Update on obinutuzumab in the treatment of B-cell malignancies

Expert Opinion on Biological Therapy

Volumn 14, Issue 10, 2014, Pages 1507-1517

  Illidge, Tim ^a   Cheadle, Eleanor J ^a   Donaghy, Claire ^a   Honeychurch, Jamie ^a  

^a UNIVERSITY OF MANCHESTER   (United Kingdom)

Author keywords

Antibody; CD20; Chronic lymphocytic leukemia; Glycoengineering; Non Hodgkin lymphoma; Obinutuzumab

Indexed keywords

CD20 ANTIBODY; CD20 ANTIGEN; CHLORAMBUCIL; FUCOSE; IMMUNOGLOBULIN G; OBINUTUZUMAB; OFATUMUMAB; OLIGOSACCHARIDE; RITUXIMAB; TETRAMER; ANTINEOPLASTIC AGENT; MONOCLONAL ANTIBODY;

ANTIBODY DEPENDENT CELLULAR CYTOTOXICITY; ANTIBODY DEPENDENT CELLULAR PHAGOCYTOSIS; APOPTOSIS; ARTICLE; B-CELL LYMPHOMA CELL LINE; CANCER PROGNOSIS; CANCER SURVIVAL; CARBOHYDRATE ANALYSIS; CD8+ T LYMPHOCYTE; CELL DEATH; CELL MEDIATED CYTOTOXICITY; CELL SURFACE; CHRONIC LYMPHATIC LEUKEMIA; COMPLEMENT DEPENDENT CYTOTOXICITY; COMPLEMENT DEPOSITION; DRUG EFFICACY; EFFECTOR CELL; FOLLICULAR LYMPHOMA; GLYCOSYLATION; HUMAN; HUMORAL IMMUNE DEFICIENCY; IMMUNOGENICITY; INTERNALIZATION; LARGE CELL LYMPHOMA; LEUKEMIA REMISSION; MANTLE CELL LYMPHOMA; NONHODGKIN LYMPHOMA; NONHUMAN; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PROGRESSION FREE SURVIVAL; TREATMENT RESPONSE; TUMOR VOLUME; LEUKEMIA, LYMPHOCYTIC, CHRONIC, B-CELL; LYMPHOMA, NON-HODGKIN; TREATMENT OUTCOME;

ANTIBODIES, MONOCLONAL, HUMANIZED; ANTINEOPLASTIC AGENTS; HUMANS; LEUKEMIA, LYMPHOCYTIC, CHRONIC, B-CELL; LYMPHOMA, NON-HODGKIN; TREATMENT OUTCOME;

EID: 84907046929     PISSN: 14712598     EISSN: 17447682     Source Type: Journal    
DOI: 10.1517/14712598.2014.948414     Document Type: Article

References (97)

