, is clinically active in patients with relapsed/refractory chronic lymphocytic leukemia. American Society of Hematology Annual Meeting 2014, 3334. (San Francisco).
46. Balakrishnan K., Peluso M., Fu M., Rosin N.Y., Burger J.A., Wierda W.G., 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, 29:1811-1822.
47. Dong S., Guinn D., Dubovsky J.A., Zhong Y., Lehman A., Kutok J., et al. IPI-145 antagonizes intrinsic and extrinsic survival signals in chronic lymphocytic leukemia cells. Blood 2014, 124:3583-3586.
48. Porcu P., Flinn I., Kahl B.S., Horwitz S.M., Oki Y., Byrd J.C., et al. Clinical activity of duvelisib (IPI-145), a phosphoinositide-3-kinase-δ,γ inhibitor, in patients previously treated with ibrutinib. American Society of Hematology Annual Meeting 2014, 3335a.
49. Burris H.A., Patel M.R., Fenske T.S., O'Connor O.A., Deng C., Brander D.M., et al. Clinical activity and safety profile of TGR-1202, a novel once daily PI3Kδ inhibitor, in patients with CLL and B-cell Lymphoma. 13th International Conference on Malignant Lymphoma (ICML) 2015, (Lugano, Switzerland).
50. Lunning M., Vose J., Fowler N., Nastoupil L., Burger J.A., Wierda W.G., et al. Ublituximab + TGR-1202 demonstrates activity and favorable safety profile in relapsed/refractory B-cell NHL and high-risk CLL. 13th International Conference on Malignant Lymphoma (ICML) 2015, (Lugano, Switzerland).
51. Nastoupil L., Fowler N., Lunning M., Vose J., Siddiqi T., Flowers F., et al. Safety and activity of the chemotherapy-free triplet of ublituximab, TGR-1202, and ibrutinib in relapsed B-cell malignancies. 13th International Conference on Malignant Lymphoma (ICML) 2015, (Lugano, Switzerland).
52. Burger J.A., Chiorazzi N. B cell receptor signaling in chronic lymphocytic leukemia. Trends Immunol 2013, 34:592-601.
53. Quiroga M.P., Balakrishnan K., Kurtova A.V., Sivina M., Keating M.J., Wierda W.G., 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 2009, 114:1029-1037.
54. Buchner M., Baer C., Prinz G., Dierks C., Burger M., Zenz T., et al. Spleen tyrosine kinase inhibition prevents chemokine- and integrin-mediated stromal protective effects in chronic lymphocytic leukemia. Blood 2010, 115:4497-4506.
55. Suljagic M., Longo P.G., Bennardo S., Perlas E., Leone G., Laurenti L., et al. The Syk inhibitor fostamatinib disodium (R788) inhibits tumor growth in the Emu-TCL1 transgenic mouse model of CLL by blocking antigen-dependent B-cell receptor signaling. Blood 2010, 116:4894-4905.
56. Herman S.E., Barr P.M., McAuley E.M., Liu D., Wiestner A., Friedberg J.W. Fostamatinib inhibits B-cell receptor signaling, cellular activation and tumor proliferation in patients with relapsed and refractory chronic lymphocytic leukemia. Leukemia 2013, 27:1769-1773.
57. Braselmann S., Taylor V., Zhao H., Wang S., Sylvain C., Baluom M., et al. R406, an orally available spleen tyrosine kinase inhibitor blocks fc receptor signaling and reduces immune complex-mediated inflammation. J Pharmacol Exp Ther 2006, 319:998-1008.
58. Friedberg J.W., Sharman J., Sweetenham J., Johnston P.B., Vose J.M., Lacasce A., et al. Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood 2010, 115:2578-2585.
59. Currie K.S., Kropf J.E., Lee T., Blomgren P., Xu J., Zhao Z., et al. Discovery of GS-9973, a selective and orally efficacious inhibitor of spleen tyrosine kinase. J Med Chem 2014, 57:3856-3873.
60. Sharman J., Hawkins M., Kolibaba K., Boxer M., Klein L., Wu M., et al. An open-label phase 2 trial of entospletinib (GS-9973), a selective spleen tyrosine kinase inhibitor, in chronic lymphocytic leukemia. Blood 2015, 125:2336-2343.
61. Barr P.M., Saylors G.B., Spurgeon S., Cheson B.D., Greenwald D.R., O'Brien S.M., et al. Phase 2 trial of GS-9973, a selective syk inhibitor, and idelalisib (idela) in chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL). American Society of Clinical Oncology Annual Meeting 2014, 7059a.
