Biosimilar monoclonal antibodies in lymphoma: A critical appraisal

Expert Review of Anticancer Therapy

Volumn 15, Issue 5, 2015, Pages 569-578

  Rioufol, Catherine ^a   Salles, Gilles ^a  

^a UNIVERSITÉ DE LYON   (France)

Author keywords

Biosimilar; biosimilar monoclonal antibody; lymphoma; MabThera ; non Hodgkin lymphoma; Rituxan ; rituximab

Indexed keywords

BENDAMUSTINE; BI 695500; BIOSIMILAR AGENT; CHLORAMBUCIL; CTP 10; CYCLOPHOSPHAMIDE; DOXORUBICIN; FC RECEPTOR; GP 2013; INFLIXIMAB; MK 8808; MONOCLONAL ANTIBODY; OFATUMUMAB; PF 05280586; PREDNISOLONE; RITUXIMAB; TL 011; UNCLASSIFIED DRUG; VINCRISTINE; ANTINEOPLASTIC AGENT; CD20 ANTIGEN;

ANKYLOSING SPONDYLITIS; CANCER CHEMOTHERAPY; CANCER RECURRENCE; CELL DIFFERENTIATION; CELL PROLIFERATION; CHRONIC LYMPHATIC LEUKEMIA; COMORBIDITY; CROHN DISEASE; DRUG APPROVAL; DRUG CYTOTOXICITY; DRUG EFFICACY; DRUG MEGADOSE; DRUG RECEPTOR BINDING; DRUG SAFETY; EVENT FREE SURVIVAL; FOLLICULAR LYMPHOMA; HODGKIN DISEASE; HUMAN; IMMUNOGENICITY; IN VITRO STUDY; IN VIVO STUDY; LARGE CELL LYMPHOMA; LYMPHOMA; NONHODGKIN LYMPHOMA; NONHUMAN; OPEN STUDY; OVERALL SURVIVAL; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PROGRESSION FREE SURVIVAL; PSORIASIS; PSORIATIC ARTHRITIS; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; RHEUMATOID ARTHRITIS; TREATMENT OUTCOME; TREATMENT RESPONSE; ULCERATIVE COLITIS; BIOASSAY; CLINICAL TRIAL (TOPIC); IMMUNOLOGY; PATENT; PATHOLOGY; PROCEDURES;

ANTIBODIES, MONOCLONAL; ANTIGENS, CD20; ANTINEOPLASTIC AGENTS; BIOSIMILAR PHARMACEUTICALS; CLINICAL TRIALS AS TOPIC; ENDPOINT DETERMINATION; HUMANS; LYMPHOMA; PATENTS AS TOPIC; RITUXIMAB;

EID: 84928630903     PISSN: 14737140     EISSN: 17448328     Source Type: Journal    
DOI: 10.1586/14737140.2015.1028919     Document Type: Review

References (103)