1. Facts Spring 2014. 2014. Available from: http://www.lls.org/content/nationalcontent/resourcecenter/freeeducationmaterials/generalcancer/pdf/facts.pdf [cited 2014]
2. Salles G, Seymour JF, Offner F. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet 2011;377(9759):42-51
3. van Oers MH, Van Glabbeke M, Giurgea L, et al. Rituximab maintenance treatment of relaps ed/resistant follicular non-hodgkin's lymphoma: long-term outcome of the EORTC 20981 Phase III randomized intergroup study. J Clin Oncol 2010;28(17):2853-8
4. Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet 2010;376(9747):1164-74
5. Marcus R, Imrie K, So lal-Celigny P, et al. Phase III study of R-CVP compared with cyclophosphamide, vincristine, and prednisone alone in patients with previously untreated advanced follicular lymphoma. J Clin Oncol 2008;26(28):4579-86
6. Hiddemann W, Kneba M, Dreyling M, et al. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 2005;106(12):3725-32
7. Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 2002;346(4):235-42
8. Pfreundschuh M, Kuhnt E, Trumper L, et al. CHOP-like chemotherapy with or without rituximab in young patients with good-prognosis diffuse large-B-cell lymphoma: 6-year results of an openlabel randomised study of the MabThera International Trial (MInT) Group. Lancet Oncol 2011;12(11):1013-22
9. Maloney DG. Immunotherapy for non-Hodgkin's lymphoma: monoclonal antibodies and vaccines. J Clin Oncol 2005;23(26):6421-8
10. Cartron G, Trappe RU, Solal-Celigny P, Hallek M. Interindividual variability of response to rituximab: from biological origins to individualized therapies. Clin Cancer Res 2011;17(1):19-30
11. Lim SH,Beers S.A.,French RR,et al., Anti-CD20 monoclonal antibodies: historical and future perspectives, Haematologica, 2010, 95, 1, 135-43.
12. Deans JP, Li H, Polyak MJ. CD20-mediated apoptosis: signalling through lipid rafts. Immunology 2002;107(2):176-82
13. Polyak MJ, Tailor SH, Deans JP. Identification of a cytoplasmic region of CD20 required for its redistribution to a d etergent-insoluble membrane compartment. J Immunol 1998;161(7):3242-8
14. Cragg MS, Morgan SM, Chan HT, et al. Complement-mediated lysis by anti-CD20 mAb correlates with segregation into lipid rafts. Blood 2003;101(3):1045-52
15. Chan HT, Hughes D, French RR, et al. CD20-induced lymphoma cell death is independent of both caspases and its redistribution into triton X-100 insolub le membrane rafts. Cancer Res 2003;63(17):5480-9
16. Cragg MS, Glennie MJ. Antibody specificity controls in vivo effector mechanisms of anti-CD20 reagents. Blood 2004;103(7):2738-43
17. Forero-Torres A, de Vos S, Pohlman BL, 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(5):1395-403
18. Tobinai K, Ogura M, Kobayashi Y, et al. Phase I study of LY2469298, an Fcengineered humanized anti-CD20 antibody, in patients with rela psed or refractory follicular lymphoma. Cancer Sci 2011;102(2):432-8
19. Teeling JL, Mackus WJ, Wiegman LJ, et al. The biological activity of human CD20 monoclonal antibodies is linked to unique epit opes on CD20. J Immunol 2006;177(1):362-71
20. Hollander N. Immunotherapy for B-cell lymphoma: current status and prospective advances. Front Immunol 2012;3:3
21. . Goldenberg DM, Rossi EA, Stein R, et al. Properties and structure-function relationships of veltuzumab (hA20), a humanized anti-CD20 monoclonal antibody. Blood 2009;113(5):1062-70
22. Le Garff-Tavernier M, Herbi L, de Romeuf C, et al. Antibody-dependent cellular cytotoxicity of the optimized anti-CD20 monoclonal antibody ublituximab on chronic lymphocytic leukemia cells with the 17p deletion. Leukemia 2014;28(1):230-3
23. Cheney CM, Stephens DM, Mo X, et al. Ocaratuzumab, an Fc-engineered antibody demonstrates enhanced antibody-dependent cell-mediated cytotoxicity in chronic lymphocytic leukemia. Mabs 2014;6(3):749-55