62. O'Brien S.M., Kantarjian H., Thomas D.A., Giles F.J., Freireich E.J., Cortes J., et al. Rituximab dose-escalation trial in chronic lymphocytic leukemia. J Clin Oncol 2001, 19:2165-2170.
63. Byrd J.C., Murphy T., Howard R.S., Lucas M.S., Goodrich A., Park K., et al. Rituximab using a thrice weekly dosing schedule in B-cell chronic lymphocytic leukemia and small lymphocytic lymphoma demonstrates clinical activity and acceptable toxicity. J Clin Oncol 2001, 19:2153-2164.
64. Hallek M., Fischer K., Fingerle-Rowson G., Fink A.M., Busch R., Mayer J., 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.
65. Teeling J.L., French R.R., Cragg M.S., van den Brakel J., Pluyter M., Huang H., et al. Characterization of new human CD20 monoclonal antibodies with potent cytolytic activity against non-Hodgkin lymphomas. Blood 2004, 104:1793-1800.
66. Teeling J.L., Mackus W.J., Wiegman L.J., van den Brakel J.H., Beers S.A., French R.R., et al. The biological activity of human CD20 monoclonal antibodies is linked to unique epitopes on CD20. J Immunol 2006, 177:362-371.
67. Bologna L., Gotti E., Da Roit F., Intermesoli T., Rambaldi A., Introna M., et al. Ofatumumab is more efficient than rituximab in lysing B chronic lymphocytic leukemia cells in whole blood and in combination with chemotherapy. J Immunol 2013, 190:231-239.
68. Rafiq S., Butchar J.P., Cheney C., Mo X., Trotta R., Caligiuri M., et al. Comparative assessment of clinically utilized CD20-directed antibodies in chronic lymphocytic leukemia cells reveals divergent NK cell, monocyte, and macrophage properties. J Immunol 2013, 190:2702-2711.
69. Pawluczkowycz A.W., Beurskens F.J., Beum P.V., Lindorfer M.A., van de Winkel J.G., Parren P.W., et al. Binding of submaximal C1q promotes complement-dependent cytotoxicity (CDC) of B cells opsonized with anti-CD20 mAbs ofatumumab (OFA) or rituximab (RTX): considerably higher levels of CDC are induced by OFA than by RTX. J Immunol 2009, 183:749-758.
70. Wierda W.G., Kipps T.J., Mayer J., Stilgenbauer S., Williams C.D., Hellmann A., et al. Ofatumumab as single-agent CD20 immunotherapy in fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol 2010, 28:1749-1755.
71. Osterborg A., Jewell R.C., Padmanabhan-Iyer S., Kipps T.J., Mayer J., Stilgenbauer S., et al. Ofatumumab monotherapy in fludarabine-refractory chronic lymphocytic leukemia: final results from a pivotal study. Haematologica 2015, 100:e311-e314.
72. Hillmen P., Robak T., Janssens A., Babu K.G., Kloczko J., Grosicki S., 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.
73. Mossner E., Brunker P., Moser S., Puntener U., Schmidt C., Herter 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.
74. Herter S., Herting F., Mundigl O., Waldhauer I., Weinzierl T., Fauti 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, 12:2031-2042.
75. Goede V., Fischer K., Busch R., Engelke A., Eichhorst B., Wendtner C.M., et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med 2014, 370:1101-1110.
76. Goede V., Fischer K., Engelke A., Schlag R., Lepretre S., Montero L.F., et al. Obinutuzumab as frontline treatment of chronic lymphocytic leukemia: updated results of the CLL11 study. Leukemia 2015, 29:1602-1604.
77. Freeman C.L., Morschhauser F., Sehn L.H., Dixon M., Houghton R., Lamy T., et al. Pattern of cytokine release in patients with chronic lymphocytic leukemia treated with obinutuzumab and possible relationship with development of infusion related reactions (IRR). American Society of Hematology Annual Meeting 2014, 4674a.
78. Bosch F., Illmer T., Turgut M., Cortelezzi A., Lasserre S.F., Truppel-Hartmann A., et al. Preliminary safety results from the phase iiib green study of obinutuzumab (GA101) alone or in combination with chemotherapy for previously untreated or relapsed/refractory chronic lymphocytic leukemia (CLL). American Society of Hematology Annual Meeting 2014, 3345a.