1. Baer WH, Maini A, Jacobs I. Barriers to the access and use of rituximab in patients with non-Hodgkin's lymphoma and chronic lymphocytic leukemia: A physician's survey. Pharmaceuticals (Basel) 2014;7:530-44
2. Campo E, Swerdlow SH, Harris NL, et al. The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications. Blood 2011;117: 5019-32
3. Non-Hodgkin lymphoma: what is non-Hodgkin lymphoma? American Cancer Society. Available from: www.cancer.org/ cancer/non-hodgkinlymphoma/ detailedguide/non-hodgkin-lymphoma-whatis-non-hodgkin-lymphoma [Last accessed 14 August 2014]
4. Non Hodgkin Lymphoma Incidence/ Mortality Online Analysis: GLOBOCAN 2012. Available from: http://globocan.iarc. fr/Pages/online.aspx [Last accessed 14 August 2014]
5. Nadler LM, Ritz J, Hardy R, et al. A unique cell surface antigen identifying lymphoid malignancies of B cell origin. J Clin Invest 1981;67:134-40
6. Shan D, Ledbetter JA, Press OW. Apoptosis of malignant human B cells by ligation of CD20 with monoclonal antibodies. Blood 1998;91:1644-52
7. Stashenko P, Nadler LM, Hardy R, Schlossman SF. Characterization of a human B lymphocyte-specific antigen. J Immunol 1980;125:1678-85
8. Glennie MJ, French RR, Cragg MS, Taylor RP. Mechanisms of killing by anti-CD20 monoclonal antibodies. Mol Immunol 2007;44:3823-37
9. Rituxan [package insert]. Biogen Idec, Inc. And Genentech, Inc; South San Francisco, CA: 2014
10. MabTherá summary of product characteristics. Roche Products Limited; Hertfordshire, UK: 2014
11. Oldham RK, Dillman RO. Monocloncal antibodies in cancer therapy: 25 years of progress. J Clin Oncol 2008;26:1774-7
12. 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;346:235-42
13. Marcus R, Imrie K, Belch A, et al. CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood 2005;105:1417-23
14. Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukemia: A randomised, open-label, phase 3 trial. Lancet 2010;376:1164-74
15. Salles G, Seymour JF, Offner F, et al. 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 2010;377:42-51
16. 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;106:3725-32
17. Pfreundschuh M, Trümper L, Osterborg A, et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: A randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 2006;7:379-1
18. Lim SH, Beers SA, French RR, et al. Anti-CD20 monocloncal antibodies: historical and future perspectives. Haematologica 2010;95:135-43
19. Gupta IV, Jewell RC. Ofatumumab, the first human anti-CD20 monoclonal antibody for the treatment of B cell hematologic malignancies. Ann NY Acad Sci 2012;1263:43-56
20. Wierda WG, Padmanabhan S, Chan GW, et al. Ofatumumab is active in patients with fludarabine-refractory CLL irrespective of prior rituximab: results from the phase 2 international study. Blood 2011;118:5126-9
21. Arzerrá summary of product characteristics. Glaxo Operations UK Ltd; Durham, United Kingdom: 2014
22. Illidge T, Cheadle EJ, Donaghy C, Honeychurch J. Update on obinutuzumab in the treatment of B-cell malignancies. Expert Opin Biol Ther 2014;14:1507-17
23. Gazyvaro summary of product characteristics. Roche Pharma AG, Grenzach-Wyhlen, Germany; 2014
24. Bachy E, Houot R, Morschhauser F, et al. Long-term follow up of the FL2000 study comparing CHVP-interferon to CHVP-interferon plus rituximab in follicular lymphoma. Haematologica 2013;98:1107-14
25. Herold M, Haas A, Srock S, et al. Rituximab added to first-line mitoxantrone, chlorambucil, and prednisolone chemotherapy followed by interferon maintenance prolongs survival in patients with advanced follicular lymphoma: An East German study group hematology and oncology study. J Clin Oncol 2007;25: 1986-92
26. Marcus R, Imrie K, Solal-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
27. Coiffier B, Thieblemont C, Van Den Neste E, et al. Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: A study by the Groupe d'Etudes des Lymphomes de l'Adulte. Blood 2010;116:2040-5
28. Ekstrand BC, Lucas JB, Horwitz SM, et al. Rituximab in lymphocyte-predominant Hodgkin disease: results of a phase 2 trial. Blood 2003;101:4285-9