24. Ivanov A, Beers SA, Walshe CA, et al. Monoclonal antibodies directed to CD20 and HLA-DR can elicit homotypic adhesion followed by lysosome-mediated cell death in human lymphoma and leukemia cells. J Clin Invest 2009;119(8):2143-59
25. Mossne r E, Brunker P, Moser S, et al. Increasing the efficacy of CD20 antibody therapy through the engineering of a new type II anti-CD20 antibody with enhanced direct and immune effector cell-mediated B-cell cytotoxicity. Blood 2010;115(2 2):4393-402 . First preclinical report detailing enhanced antibody effector mechanisms of obinutuzumab
26. Robak T, Robak E. New anti-CD20 monoclonal antibodies for the treatment of B-cell lymphoid malignancies. BioDrugs 2011;25(1):13-25
27. Bowles JA, Wang SY, Link BK, et al. Anti-CD20 monoclonal antibody with enhanced affinity for CD16 activa tes NK cells at lower concentrations and more effectively than rituximab. Blood 2006;108(8):2648-54
28. Breitmeyer J, Campbell MA, Allan B, et al. AME-133: a next-generation Anti-CD20 engineered for enhanced killer function. J Immunother 2004;27(6):S52-2
29. Herter S, Herting F, Mundigl O, et al. Preclinical activity of the type II CD20 antibody GA101 (obinutuzumab) compared with rituxim ab and ofatumumab in vitro and in xenograft models. Mol Cancer Ther 2013;12(10):2031-42
30. Niederfellner G, Lammens A, Mundigl O, et al. Epitope characterization and crystal structure of GA101 provide in sights into the molecular basis for type I/II distinction of CD20 antibodies. Blood 2011;118(2):358-67
31. Klein C, Lammens A, Schafer W, et al. Epitope interactions of monoclonal antibodies targeting CD20 and their relationship to functional properties. Mabs 2013;5(1):22-33
32. Cartron G,Dacheux L,Salles G,et al, Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor Fc gamma RIIIa gene, Blood, 2002, 99, 3, 754-8.
33. Persky DO, Dornan D, Goldman BH, et al. Fc gamma receptor 3a genotype predicts overall survival in follicular lymphoma patients tre ated on SWOG trials with combined monoclonal antibody plus chemotherapy but not chemotherapy alone. Haematologica 2012;97(6):937-42
34. Zhang W, Wang X, Li J, et al. Fc gamma receptor IIIA polymorphi sms and efficacy of rituximab therapy on Chinese diffuse large B-cell lymphoma. Chin Med J(Engl) 2010;123(2):198-202
35. Kim DH, Du Jung H, Kim JG, et al. FCGR3A gene polymorphisms may correlate with response to frontline RCHOP therapy for diffuse large B-cell lymphoma. Blood 2006;108(8):2720-5
36. Ahlgrimm M, Pfreundschuh M, Kreuz M, et al. The impact of Fc-gamma receptor polymorphisms in elderly patients with diffuse large B-cell lymphoma treated with CHOP with or without rituximab. Blood 2011;118(17):4657-62
37. Varoczy L, Zilahi E, Gyetvai A, et al. Fc-gamma-receptor IIIa polymorphi sm and gene expression profile do not predict the prognosis in diffuse large B-cell lymphoma treated with R-CHOP protocol. Pathol Oncol Res 2012;18(1):43-8
38. Prochazka V, Papajik T, Gazdo va J, et al. Fc gamma RIIIA receptor genotype does not influence an outcome in patients with follicular lymphoma treated with risk-adapted immunochemotherapy. Neoplasma 2011;58(3):263-70
39. Carlotti E, Salmo iraghi S, Palumbo GA, et al. Fc alpha RIIIA and Fc Gamma RIIA polymorphisms do not predict the clinical outcome of follicular non Hodgkin's lymphoma patients treated with sequential CHOP and Rituximab. Haematologica 2007;92:49-9
40. Mitrovic Z, Aurer I, Radman I, et al. FC gamma RIIIA and FC gamma RIIA polymorphisms are not associated with response to rituximab and CHOP in patients with diffuse large B-cell lymphorna. Haematologi ca 2007;92(7):998-9