79. de Romeuf C., Dutertre C.A., Le Garff-Tavernier M., Fournier N., Gaucher C., Glacet A., et al. Chronic lymphocytic leukaemia cells are efficiently killed by an anti-CD20 monoclonal antibody selected for improved engagement of FcgammaRIIIA/CD16. Br J Haematol 2008, 140:635-643.
80. O'Connor O.A., Schreeder M.T., Deng C., Amengual J.E., Boccia R., Khalil M.Y., et al. Ublituximab (TG-1101), a novel anti-CD20 monoclonal antibody for rituximab relapsed/refractory B-cell malignancies 2014, European Hematology Association (EHA), Milan, Italy.
81. Forero-Torres A., de Vos S., Pohlman B.L., Pashkevich M., Cronier D.M., Dang N.H., et al. Results of a phase 1 study of AME-133v (LY2469298), an Fc-engineered humanized monoclonal anti-CD20 antibody, in FcgammaRIIIa-genotyped patients with previously treated follicular lymphoma. Clin Cancer Res 2012, 18:1395-1403.
82. Cheney C.M., Stephens D.M., Mo X., Rafiq S., Butchar J., Flynn J.M., et al. Ocaratuzumab, an Fc-engineered antibody demonstrates enhanced antibody-dependent cell-mediated cytotoxicity in chronic lymphocytic leukemia. MAbs 2014, 6:749-755.
83. Ganjoo K.N., de Vos S., Pohlman B.L., Flinn I.W., Forero-Torres A., Enas N.H., et al. Phase 1/2 study of ocaratuzumab, an Fc-engineered humanized anti-CD20 monoclonal antibody, in low-affinity FcgammaRIIIa patients with previously treated follicular lymphoma. Leuk Lymphoma 2015, 56:42-48.
84. Goldenberg D.M., Rossi E.A., Stein R., Cardillo T.M., Czuczman M.S., Hernandez-Ilizaliturri F.J., et al. Properties and structure-function relationships of veltuzumab (hA20), a humanized anti-CD20 monoclonal antibody. Blood 2009, 113:1062-1070.
85. Negrea G.O., Elstrom R., Allen S.L., Rai K.R., Abbasi R.M., Farber C.M., et al. Subcutaneous injections of low-dose veltuzumab (humanized anti-CD20 antibody) are safe and active in patients with indolent non-Hodgkin's lymphoma. Haematologica 2011, 96:567-573.
86. Kalaycio M., Negrea O.G., Elstrom R., Farber C., Horne H., Wegener W.A., et al. Monotherapy with subcutaneous (SC) injections of low doses of humanized anti-CD20 veltuzumab is active in chronic lymphocytic leukemia (CLL). Blood 2012, 120:192a.
87. Christian B.A., Poi M., Jones J.A., Porcu P., Maddocks K., Flynn J.M., et al. The combination of milatuzumab, a humanized anti-CD74 antibody, and veltuzumab, a humanized anti-CD20 antibody, demonstrates activity in patients with relapsed and refractory B-cell non-Hodgkin lymphoma. Br J Haematol 2015, 169:701-710.
88. Keating M.J., Flinn I., Jain V., Binet J.L., Hillmen P., Byrd J., 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.
89. Hillmen P., Skotnicki A.B., Robak T., Jaksic B., Dmoszynska A., Wu J., et al. Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia. J Clin Oncol 2007, 25:5616-5623.
90. Fischer K., Cramer P., Busch R., Bottcher S., Bahlo J., Schubert 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, 30:3209-3216.
91. Thornton P.D., Matutes E., Bosanquet A.G., Lakhani A.K., Grech H., Ropner J.E., et al. High dose methylprednisolone can induce remissions in CLL patients with p53 abnormalities. Ann Hematol 2003, 82:759-765.
92. Pettitt A.R., Jackson R., Carruthers S., Dodd J., Dodd S., Oates M., et al. Alemtuzumab in combination with methylprednisolone is a highly effective induction regimen for patients with chronic lymphocytic leukemia and deletion of TP53: final results of the national cancer research institute CLL206 trial. J Clin Oncol 2012, 30:1647-1655.
93. Stilgenbauer S., Cymbalista F., Leblond V., Delmer A., Ibach S., Choquet S., et al. Alemtuzumab combined with dexamethasone, followed by alemtuzumab maintenance or Allo-SCT in "ultra high-risk" CLL: final results from the CLL2O phase II study. Blood 2014, 124:1991a.
94. Parikh S.A., Keating M.J., O'Brien S., Wang X., Ferrajoli A., Faderl S., et al. Frontline chemoimmunotherapy with fludarabine, cyclophosphamide, alemtuzumab, and rituximab for high-risk chronic lymphocytic leukemia. Blood 2011, 118:2062-2068.