29. Younes A, Romaguera J, Hagemeister F, et al. A pilot study of rituximab in patients with recurrent, classic Hodgkin disease. Cancer 2003;98:310-14
30. Oki Y, Pro B, Fayad LE, et al. Phase 2 study of gemcitabine in combination with rituximab in patients with recurrent or refractory Hodgkin lymphoma. Cancer 2008;112:831-6
31. Andersen NS, Pedersen LB, Laurell A, et al. Pre-emptive treatment with rituximab of molecular relapse after autologous stem cell transplantation in mantle cell lymphoma. J Clin Oncol 2009;27:4365-70
32. Barnes JA, LaCasce AS, Feng Y, et al. Evaluation of the addition of rituximab to CODOX-M/IVAC for Burkitt's lymphoma: A retrospective analysis. Ann Oncol 2011;22:1859-64
33. Dimopoulos MA, Garc?á-Sanz R, Gavriatopoulou M, et al. Primary therapy of Waldenström macroglobulinemia (WM) with weekly bortezomib, low-dose dexamethasone, and rituximab (BDR): long-term results of a phase 2 study of the European Myeloma Network (EMN). Blood 2013;122:3276-82
34. Tedeschi A, Benevolo G, Varettoni M, et al. Fludarabine plus cyclophosphamide and rituximab in Waldenstrom macroglobulinemia: An effective but myelosuppressive regimen to be offered to patients with advanced disease. Cancer 2012;118:434-43
35. Zelentz AD, Ahmed I, Braud EL, et al. NCCN biosimilars white paper: regulatory, scientific, and patient safety perspectives. J Natl Compr Canc Netw 2011;9(Suppl 4): S1-22
36. Biosimilars handbook. European Generic Medicines Association (EGA). Available from: www.egagenerics.com/index.php/ biosimilar-medicines/information-aboutbiosimilars [Last accessed 14 August 2014]
37. Guideline on similar biological medicinal products containing monoclonal antibodies non-clinical and clinical issues. London, United Kingdom: Committee for Medicinal Products for Human Use, European Medicines Agency; 2012. Available from: www.ema.europa.eu/docs/ en-GB/document-library/Presentation/ 2012/06/WC500128724.pdf. Accessed March 24th 2015
38. European Medicines Agency. European public assessment reports: biosimilars. Available from: www.ema.europa.eu/ema/ index.jsp?curl=pages%2Fmedicines% 2Flanding%2Fepar-search. jsp&mid=WC0b01ac058001d125& searchTab=searchByAuthType& alreadyLoaded=true&isNewQuery= true&status=Authorised&status= Withdrawn&status= Suspended&status=Refused& keyword=Enter+keywords&searchType= name&taxonomyPath=&treeNumber=& searchGenericType=biosimilars& genericsKeywordSearch=Submit [Last accessed 18 August 2014]
39. Generics and Biosimilars Initiative. US$54 billion worth of biosimilar patents expiring before 2020. Generics and Biosimilars Institute. GaBI Online Website. Available from: http://gabionline.net/ Biosimilars/Research/US-54-billion-worthof-biosimilar-patents-expiring-before-2020 [Last accessed 12 December 2014]
40. Müller R, Renner C, Gabay C, et al. The advent of biosimilars: challenges and risks. Swiss Med Wkly 2014;144:w13980
41. McCamish M, Woollett G. The state of the art in the development of biosimilars. Clin Pharmacol Ther 2012;91:405-17
42. Reichert JM. Next generation and biosimilar monoclonal antibodies: essential considerations towards regulatory acceptance in Europe; February 3-4, 2011, Freiburg, Germany. MAbs 2011;3(3):223-40
43. Vitolo U, Ladetto M, Boccomini C, et al. Rituximab maintenance compared with observation after brief first-line R-FND chemoimmunotherapy with rituximab consolidation in patients age older than 60 years with advanced follicular lymphoma: A phase III randomized study by the Fondazione Italiana Linfomi. J Clin Oncol 2013;31:3351-9
44. Delarue R, Tilly H, Mounier N, et al. Dose-dense rituximab-CHOP compared with standard rituximab-CHOP in elderly patients with diffuse large B-cell lymphoma (the LNH03-6B study): A randomised phase 3 trial. Lancet Oncol 2013;14:525-33
45. Cunningham D, Hawkes EA, Jack A, et al. Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: A phase 3 comparison of dose intensification with 14-day versus 21-day cycles. Lancet 2013;381:1817-26
46. Feugier P, Van Hoof A, Sebban C, et al. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: A study by the Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol 2005;23:4117-26