41. Fabisiewicz A, Paszkiewicz-Kozik E, Osowiecki M, et al. Fc gamma RIIA and Fc gamma RIIIA polymorphisms do not influence survival and response to rituximab, cyclophosphamide, do xorubicin, vincristine, and prednisone immunochemotherapy in patients with diffuse large B-cell lymphoma. Leuk Lymphoma 2011;52(8):1604-6
42. Dornan D, Spleiss O, Yeh RF, et al. Effect of FCGR2A and FCGR3A variants on CLL outcome. Blood 2010;116(20):4212-22
43. Farag SS, Flinn IW, Modali R, et al. Fc gamma RIIIa and Fc-gamma RIIa polymorphisms do not predict response to rituximab in B-cell chronic ly mphocytic leukemia. Blood 2004;103(4):1472-4
44. Jaglowski SM, Alinari L, Lapalombella R, et al. The clinical application of monoclonal antibodies in chronic lymphocytic leukemia. Blood 2010;116(19):3705-14
45. Jefferis R. Glycosylation as a strategy to improve antibody-based therapeutics. Nat Rev Drug Discov 2009;8(3):226-34
46. Ferrara C, Grau S, Jager C, et al. Unique carbohydrate-carbohydrate interactions are required for high affinity binding between FcgammaRIII and antibodies lacking core fucose. Proc Natl Acad Sci USA 2011;108(31):12669-74
47. Ferr ara C, Stuart F, Sondermann P, et al. The carbohydrate at FcgammaRIIIa Asn-162. An element required for high affinity binding to non-fucosylated IgG glycoforms. J Biol Chem 2006;281(8):5032-6
48. . Shibata-Koyama M, Iida S, Okazaki A, et al. The N-linked oligosaccharide at Fc gamma RIIIa Asn-45: an inhibitory element for high Fc gamma RIIIa binding affinity to IgG glycoforms lacking core fucosylation. Glycobiology 200 9;19(2):126-34
49. Mizushima T, Yagi H, Takemoto E, et al. Structural basis for improved efficacy of therapeutic antibodies on defucosylation of their Fc glycans. Genes Cells 2011;16(11):1071-80
50. Umana P, Moessner E, Bruenker P, et al. Novel 3(rd) generation humanized type IICD20 antibody with glycoengineered fc and modified elbow hinge for enhanced ADCC and superior apoptosis induction. Blood 2006;108(11):72a-a
51. Kern DJ, James BR, Blackwell S, et al. GA101 induces NK-cell activation and antibody-dependent cellular cytotoxicity more effectively than rituximab when complement is present. Le uk Lymphoma 2013;54(11):2500-5
52. Patz M, Isaeva P, Forcob N, et al. Comparison of the in vitro effects of the anti-CD20 antibodies rituximab and GA101 on chronic lymphocytic leukaemia cells. Br J Haematol 2011;152(3):295-306
53. Bologna L,Gotti E,Manganini M,et al, Mechanism of action of type II, glycoengineered, anti-CD20 monoclonal antibody GA101 in B-chronic lymphocytic leukemia whole blood assays in comparison with rituximab and alemtuzumab, J Immunol, 2011, 186, 6, 3762-9.
54. Golay J, Da Roit F , Bologna L, et al. Glycoengineered CD20 antibody obinutuzumab activates neutrophils and mediates phagocytosis through CD16B more efficiently than rituximab. Blood 2013;122(20):3482-91
55. Herter S, Birk MC, Klein C, et al. Glycoengineering of therapeutic antibodies enhances monocyte/macrophage-mediated phagocytosis and cytotoxicity. J Immunol 2014;192(5):2252-60
56. Dalle S, Reslan L, Bess eyre de Horts T, 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(1):178-85
57. Alduaij W, Ivanov A, Hone ychurch J, et al. Novel type II anti-CD20 monoclonal antibody (GA101) evokes homotypic adhesion and actindependent, lysosome-mediated cell death in B-cell malignancies. Blood 2011;117(17):4519-29
58. Jak M, v an Bochove GG, Reits EA, et al. CD40 stimulation sensitizes CLL cells to lysosomal cell death induction by type II anti-CD20 mAb GA101. Blood 2011;118(19):5178-88
59. Alduaij W, Illidge TM. The futur e of anti-CD20 monoclonal antibodies: are we making progress? Blood 2011;117(11):2993-3001
60. Honeychurch J, Alduaij W, Azizyan M, et al. Antibody-induced nonapoptotic cell death in human lymphoma and le ukemia cells is mediated through a novel reactive oxygen species-dependent pathway. Blood 2012;119(15):3523-33