95. Lepretre S., Aurran T., Mahe B., Cazin B., Tournilhac O., Maisonneuve H., 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.
96. Geisler C.H., van T' Veer M.B., Jurlander J., Walewski J., Tjonnfjord G., Itala Remes M., et al. Frontline low-dose alemtuzumab with fludarabine and cyclophosphamide prolongs progression-free survival in high-risk CLL. Blood 2014, 123:3255-3262.
97. Badoux X.C., Keating M.J., Wang X., O'Brien S.M., Ferrajoli A., Faderl S., et al. Cyclophosphamide, fludarabine, alemtuzumab, and rituximab as salvage therapy for heavily pretreated patients with chronic lymphocytic leukemia. Blood 2011, 118:2085-2093.
98. Montillo M., Tedeschi A., Petrizzi V.B., Ricci F., Crugnola M., Spriano M., et al. An open-label, pilot study of fludarabine, cyclophosphamide, and alemtuzumab in relapsed/refractory patients with B-cell chronic lymphocytic leukemia. Blood 2011, 118:4079-4085.
99. Elter T., James R., Busch R., Winkler D., Ritgen M., Bottcher S., et al. Fludarabine and cyclophosphamide in combination with alemtuzumab in patients with primary high-risk, relapsed or refractory chronic lymphocytic leukemia. Leukemia 2012, 26:2549-2552.
100. Robak T., Robak P. Anti-CD37 antibodies for chronic lymphocytic leukemia. Expert Opin Biol Ther 2014, 14:651-661.
101. Robak T., Robak P., Smolewski P. TRU-016, a humanized anti-CD37 IgG fusion protein for the potential treatment of B-cell malignancies. Curr Opin Investig Drugs 2009, 10:1383-1390.
102. Byrd J.C., Pagel J.M., Awan F.T., Forero A., Flinn I.W., Deauna-Limayo D.P., et al. A phase 1 study evaluating the safety and tolerability of otlertuzumab, an anti-CD37 mono-specific ADAPTIR therapeutic protein in chronic lymphocytic leukemia. Blood 2014, 123:1302-1308.
103. Maddocks K.J., Pagel J., Byrd J.C., Stromatt S., Awan F. Phase 1b Study of otlertuzumab (TRU-016), an anti-CD37 ADAPTIRTM protein, in combination with rituximab in patients with chronic lymphocytic leukemia (CLL). American Society of Hematology Annual Meeting 2014, 4671a.
104. Lapalombella R., Yeh Y.Y., Wang L., Ramanunni A., Rafiq S., Jha S., et al. Tetraspanin CD37 directly mediates transduction of survival and apoptotic signals. Cancer Cell 2012, 21:694-708.
105. Deckert J., Park P.U., Chicklas S., Yi Y., Li M., Lai K.C., et al. A novel anti-CD37 antibody-drug conjugate with multiple anti-tumor mechanisms for the treatment of B-cell malignancies. Blood 2013, 122:3500-3510.
106. Beckwith K.A., Frissora F.W., Stefanovski M.R., Towns W.H., Cheney C., Mo X., et al. The CD37-targeted antibody-drug conjugate IMGN529 is highly active against human CLL and in a novel CD37 transgenic murine leukemia model. Leukemia 2014, 28:1501-1510.
107. Heider K.H., Kiefer K., Zenz T., Volden M., Stilgenbauer S., Ostermann E., et al. A novel Fc-engineered monoclonal antibody to CD37 with enhanced ADCC and high proapoptotic activity for treatment of B-cell malignancies. Blood 2011, 118:4159-4168.
108. Byrd J.C., O'Brien S., Flinn I.W., Kipps T.J., Weiss M., Rai K., et al. Phase 1 study of lumiliximab with detailed pharmacokinetic and pharmacodynamic measurements in patients with relapsed or refractory chronic lymphocytic leukemia. Clin Cancer Res 2007, 13:4448-4455.
109. Byrd J.C., Kipps T.J., Flinn I.W., Castro J., Lin T.S., Wierda W., et al. Phase 1/2 study of lumiliximab combined with fludarabine, cyclophosphamide, and rituximab in patients with relapsed or refractory chronic lymphocytic leukemia. Blood 2010, 115:489-495.
