Preventing or Eradicating Factor VIII Antibody Formation in Patients with Hemophilia A: What Can We Learn from Other Disorders?

Abstract

Eradication of factor VIII (FVIII) specific neutralizing antibodies (also known as inhibitors) by the traditional method of immune tolerance induction (ITI) is costly and unsuccessful in one out of three patients. Furthermore, effective inhibitor prevention strategies are presently lacking. An overview is given in this narrative review of antidrug antibody prevention or eradication strategies that have been used in disorders beyond hemophilia A, with the aim of analyzing what we can learn from these strategies for hemophilia A. Prevention of antidrug antibody formation using rituximab, methotrexate, and intravenous immunoglobulins in patients with Pompe's disease seems effective but carries a high risk of adverse events. Based on studies in patients with rheumatoid arthritis and inflammatory bowel disease, it seems likely that treatment with methotrexate alone would also be able to prevent inhibitor formation in hemophilia A patients. Besides side effects, it is unclear whether immune tolerance to FVIII would persist after cessation of immunomodulatory therapy with methotrexate. A combination of cyclophosphamide and corticosteroids, used to treat antibody-mediated pure red cell aplasia, could be further investigated to eradicate inhibitors in hemophilia A patients who are refractory to ITI. In summary, insights gained from research on antidrug antibody formation in other diseases could be helpful in devising alternative treatment strategies for inhibitor development.

Keywords

inhibitor formation - immunomodulation - antidrug antibodies

• References

• 1 Peyvandi F, Garagiola I, Young G. The past and future of haemophilia: diagnosis, treatments, and its complications. Lancet 2016; 388 (10040): 187-197
• 2 Gouw SC, van der Bom JG, Ljung R. , et al; PedNet and RODIN Study Group. Factor VIII products and inhibitor development in severe hemophilia A. N Engl J Med 2013; 368 (03) 231-239
• 3 Gouw SC, van den Berg HM, Fischer K. , et al; PedNet and Research of Determinants of INhibitor development (RODIN) Study Group. Intensity of factor VIII treatment and inhibitor development in children with severe hemophilia A: the RODIN study. Blood 2013; 121 (20) 4046-4055
• 4 Peyvandi F, Mannucci PM, Garagiola I. , et al. A randomized trial of factor VIII and neutralizing antibodies in hemophilia A. N Engl J Med 2016; 374 (21) 2054-2064
• 5 Iorio A, Halimeh S, Holzhauer S. , et al. Rate of inhibitor development in previously untreated hemophilia A patients treated with plasma-derived or recombinant factor VIII concentrates: a systematic review. J Thromb Haemost 2010; 8 (06) 1256-1265
• 6 Fischer K, Lassila R, Peyvandi F. , et al; EUHASS participants. Inhibitor development in haemophilia according to concentrate. Four-year results from the European HAemophilia Safety Surveillance (EUHASS) project. Thromb Haemost 2015; 113 (05) 968-975
• 7 Rocino A, Franchini M, Coppola A. Treatment and prevention of bleeds in haemophilia patients with inhibitors to factor VIII/IX. J Clin Med 2017; 6 (04) 46
• 8 Collins PW, Chalmers E, Hart DP. , et al; UK Haemophilia Centre Doctors. Diagnosis and treatment of factor VIII and IX inhibitors in congenital haemophilia: (4th edition). Br J Haematol 2013; 160 (02) 153-170
• 9 Brackmann HH, Lenk H, Scharrer I, Auerswald G, Kreuz W. German recommendations for immune tolerance therapy in type A haemophiliacs with antibodies. Haemophilia 1999; 5 (03) 203-206
• 10 Mauser-Bunschoten EP, Nieuwenhuis HK, Roosendaal G, van den Berg HM. Low-dose immune tolerance induction in hemophilia A patients with inhibitors. Blood 1995; 86 (03) 983-988
• 11 Ettingshausen CE, Kreuz W. The immune tolerance induction (ITI) dose debate: does the International ITI Study provide a clearer picture?. Haemophilia 2013; 19 (Suppl. 01) 12-17