47. Sarkozy C, Coiffier B. Diffuse large B-cell lymphoma in the elderly: A review of potential difficulties. Clin Cancer Res 2013;19:1660-9
48. Robak T, Dmoszynska A, Solal-Céligny P, et al. Rituximab plus fludarabine and cyclophosphamide prolongs progression-free survival compared with fludarabine and cyclophosphamide alone in previously treated chronic lymphocytic leukemia. J Clin Oncol 2010;28:1756-65
49. Parikh SA, Keating MJ, O'Brien S, et al. Frontline chemoimmunotherapy with fludarabine, cyclophosphamide, alemtuzumab, and rituximab for high-risk chronic lymphocytic leukemia. Blood 2011; 118(8):2062-8
50. Böttcher S, Ritgen M, Fischer K, et al. Minimal residual disease quantification is an independent predictor of progression-free and overall survival in chronic lymphocytic leukemia: A multivariate analysis from the randomized CGLLSG CLL8 trial. J Clin Oncol 2012;30:980-8
51. Pinilla-Ibarz J, McQuary A. Chronic lymphocytic leukemia: putting new treatment options into perspective. Cancer Contr 2010;17(2 Suppl):4-15.quiz 16
52. Pazdur R. Endpoints for assessing drug activity in clinical trials. Oncologist 2008; 13(Suppl 2):19-21
53. Sargent D. General and statistical hierarchy of appropriate biologic endpoints. Oncology (Williston Park) 2006;20(6 Suppl 5):5-9
54. Lee L, Wang L, Crump M. Identification of potential surrogate end points in randomized clinical trials of aggressive and indolent non-Hodgkin's lymphoma: correlation of complete response, time-to-event and overall survival end points. Ann Oncol 2011;22:1392-403
55. Récher C, Coffier B, Haioun C, et al. Intensified chemotherapy with ACVBP plus rituximab versus standard CHOP plus rituximab for the treatment of diffuse large B-cell lymphoma (LNHO3-2B): An open-label randomised phase 3 trial. Lancet 2011;378:1858-67
56. Shitara K, Matsuo K, Muro K, et al. Correlation between overall survival and other endpoints in clinical trials of second-line chemotherapy for patients with advanced gastric cancer. Gastric Cancer 2014;17:362-70
57. Mass RD, Sarkar S, Holden SN, Hurwitz H. Clinical benefit from bevacizumab (BV) in responding (R) and non-responding (NR) patients (pts) with metastatic colorectal cancer (mCRC). J Clin Oncol 2005;23(16 Suppl):Abstract 3514
58. Cheson BD, Horning SJ, Coiffier B, et al. Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas. NCI sponsored international working group. J Clin Oncol 1999;17:1244
59. Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol 2007;25:579-86
60. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial. evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano Classification. J Clin Oncol 2014; 32(27):3059-68
61. Barrington SF, Mikhaeel NG, Kostakoglu L, et al. Role of imaging in the staging and response assessment of lymphoma: consensus of the International Conference on Malignant Lymphomas Imaging Working Group. J Clin Oncol 2014;32(27):3048-58
62. Trotman J, Luminari S, Boussetta S, et al. Prognostic value of PET-CT after first-line therapy in patients with follicular lymphoma: A pooled analysis of central scan review in three multicentre studies. Lancet Haematol 2014;1:e17-27
63. National Institutes of Health. A randomized, controlled, double-blind phase III trial to compare the efficacy, safety, and pharmacokinetics of GP2013 vs. MabTherá in patients with previously untreated advanced stage follicular lymphoma. Available from: https:// clinicaltrials.gov/ct2/show/NCT01419665 [Last accessed 12 December 2014]
64. European medicines agency's scientific guidelines on biosimilar medicines. European medicines agency. Available from: www.ema.europa.eu/ema/index.jsp? curl=pages/regulation/general/ general-content-000408.jsp&murl=menus/ regulations/regulations.jsp&mid= [Last accessed 27 August 2014]
65. Schneider CK, Kalinke U. Toward biosimilar monoclonal antibodies. Nat Biotechnol 2008;26:985-90