110. Awan F.T., Hillmen P., Hellmann A., Robak T., Hughes S.G., Trone D., et al. A randomized, open-label, multicentre, phase 2/3 study to evaluate the safety and efficacy of lumiliximab in combination with fludarabine, cyclophosphamide and rituximab versus fludarabine, cyclophosphamide and rituximab alone in subjects with relapsed chronic lymphocytic leukaemia. Br J Haematol 2014, 167:466-477.
111. Herbst R., Wang Y., Gallagher S., Mittereder N., Kuta E., Damschroder M., et al. B-cell depletion in vitro and in vivo with an afucosylated anti-CD19 antibody. J Pharmacol Exp Ther 2010, 335:213-222.
112. Ward E., Mittereder N., Kuta E., Sims G.P., Bowen M.A., Dall'Acqua W., et al. A glycoengineered anti-CD19 antibody with potent antibody-dependent cellular cytotoxicity activity in vitro and lymphoma growth inhibition in vivo. Br J Haematol 2011, 155:426-437.
113. Matlawska-Wasowska K., Ward E., Stevens S., Wang Y., Herbst R., Winter S.S., et al. Macrophage and NK-mediated killing of precursor-B acute lymphoblastic leukemia cells targeted with a-fucosylated anti-CD19 humanized antibodies. Leukemia 2013, 27:1263-1274.
114. Lazar G.A., Dang W., Karki S., Vafa O., Peng J.S., Hyun L., et al. Engineered antibody Fc variants with enhanced effector function. Proc Natl Acad Sci U S A 2006, 103:4005-4010.
115. Zalevsky J., Leung I.W., Karki S., Chu S.Y., Zhukovsky E.A., Desjarlais J.R., et al. The impact of Fc engineering on an anti-CD19 antibody: increased fcgamma receptor affinity enhances B-cell clearing in nonhuman primates. Blood 2009, 113:3735-3743.
116. Awan F.T., Lapalombella R., Trotta R., Butchar J.P., Yu B., Benson D.M., et al. CD19 targeting of chronic lymphocytic leukemia with a novel Fc-domain-engineered monoclonal antibody. Blood 2010, 115:1204-1213.
117. Woyach J.A., Awan F., Flinn I.W., Berdeja J.G., Wiley E., Mansoor S., et al. A phase 1 trial of the Fc-engineered CD19 antibody XmAb5574 (MOR00208) demonstrates safety and preliminary efficacy in relapsed CLL. Blood 2014, 124:3553-3560.
118. Palanca-Wessels M.C., Czuczman M., Salles G., Assouline S., Sehn L.H., Flinn I., et al. Safety and activity of the anti-CD79B antibody-drug conjugate polatuzumab vedotin in relapsed or refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia: a phase 1 study. Lancet Oncol 2015, 16:704-715.
119. Davids M.S., Letai A., Brown J.R. Overcoming stroma-mediated treatment resistance in chronic lymphocytic leukemia through BCL-2 inhibition. Leuk Lymphoma 2013, 54:1823-1825.
120. Roberts A.W., Seymour J.F., Brown J.R., Wierda W.G., Kipps T.J., Khaw S.L., 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, 30:488-496.
121. Souers A.J., Leverson J.D., Boghaert E.R., Ackler S.L., Catron N.D., Chen J., et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med 2013, 19:202-208.
122. Seymour J.F., Davids M.S., Pagel J.M., Kahl B.S., Wierda W.G., Puvvada S., et al. ABT-199: novel Bcl-2 specific inhibitor updated results confirm substantial activity and durable responses in high-risk CLL. European Hematology Association Annual Meeting 2014, S702. (Milan, Italy).
123. Roberts A.W., Ma S., Brander D., Kipps T.J., Barrientos J.C., Davids M.S., et al. Venetoclax (ABT-199/GDC-0199) combined with rituximab induces deep responses in patients with relapsed/refractory chronic lymphocytic leukemia. European Hematology Association Annual Meeting June 2015, S481.
124. Cervantes-Gomez F., Lamothe B., Woyach J.A., Wierda W.G., Keating M.J., Balakrishnan K., et al. Pharmacological and protein profiling suggests venetoclax (ABT-199) as optimal partner with ibrutinib in chronic lymphocytic leukemia. Clin Cancer Res 2015, 21:3705-3715.
125. Ramsay A.G., Johnson A.J., Lee A.M., Gorgun G., Le Dieu R., Blum W., et al. Chronic lymphocytic leukemia T cells show impaired immunological synapse formation that can be reversed with an immunomodulating drug. J Clin Invest 2008, 118:2427-2437.