• 12 Hay CR, DiMichele DM. ; International Immune Tolerance Study. The principal results of the International Immune Tolerance Study: a randomized dose comparison. Blood 2012; 119 (06) 1335-1344
• 13 DiMichele DM, Kroner BL. ; North American Immune Tolerance Study Group. The North American Immune Tolerance Registry: practices, outcomes, outcome predictors. Thromb Haemost 2002; 87 (01) 52-57
• 14 Coppola A, Margaglione M, Santagostino E. , et al; AICE PROFIT Study Group. Factor VIII gene (F8) mutations as predictors of outcome in immune tolerance induction of hemophilia A patients with high-responding inhibitors. J Thromb Haemost 2009; 7 (11) 1809-1815
• 15 Mariani G, Kroner B. ; Immune Tolerance Study Group (ITSG). Immune tolerance in hemophilia with factor VIII inhibitors: predictors of success. Haematologica 2001; 86 (11) 1186-1193
• 16 Morfini M, Haya S, Tagariello G. , et al. European study on orthopaedic status of haemophilia patients with inhibitors. Haemophilia 2007; 13 (05) 606-612
• 17 Walsh CE, Soucie JM, Miller CH. ; United States Hemophilia Treatment Center Network. Impact of inhibitors on hemophilia A mortality in the United States. Am J Hematol 2015; 90 (05) 400-405
• 18 van Velzen AS, Eckhardt CL, Hart DP. , et al; INSIGHT study group. Inhibitors in nonsevere haemophilia A: outcome and eradication strategies. Thromb Haemost 2015; 114 (01) 46-55
• 19 Krishna M, Nadler SG. Immunogenicity to biotherapeutics - the role of anti-drug immune complexes. Front Immunol 2016; 7: 21
• 20 Vincent FB, Morand EF, Murphy K, Mackay F, Mariette X, Marcelli C. Antidrug antibodies (ADAb) to tumour necrosis factor (TNF)-specific neutralising agents in chronic inflammatory diseases: a real issue, a clinical perspective. Ann Rheum Dis 2013; 72 (02) 165-178
• 21 Macdougall IC, Casadevall N, Locatelli F. , et al; PRIMS study group. Incidence of erythropoietin antibody-mediated pure red cell aplasia: the Prospective Immunogenicity Surveillance Registry (PRIMS). Nephrol Dial Transplant 2015; 30 (03) 451-460
• 22 Sorensen PS. Neutralizing antibodies against interferon-Beta. Ther Adv Neurol Disorder 2008; 1 (02) 125-141
• 23 van Gelder CM, Hoogeveen-Westerveld M, Kroos MA, Plug I, van der Ploeg AT, Reuser AJ. Enzyme therapy and immune response in relation to CRIM status: the Dutch experience in classic infantile Pompe disease. J Inherit Metab Dis 2015; 38 (02) 305-314
• 24 Baraf HS, Becker MA, Gutierrez-Urena SR. , et al. Tophus burden reduction with pegloticase: results from phase 3 randomized trials and open-label extension in patients with chronic gout refractory to conventional therapy. Arthritis Res Ther 2013; 15 (05) R137
• 25 Sundy JS, Baraf HS, Yood RA. , et al. Efficacy and tolerability of pegloticase for the treatment of chronic gout in patients refractory to conventional treatment: two randomized controlled trials. JAMA 2011; 306 (07) 711-720
• 26 Scott DW. Inhibitors - cellular aspects and novel approaches for tolerance. Haemophilia 2014; 20 (Suppl. 04) 80-86
• 27 Witmer C, Young G. Factor VIII inhibitors in hemophilia A: rationale and latest evidence. Ther Adv Hematol 2013; 4 (01) 59-72
• 28 Gouw SC, Fijnvandraat K. Identifying nongenetic risk factors for inhibitor development in severe hemophilia a. Semin Thromb Hemost 2013; 39 (07) 740-751
• 29 Kurnik K, Bidlingmaier C, Engl W, Chehadeh H, Reipert B, Auerswald G. New early prophylaxis regimen that avoids immunological danger signals can reduce FVIII inhibitor development. Haemophilia 2010; 16 (02) 256-262
• 30 Auerswald G, Kurnik K, Aledort LM. , et al; EPIC clinical study group. The EPIC study: a lesson to learn. Haemophilia 2015; 21 (05) 622-628
• 31 Mannucci PM, Mancuso ME, Santagostino E, Franchini M. Innovative pharmacological therapies for the hemophilias not based on deficient factor replacement. Semin Thromb Hemost 2016; 42 (05) 526-532