66. Park W, Hrycaj P, Jeka S, et al. A randomised, doubleblind, multicentre, parallel-group, prospective study comparing the pharmacokinetics, safety, and efficacy of CT-P13 and innovator infliximab in patients with ankylosing spondylitis: the PLANETAS study. Ann Rheum Dis 2013;72:1605-12
67. Yoo DH, Hrycaj P, Miranda P, et al. A randomised, double-blind, parallel-group study to demonstrate equivalence in efficacy and safety of CT-P13 compared with innovator infliximab when coadministered with methotrexate in patients with active rheumatoid arthritis: the PLANETRA study. Ann Rheum Dis 2013;72:1613-20
68. Inflectra summary of opinion (initial authorisation). London, United Kingdom: Committee for Medicinal Products for Human Use, European Medicines Agency; 2013. Available from: www.ema.europa.eu/ ema/pages/includes/document/ open-document.jsp? webContentId=WC500144831. Accessed March 24 2015
69. Inflectra assessment report. London, United Kingdom: Committee for Medicinal Products for Human Use, European Medicines Agency; 2013. Available from: www.ema.europa.eu/document-library/ EPAR-Public-assessment-report/human/ 002778/WC500151490.pdf. Accessed March 24 2015
70. Coiffier B, Haioun C, Ketterer N, et al. Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: A multicenter phase II study. Blood 1998;92:1927-32
71. Edwards JC, Cambridge G. Sustained improvement in rheumatoid arthritis following a protocol designed to deplete B lymphocytes. Rheumatology (Oxford) 2001;40:205-11
72. O'Brien SM, Kantarjian H, Thomas DA, et al. Rituximab dose-escalation trial in chronic lymphocytic leukemia. J Clin Oncol 2001;19:2165-70
73. Qureshi ZP, Magwood JS, Singh S, Bennett CL. Rituximab and biosimilars-equivalence and reciprocity. Biosimilars 2013;2013:19-25
74. Rossini AA, Greiner DL, Mordes JP. Induction of immunologic tolerance for transplantation. Physiol Rev 1999;79:99-141
75. Oflazoglu E, Audoly LP. Evolution of anti-CD20 monoclonal antibody therapeutics in oncology. MAbs 2010;2: 14-19
76. Smith P, DiLillo DJ, Bournazos S, et al. Mouse model recapitulating human Fcg structural and functional diversity. Proc Natl Acad Sci USA 2012;109:6181-6
77. Alduaiji W, Illidge TM. The future of anti-CD20 monoclonal antibodies: Are we making progress? Blood 2011;117: 2993-3001
78. 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;113:3809-12
79. Carton G, Trappe RU, Solal-Céligny P, Hallek M. Interindividual variability of response to rituximab: from biological origins to individualized therapies. Clin Cancer Res 2011;17:19-30
80. Kennedy AD, Beum PV, Solga MD, et al. Rituximab infusion promotes rapid complement depletion and acute CD20 loss in chronic lymphocytic leukemia. J Immunol 2004;172:3280-8
81. Cragg MS, Morgan SM, Chan HT, et al. Complement-mediated lysis by anti-CD20 mAb correlates with segregation into lipid rafts. Blood 2003;101:1045-52
82. Chan HT, Hughes D, French RR, et al. CD20-induced lymphoma cell death is independent of both capsases and its redistribution into Triton X-100 insoluble membrane rafts. Cancer Res 2003;63: 5480-9
83. Honeychurch J, Alduaij W, Azizyan M, et al. Antibody-induced nonapoptotic cell death in human lymphoma and leukemia cells is mediated through a novel reactive oxygen species-dependent pathway. Blood 2012;119:3523-33
84. Niederfellner G, Lammens A, Mundigl O, et al. Epitope characterization and crystal structure of GA101 provide insights into the molecular basis for type I/II distinction of CD20 antibodies. Blood 2011;118: 358-67
85. Declerck PJ. Biosimilar monocloncal antibodies: A science-based regulatory challenge. Expert Opin Bio Ther 2013;13: 153-6
86. Shinkawa T, Nakamura K, Yamane K, et al. The absence of fucose but not the presence of galactose or bisecting N-acetylglucosamine of Human IgG1 complex-type oligosaccharides shows the critical role of enhancing antibody-dependent cellular cytotoxicity. J Biol Chem 2003;278:3466-73
87. Alduaij W, Ivanov A, Honeychurch J, et al. Novel type II anti-CD20 monocloncal antibody (GA101) evokes homotypic adhesion and actin-depedent, lysosome-mediated cell death in B-cell malignancies. Blood 2011;117:4519-29
88. 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