126. Herman S.E., Lapalombella R., Gordon A.L., Ramanunni A., Blum K.A., Jones J., et al. The role of phosphatidylinositol 3-kinase-delta in the immunomodulatory effects of lenalidomide in chronic lymphocytic leukemia. Blood 2011, 117:4323-4327.
127. Ramsay A.G., Clear A.J., Fatah R., Gribben J.G. 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 2012, 120:1412-1421.
128. Kater A.P., Tonino S.H., Egle A., Ramsay A.G. How does lenalidomide target the chronic lymphocytic leukemia microenvironment?. Blood 2014, 124:2184-2189.
129. Chanan-Khan A., Miller K.C., Musial L., Lawrence D., Padmanabhan S., Takeshita K., et al. Clinical efficacy of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase II study. J Clin Oncol 2006, 24:5343-5349.
130. Ferrajoli A., Lee B.N., Schlette E.J., O'Brien S.M., Gao H., Wen S., et al. Lenalidomide induces complete and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia. Blood 2008, 111:5291-5297.
131. Badoux X.C., Keating M.J., Wen S., Lee B.N., Sivina M., Reuben J., et al. Lenalidomide as initial therapy of elderly patients with chronic lymphocytic leukemia. Blood 2011, 118:3489-3498.
132. Strati P., Keating M.J., Wierda W.G., Badoux X.C., Calin S., Reuben J.M., et al. Lenalidomide induces long-lasting responses in elderly patients with chronic lymphocytic leukemia. Blood 2013, 122:734-737.
133. Chen C.I., Bergsagel P.L., Paul H., Xu W., Lau A., Dave N., et al. Single-agent lenalidomide in the treatment of previously untreated chronic lymphocytic leukemia. J Clin Oncol 2011, 29:1175-1181.
134. Chen C.I., Paul H., Wang T., Le L.W., Dave N., Kukreti V., et al. Long-term follow-up of a phase 2 trial of single agent lenalidomide in previously untreated patients with chronic lymphocytic leukaemia. Br J Haematol 2014, 165:731-733.
135. Wu L., Adams M., Carter T., Chen R., Muller G., Stirling D., et al. lenalidomide enhances natural killer cell and monocyte-mediated antibody-dependent cellular cytotoxicity of rituximab-treated CD20+ tumor cells. Clin Cancer Res 2008, 14:4650-4657.
136. Badoux X.C., Keating M.J., Wen S., Wierda W.G., O'Brien S.M., Faderl 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.
137. Thompson P.A., Keating M.J., Hinojosa C., Smith S.C., Daver N.G., Jain N., et al. Lenalidomide and rituximab in combination as initial treatment of chronic lymphocytic leukemia: initial results of a phase II study. Blood 2014, 124:1988a.
138. James D.F., Werner L., Brown J.R., Wierda W.G., Barrientos J.C., Castro J.E., 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 2014, 32:2067-2073.
139. Mato A.R., Foon K.A., Feldman T., Schuster S.J., Svoboda J., Chow K.F., et al. Reduced-dose fludarabine, cyclophosphamide, and rituximab (FCR-Lite) plus lenalidomide, followed by lenalidomide consolidation/maintenance, in previously untreated chronic lymphocytic leukemia. Am J Hematol 2015, 90:487-492.
140. Ferrajoli A., Falchi L., O'Brien S., Wierda W., Faderl S., Smith S.C., et al. Combination of ofatumumab and lenalidomide in patients with relapsed chronic lymphocytic leukemia (CLL): results of a phase II trial. ASH Annual Meeting Abstracts 2012, 720a.
141. Costa L.J., Fanning S.R., Stephenson J., Afrin L.B., Kistner-Griffin E., Bentz T.A., et al. Sequential ofatumumab and lenalidomide for the treatment of relapsed and refractory chronic lymphocytic leukemia and small lymphocytic lymphoma. Leuk Lymphoma 2015, 56:645-649.
142. Chanan-Khan A., Miller K.C., Lawrence D., Padmanabhan S., Miller A., Hernandez-Illatazurri F., et al. Tumor flare reaction associated with lenalidomide treatment in patients with chronic lymphocytic leukemia predicts clinical response. Cancer 2011, 117:2127-2135.
143. Byrd J.C., Lin T.S., Dalton J.T., Wu D., Phelps M.A., Fischer B., et al. Flavopiridol administered using a pharmacologically derived schedule is associated with marked clinical efficacy in refractory, genetically high-risk chronic lymphocytic leukemia. Blood 2007, 109:399-404.