• 32 Moghimi B, Sack BK, Nayak S, Markusic DM, Mah CS, Herzog RW. Induction of tolerance to factor VIII by transient co-administration with rapamycin. J Thromb Haemost 2011; 9 (08) 1524-1533
• 33 Zhang AH, Skupsky J, Scott DW. Effect of B-cell depletion using anti-CD20 therapy on inhibitory antibody formation to human FVIII in hemophilia A mice. Blood 2011; 117 (07) 2223-2226
• 34 Waters B, Qadura M, Burnett E. , et al. Anti-CD3 prevents factor VIII inhibitor development in hemophilia A mice by a regulatory CD4+CD25+-dependent mechanism and by shifting cytokine production to favor a Th1 response. Blood 2009; 113 (01) 193-203
• 35 Moorehead PC, Georgescu MT, van Velzen AS. , et al. Administration of dexamethasone during initial exposure to factor VIII induces durable and antigen-specific tolerance to factor VIII in hemophilia A mice with a humanized major histocompatibility complex II transgene. Blood 2014; 124 (21) 1489
• 36 Güngör D, Reuser AJ. How to describe the clinical spectrum in Pompe disease?. Am J Med Genet A 2013; 161A [phone]
• 37 Ausems MG, Verbiest J, Hermans MP. , et al. Frequency of glycogen storage disease type II in the Netherlands: implications for diagnosis and genetic counselling. Eur J Hum Genet 1999; 7 (06) 713-716
• 38 Martiniuk F, Chen A, Mack A. , et al. Carrier frequency for glycogen storage disease type II in New York and estimates of affected individuals born with the disease. Am J Med Genet 1998; 79 (01) 69-72
• 39 de Vries JM, Kuperus E, Hoogeveen-Westerveld M. , et al. Pompe disease in adulthood: effects of antibody formation on enzyme replacement therapy. Genet Med 2017; 19 (01) 90-97
• 40 Masat E, Laforêt P, De Antonio M. , et al; French Pompe Registry Study Group. Long-term exposure to Myozyme results in a decrease of anti-drug antibodies in late-onset Pompe disease patients. Sci Rep 2016; 6: 36182
• 41 Kishnani PS, Hwu WL, Mandel H, Nicolino M, Yong F, Corzo D. ; Infantile-Onset Pompe Disease Natural History Study Group. A retrospective, multinational, multicenter study on the natural history of infantile-onset Pompe disease. J Pediatr 2006; 148 (05) 671-676
• 42 van den Hout HM, Hop W, van Diggelen OP. , et al. The natural course of infantile Pompe's disease: 20 original cases compared with 133 cases from the literature. Pediatrics 2003; 112 (02) 332-340
• 43 Bali DS, Goldstein JL, Banugaria S. , et al. Predicting cross-reactive immunological material (CRIM) status in Pompe disease using GAA mutations: lessons learned from 10 years of clinical laboratory testing experience. Am J Med Genet C Semin Med Genet 2012; 160C (01) 40-49
• 44 Kishnani PS, Goldenberg PC, DeArmey SL. , et al. Cross-reactive immunologic material status affects treatment outcomes in Pompe disease infants. Mol Genet Metab 2010; 99 (01) 26-33
• 45 Berrier KL, Kazi ZB, Prater SN. , et al. CRIM-negative infantile Pompe disease: characterization of immune responses in patients treated with ERT monotherapy. Genet Med 2015; 17 (11) 912-918
• 46 Banugaria SG, Prater SN, Ng YK. , et al. The impact of antibodies on clinical outcomes in diseases treated with therapeutic protein: lessons learned from infantile Pompe disease. Genet Med 2011; 13 (08) 729-736
• 47 Charrow J, Andersson HC, Kaplan P. , et al. The Gaucher registry: demographics and disease characteristics of 1698 patients with Gaucher disease. Arch Intern Med 2000; 160 (18) 2835-2843
• 48 Starzyk K, Richards S, Yee J, Smith SE, Kingma W. The long-term international safety experience of imiglucerase therapy for Gaucher disease. Mol Genet Metab 2007; 90 (02) 157-163
• 49 Rosenberg M, Kingma W, Fitzpatrick MA, Richards SM. Immunosurveillance of alglucerase enzyme therapy for Gaucher patients: induction of humoral tolerance in seroconverted patients after repeat administration. Blood 1999; 93 (06) 2081-2088
• 50 Bigger BW, Saif M, Linthorst GE. The role of antibodies in enzyme treatments and therapeutic strategies. Best Pract Res Clin Endocrinol Metab 2015; 29 (02) 183-194