89. Schiestel M, Stangler T, Torella C, et al. Acceptable changes in quality attributes of glycosylated biopharmaceuticals. Nat Biotechnol 2011;29(4):310-12
90. Roche gains EU approval of subcutaneous MabThera. Biosimilar news website. Available from: www.biosimilarnews.com/ roche-gains-eu-approval-of-subcutaneous-mabthera [Last accessed 12 December 2014 2014]
91. Danese S, Gomollon F; on behalf of the Governing Board and Operational Board of ECCO. ECCO position statement: The use of biosimilar medicines in the treatment of inflammatory bowel disease (IBD). J Crohns Colitis 2013;7:586-9
92. ABPI position on biosimilar medicines. London, United Kingdom: The Association of the British Pharmaceuticals Industry; 2013. Available from: http://www.abpi.org. uk/media-centre/newsreleases/2014/Pages/ 140514b.aspx. Accessed March 24 2015
93. National Institutes of Health. Phase I trial to assess the safety and pharmacokinetics of GP2013 Monotherapy administered weekly in Japanese patients with CD20 positive low tumor burden indolent b-cell non-Hodgkin's lymphoma. Clinicaltrials.gov Website. Available from: https:// clinicaltrials.gov/ct2/show/NCT01933516 [Last accessed 12 December 2014]
94. National Institutes of Health. A phase 1/3, randomised, parallel-group, active-controlled, double-blind study to demonstrate equivalence of pharmacokinetics and noninferiority of efficacy for CT-P10 in comparison with Rituxan, each administered in combination with cyclophosphamide, vincristine, and prednisone (CVP) in patients with advanced follicular lymphoma. Available from: https://clinicaltrials.gov/ct2/show/ NCT02162771 [Last accessed 12 December 2014]
95. National Institutes of Health. An open-label, single arm study of MK-8808 in patients with advanced CD20-positive follicular lymphoma. Available from: https://clinicaltrials.gov/ct2/show/ NCT01370694 [Last accessed 12 December 2014]
96. National Institutes of Health. A phase Ib, double blind RCT to evaluate and compare the PK, PD and safety of MabTherá With TL011, in combination with CHOP, in subjects with CD20+ DLBCL. Available from: https://clinicaltrials.gov/ct2/show/ NCT01205737 [Last accessed 12 December 2014]
97. National Institutes of Health. A phase 3, randomized, double-blind study of Pf-05280586 versus rituximab for the first-line treatment of patients with Cd20-positive, low tumor burden, follicular lymphoma. Available from: https:// clinicaltrials.gov/ct2/show/NCT02213263 [Last accessed 12 December 2014]
98. National Institutes of Health. A randomized, double-blind, parallel-arm, phase I study to evaluate the pharmacokinetics and pharmacodynamics of BI 695500 vs. rituximab (MabThera) induction immunotherapy as a first-line treatment in patients with low tumor burden follicular lymphoma. Clinicaltrials. gov Website. Available from: https:// clinicaltrials.gov/ct2/show/NCT01950273 [Last accessed 12 December 2014]
99. MacDonald G. Samsung halts biosimilar rituximab trial on regulatory concerns. BioPharma reporter website. 2014. Available from: www.biopharma-reporter.com/Bio-Developments/Samsung-halts-biosimilarrituximab-trial-on-regulatory-concerns [Last accessed 12 December 2014]
100. National Institutes of Health. A phase 1, multicenter, open-label, single-arm study to evaluate the initial safety, pharmacokinetics, pharmacodynamics, and efficacy of CT-P10 given in combination with dexamethasone, cytosine arabinoside, and cisplatin (DHAP) in patients with diffuse large b-cell lymphoma as second-line chemotherapy. Available from: https:// clinicaltrials.gov/ct2/show/NCT01534949 [Last accessed 12 December 2014]
101. Generics and Biosimilars Initiative. Teva halts phase III biosimilar rituxuimab trial. GaBI Online Website. Available from: http://gabionline.net/Biosimilars/News/Tevahalts-phase-III-biosimilar-rituximab-trial [Last accessed 12 December 2014]
102. Maloney DG. Anti-CD20 antibody therapy for B-cell lymphomas. N Engl J Med 2012;366:2008-16
103. Bachy E, Salles G. Are we nearing an era of chemotherapy-free management of indolent lymphoma? Clin Cancer Res 2014;20: 5226-39