144. Phelps M.A., Lin T.S., Johnson A.J., Hurh E., Rozewski D.M., Farley K.L., et al. Clinical response and pharmacokinetics from a phase 1 study of an active dosing schedule of flavopiridol in relapsed chronic lymphocytic leukemia. Blood 2009, 113:2637-2645.
145. Lin T.S., Ruppert A.S., Johnson A.J., Fischer B., Heerema N.A., Andritsos L.A., et al. Phase II study of flavopiridol in relapsed chronic lymphocytic leukemia demonstrating high response rates in genetically high-risk disease. J Clin Oncol 2009, 27:6012-6018.
146. Lanasa M.C., Andritsos L., Brown J.R., Gabrilove J., Caligaris-Cappio F., Ghia P., et al. Final results of EFC6663: a multicenter, international, phase 2 study of alvocidib for patients with fludarabine-refractory chronic lymphocytic leukemia. Leuk Res 2015, 39:495-500.
147. Paruch K., Dwyer M.P., Alvarez C., Brown C., Chan T.Y., Doll R.J., et al. Discovery of dinaciclib (SCH 727965): a potent and selective inhibitor of cyclin-dependent kinases. ACS Med Chem Lett 2010, 1:204-208.
148. Johnson A.J., Yeh Y.Y., Smith L.L., Wagner A.J., Hessler J., Gupta S., et al. The novel cyclin-dependent kinase inhibitor dinaciclib (SCH727965) promotes apoptosis and abrogates microenvironmental cytokine protection in chronic lymphocytic leukemia cells. Leukemia 2012, 26:2554-2557.
149. Flynn J., Jones J., Johnson A.J., Andritsos L., Maddocks K., Jaglowski S., et al. Dinaciclib is a novel cyclin-dependent kinase inhibitor with significant clinical activity in relapsed and refractory chronic lymphocytic leukemia. Leukemia 2015, 29:1524-1529.
150. Jones J.A., Geyer S., Andritsos L.A., Awan F., Flynn J.M., Maddocks K.J., et al. Dinaciclib (SCH 727965) and ofatumumab for the treatment of relapsed and refractory (R/R) chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL): results of a phase 1b/2 study. American Society of Hematology Annual Meeting 2014, 329a.
151. Goh K.C., Novotny-Diermayr V., Hart S., Ong L.C., Loh Y.K., Cheong A., et al. TG02, a novel oral multi-kinase inhibitor of CDKs, JAK2 and FLT3 with potent anti-leukemic properties. Leukemia 2012, 26:236-243.
152. Chen R., Tsai J., Chen Y., Burrows F., Wierda W., Plunkett W. Mechanism of action of the multikinase inhibitor TG02 in chronic lymphocytic leukemia. Proceedings of American Association for Cancer Research 2012, Abstract 2808. doi: 1538-7445.AM2012-2808).
153. Davila M.L., Bouhassira D.C., Park J.H., Curran K.J., Smith E.L., Pegram H.J., et al. Chimeric antigen receptors for the adoptive T cell therapy of hematologic malignancies. Int J Hematol 2014, 99:361-371.
154. Brentjens R.J., Riviere I., Park J.H., Davila M.L., Wang X., Stefanski J., et al. Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood 2011, 118:4817-4828.
155. Kalos M., Levine B.L., Porter D.L., Katz S., Grupp S.A., Bagg A., et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med 2011, 3:95ra73.
156. Porter D.L., Levine B.L., Kalos M., Bagg A., June C.H. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med 2011, 365:725-733.
157. Grupp S.A., Kalos M., Barrett D., Aplenc R., Porter D.L., Rheingold S.R., et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 2013, 368:1509-1518.
158. Mato A., Porter D.L. A drive through cellular therapy for CLL in 2015: allogeneic cell transplantation and CARs. Blood 2015, 126:478-485.
159. Porter D.L., Hwang W.T., Frey N.V., Lacey S.F., Shaw P.A., Loren A.W., et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med 2015, 7:303ra139.
160. Riches J.C., Davies J.K., McClanahan F., Fatah R., Iqbal S., Agrawal S., et al. T cells from CLL patients exhibit features of T-cell exhaustion but retain capacity for cytokine production. Blood 2013, 121:1612-1621.
161. Huergo-Zapico L., Acebes-Huerta A., Gonzalez-Rodriguez A.P., Contesti J., Gonzalez-Garcia E., Payer A.R., et al. Expansion of NK cells and reduction of NKG2D expression in chronic lymphocytic leukemia. Correlation with progressive disease. PLoS One 2014, 9.