61. Glennie MJ, French RR, Cragg MS, Taylor RP. Mechanisms of killing by anti-CD20 monoclonal antibodies. Mol Immunol 2007;44(16):3823-37
62. Beurskens FJ, Lindorfer MA, Farooqui M, et al. Exhaustion of cytotoxic effector systems may limit monoclonal antibody-based immunotherap y in cancer patients. J Immunol 2012;188(7):3532-41
63. Hiraga J, Tomita A, Sugimoto T, et al. Down-regulation of CD20 expression in B-cell lymphoma cells after treatment with rituximab-containi ng combination chemotherapies: its prevalence and clinical significance. Blood 2009;113(20):4885-93
64. Small GW, McLeod HL, Richards KL. Analysis of innate and acquired resistance to anti-CD20 antibodies in malignant and nonmalignant B cells. PeerJ 2013;1:e31
65. Mishima Y, Terui Y, Takeuchi K, et al. The identification of irreversible rituximab-resistant lymphoma caused by CD20 gene mutations. Blood Cancer J 2011;1(4):e15
66. Beers SA, French RR, Chan HT, et al. Antigenic modulation limits the efficacy of anti-CD20 antibodies: implications for antibody selection. Blood 2010;115(25):5191-201
67. Beum PV, Peek EM, Lindorfer MA, et al. Loss of CD20 and bound CD20 antibody from opsonized B cells occurs more rapidly because of trogocytosis mediated by Fc receptorexpressing effector cells than direct internalization by the B cells. J Immunol 2011;187(6):3438-47
68. Awan FT, Kay NE, Davis ME, et al. Mcl-1 expression predicts progressionfree survival in chronic lymphocytic leukemia patients treated with pentostatin, cyclophosphamide, and r ituximab. Blood 2009;113(3):535-7
69. Winter JN, Weller EA, Horning SJ, et al. Prognostic significance of Bcl-6 protein expression in DLBCL treated with CHOP or R-CHOP: a prospective correla tive study. Blood 2006;107(11):4207-13
70. Cheadle EJ, Sidon L, Dovedi SJ, et al. The induction of immunogenic cell death by type II anti-CD20 monoclonal antibodies has mechanistic differenc es compared with type I rituximab. Br J Haematol 2013;162(6):842-5
71. Kroemer G, Galluzzi L, Kepp O, Zitvogel L. Immunogenic cell death in cancer therapy. Annu Rev Immunol 2013;31:51-72
72. Hilchey SP, Hyrien O, Mosmann TR, et al. Rituximab immunotherapy results in the induction of a lymphoma idiotype-specific T-cell response in patients with follicular lymphoma: support for a "vaccinal effect " of rituximab. Blood 2009;113(16):3809-12
73. Cartron G, Watier H, Golay J, Solal-Celigny P. From the bench to the bedside: ways to improve rituximab efficacy. Blood 2004;104(9):2635-42
74. Abes R,Gelize E,Fridman WH,Teillaud JL., Long-lasting antitumor protection by anti-CD20 antibody through cellular immune response, Blood, 2010, 116, 6, 926-34.
75. Abes R, Gelize E, Fridman WH, Teillaud JL. Long-lasting antitumor protection by anti-CD20 antibody through cellular immune response. Blood 2010;116(6):926-34 75. Nimmerjahn F, Ravetch JV. Fcgamma receptors as regulators of immune responses. Nat Rev Immunol 2008;8(1):34-47
76. Shields RL, Lai J, Keck R, et al. Lack of f ucose on human IgG1 N-linked oligosaccharide improves binding to human Fcgamma RIII and antibodydependent cellular toxicity. J Biol Chem 2002;277(30):26733-40
77. Herting F, Friess T, Bader S, et al. Enhanced anti-tumor activity of the glycoengineered type II CD20 antibody obinutuzumab (GA101) in combination with chemotherapy in xenograft models of human lymphoma. Leuk Lymphoma 2014;Epub ahead of print
78. Niederfellner G, Mundigl O, Lifke A, et al. The Type Ii Cd20 antibody Ga101 differs from the type I Cd20 antibody rituximab in inducing differential gene expression profiles and by binding separate and functionally distinct Cd20 complexes on B cell ly mphoma cell lines. Ann Oncol 2011;22:241-1