162. Jitschin R., Braun M., Buttner M., Dettmer-Wilde K., Bricks J., Berger J., et al. CLL-cells induce IDOhi CD14 + HLA-DRlo myeloid-derived suppressor cells that inhibit T-cell responses and promote TRegs. Blood 2014, 124:750-760.
163. McClanahan F., Hanna B., Miller S., Clear A.J., Lichter P., Gribben J.G., et al. PD-L1 checkpoint blockade prevents immune dysfunction and leukemia development in a mouse model of chronic lymphocytic leukemia. Blood 2015, 126:203-211.
164. McClanahan F., Riches J.C., Miller S., Day W.P., Kotsiou E., Neuberg D., et al. Mechanisms of PD-L1/PD-1-mediated CD8 T-cell dysfunction in the context of aging-related immune defects in the emicro-TCL1 CLL mouse model. Blood 2015, 126:212-221.
165. Dubovsky J.A., Beckwith K.A., Natarajan G., Woyach J.A., Jaglowski S., Zhong Y., et al. Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes. Blood 2013, 122:2539-2549.
166. Sagiv-Barfi I., Kohrt H.E., Czerwinski D.K., Ng P.P., Chang B.Y., Levy R. Therapeutic antitumor immunity by checkpoint blockade is enhanced by ibrutinib, an inhibitor of both BTK and ITK. Proc Natl Acad Sci U S A 2015, 112:E966-E972.
167. Lapalombella R., Sun Q., Williams K., Tangeman L., Jha S., Zhong Y., et al. Selective inhibitors of nuclear export show that CRM1/XPO1 is a target in chronic lymphocytic leukemia. Blood 2012, 120:4621-4634.
168. Zhong Y., El-Gamal D., Dubovsky J.A., Beckwith K.A., Harrington B.K., Williams K.E., et al. Selinexor suppresses downstream effectors of B-cell activation, proliferation and migration in chronic lymphocytic leukemia cells. Leukemia 2014, 28:1158-1163.
169. Kuruvilla J., Gutierrez M., Shah B.D., Gabrail N.Y., de Nully B.P., Stone R.M., et al. Preliminary evidence of anti tumor activity of selinexor (KPT-330) in a phase I trial ofa first-in-class oral selective inhibitor of nuclear export (SINE) in patients (pts) with relapsed/refractory non hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL). American Society of Hematology Annual Meeting 2013, 90a.
170. Hing Z.A., Mantel R., Beckwith K.A., Guinn D., Williams E., Smith L.L., et al. Selinexor is effective in acquired resistance to ibrutinib and synergizes with ibrutinib in chronic lymphocytic leukemia. Blood 2015, 125:3128-3132.
171. Keating M.J., O'Brien S., Albitar M., Lerner S., Plunkett W., Giles F., et al. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol 2005, 23:4079-4088.
172. Tam C.S., O'Brien S., Wierda W., Kantarjian H., Wen S., Do K.A., et al. Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood 2008, 112:975-980.
173. Eichhorst B., Fink A.M., Busch R., Kovacs G., Maurer C., Lange E., et al. Frontline chemoimmunotherapy with fludarabine (F), cyclophosphamide (C), and rituximab (R) (FCR) shows superior efficacy in comparison to bendamustine (B) and rituximab (BR) in previously untreated and physically fit patients (pts) with advanced chronic lymphocytic leukemia (CLL): final analysis of an international, randomized study of the German CLL Study Group (GCLLSG) (CLL10 Study). Blood 2014, 124:19a.
174. Thompson P.A., Tam C.S., O'Brien S.M., Wierda W.G., Stingo F., Plunkett W., et al. Fludarabine, cyclophosphamide and rituximab achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood 2015, 10.1182/blood-2015-09-667675.
175. Farooqui M.Z., Valdez J., Martyr S., Aue G., Saba N., Niemann C.U., 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, 16:169-176.
176. Hallek M., Cheson B.D., Catovsky D., Caligaris-Cappio F., Dighiero G., Dohner H., 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.
177. Dreger P., Schetelig J., Andersen N., Corradini P., van Gelder M., Gribben J., et al. Managing high-risk CLL during transition to a new treatment era: stem cell transplantation or novel agents?. Blood 2014, 124:3841-3849.
178. Shanafelt T.D., Borah B.J., Finnes H.D., Chaffee K.G., Ding W., Leis J.F., et al. Impact of ibrutinib and idelalisib on the pharmaceutical cost of treating chronic lymphocytic leukemia at the individual and societal levels. J Oncol Pract 2015, 11:252-258.