79. Salles G, Morschhauser F, Lamy T, et al. Phase 1 study results of the type II glycoengineered humanized anti-CD20 monoclonal antibody obinutuzumab (GA101 ) in B-cell lymphoma patients. Blood 2012;119(22):5126-32
80. Sehn LH, Assouline SE, Stewart DA, et al. A phase 1 study of obinutuzumab induction followed by 2 years of maintenance in patients with relapsed CD20-positive B-cell malignancies. Blood 2012;119(22):5118-25.
81. Morschhauser F, Cartron G, Lamy T, et al. Phase I study of RO5072759 (GA101) in relapsed/refractory chronic lymphocytic leukemia. Blood 2009;114(22):364-4
82. Cart ron G, Morshhauser F, Thieblemont C. Results from a phase II study of obinutuzumab (GA101) monotherapy in relapsed/refractory chronic lymphocytic leukemia (CLL). Haematologica 2011;96:39
83. Muller C, Murawski N, Wiesen MH, et al. The role of sex and weight on rituximab clearance and serum elimination half-life in elderly patients with DLBCL. Blood 2012;119(14):3276-84
84. Davis TA, White CA, Grillo-Lopez AJ, et al. Single-agent monoclonal antibody efficacy in bulky non-Hodgkin's lymphoma: results of a phase II trial of rituximab. J Clin Oncol 1999;17(6):1851-7
85. Berinstein NL, G rillo-Lopez AJ, White CA, et al. Association of serum Rituximab (IDEC-C2B8) concentration and anti-tumor response in the treatment of recurrent low-grade or follicular non-Hodgkin's lymphoma. Ann Oncol 1998;9(9):995- 1001
86. Illidge TM, Bayne M, Brown NS, et al. Phase 1/2 study of fractionated (131)Irituximab in low-grade B-cell lymphoma: the effect of prior rituximab dosing and tumor burden on subsequent radioimmunotherapy. Blood 2009;113(7):1412-21
87. Salles GA, Morschhauser F, Solal-Celigny P, et al. Obinutuzumab (GA101) in patients with relapsed/refractory indolent non-Hodgkin lymphoma: results from the phase II GA UGUIN study. J Clin Oncol 2013;31(23):2920-6
88. Morschhauser FA, Cartron G, Thieblemont C, et al. Obinutuzumab (GA101) monotherapy in relapsed/refractory diffuse large b-cell lymphoma or mantl e-cell lymphoma: results from the phase II GAUGUIN study. J Clin Oncol 2013;31(23):2912-19
89. Coiffier B, Haioun C, Ketterer N, et al. Rituximab (anti-CD20 monoclonal antibody) for the treatmen t of patients with relapsing or refractory aggressive lymphoma: a multicenter phase II study. Blood 1998;92(6):1927-32
90. Foran JM, Rohatiner AZ, Cunningham D, et al. European phase II stud y of rituximab (chimeric anti-CD20 monoclonal antibody) for patients with newly diagnosed mantle-cell lymphoma and previously treated mantle-cell lymphoma, immunocytoma, and small B-cell lymphocytic lymphoma. J Clin Oncol 2000;18(2):317-24
91. Sehn L, Goy A, Offner F, et al. Randomized phase II trial comparing GA101 (obinutuzumab) with rituximab in patients with relapsed CD20+ indolent B-cell non-Hodgkin lymphoma: preliminary analysis of the GAUSS study. Blood 2011;118:abstract 269
92. Radford J, Davies A, Cartron G, et al. Obinutuzumab (GA101) plus CHOP or FC in relapsed/refractory follicular lymphoma: results of the GAUDI study (BO2100 0). Blood 2013;122(7):1137-43
93. Eichhorst BF, Busch R, Stilgenbauer S, et al. First-line therapy with fludarabine compared with chlorambucil does not result in a major benefit for elderly patients with advanced chronic lymphocytic leukemia. Blood 2009;114(16):3382-91
94. Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med 2014;370(12):1101-10
95. Chang CH, Rossi EA, Goldenberg DM. Monoclonal antibodies targeting CD20. Mabs 2013;5(3):335-6
96. Hillmen P,Robak T,Janssens A,et al, Ofatumumab + chlorambucil versis chlorambucil alone in patients with untreated chr onic lymphocytic leukaemia (CLL), results of the Phase III study complement 1 (OMB110911). Blood, 2013, 122,(21):abstract 528.
97. Hallek M. Signaling the end of chronic lymphocytic leukemia: new frontline treatment strategies. Blood 2013;122(23):3723-34