• 51 Rombach SM, Smid BE, Linthorst GE, Dijkgraaf MG, Hollak CE. Natural course of Fabry disease and the effectiveness of enzyme replacement therapy: a systematic review and meta-analysis: effectiveness of ERT in different disease stages. J Inherit Metab Dis 2014; 37 (03) 341-352
• 52 Linthorst GE, Hollak CE, Donker-Koopman WE, Strijland A, Aerts JM. Enzyme therapy for Fabry disease: neutralizing antibodies toward agalsidase alpha and beta. Kidney Int 2004; 66 (04) 1589-1595
• 53 Rombach SM, Aerts JM, Poorthuis BJ. , et al. Long-term effect of antibodies against infused alpha-galactosidase A in Fabry disease on plasma and urinary (lyso)Gb3 reduction and treatment outcome. PLoS One 2012; 7 (10) e47805
• 54 Lenders M, Stypmann J, Duning T, Schmitz B, Brand SM, Brand E. Serum-mediated inhibition of enzyme replacement therapy in Fabry disease. J Am Soc Nephrol 2016; 27 (01) 256-264
• 55 Elder ME, Nayak S, Collins SW. , et al. B-Cell depletion and immunomodulation before initiation of enzyme replacement therapy blocks the immune response to acid alpha-glucosidase in infantile-onset Pompe disease. J Pediatr 2013; 163 (03) 847-54.e1
• 56 Banugaria SG, Prater SN, Patel TT. , et al. Algorithm for the early diagnosis and treatment of patients with cross reactive immunologic material-negative classic infantile Pompe disease: a step towards improving the efficacy of ERT. PLoS One 2013; 8 (06) e67052
• 57 Broomfield A, Fletcher J, Davison J. , et al. Response of 33 UK patients with infantile-onset Pompe disease to enzyme replacement therapy. J Inherit Metab Dis 2016; 39 (02) 261-271
• 58 Kazi ZB, Desai AK, Berrier KL. , et al. Sustained immune tolerance induction in enzyme replacement therapy-treated CRIM-negative patients with infantile Pompe disease. JCI Insight 2017; 2 (16) e94328
• 59 Lázár-Molnár E, Delgado JC. Immunogenicity assessment of tumor necrosis factor antagonists in the clinical laboratory. Clin Chem 2016; 62 (09) 1186-1198
• 60 Colombel JF, Sandborn WJ, Reinisch W. , et al; SONIC Study Group. Infliximab, azathioprine, or combination therapy for Crohn's disease. N Engl J Med 2010; 362 (15) 1383-1395
• 61 Panaccione R, Ghosh S, Middleton S. , et al. Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis. Gastroenterology 2014; 146 (02) 392-400.e3
• 62 Matsumoto T, Motoya S, Watanabe K. , et al; DIAMOND study group. Adalimumab monotherapy and a combination with azathioprine for Crohn's disease: a prospective, randomized trial. J Crohn's Colitis 2016; 10 (11) 1259-1266
• 63 Emery P, Fleischmann RM, Moreland LW. , et al. Golimumab, a human anti-tumor necrosis factor alpha monoclonal antibody, injected subcutaneously every four weeks in methotrexate-naive patients with active rheumatoid arthritis: twenty-four-week results of a phase III, multicenter, randomized, double-blind, placebo-controlled study of golimumab before methotrexate as first-line therapy for early-onset rheumatoid arthritis. Arthritis Rheum 2009; 60 (08) 2272-2283
• 64 Kremer J, Ritchlin C, Mendelsohn A. , et al. Golimumab, a new human anti-tumor necrosis factor alpha antibody, administered intravenously in patients with active rheumatoid arthritis: forty-eight-week efficacy and safety results of a phase III randomized, double-blind, placebo-controlled study. Arthritis Rheum 2010; 62 (04) 917-928
• 65 Maneiro JR, Salgado E, Gomez-Reino JJ. Immunogenicity of monoclonal antibodies against tumor necrosis factor used in chronic immune-mediated Inflammatory conditions: systematic review and meta-analysis. JAMA Intern Med 2013; 173 (15) 1416-1428
• 66 Hruby MA, Schulman I. Failure of combined factor VIII and cyclophosphamide to suppress antibody to factor VIII in hemophilia. Blood 1973; 42 (06) 919-923
• 67 Stein RS, Colman RW. Hemophilia with factor VIII inhibitor. Elimination of anamnestic response. Ann Intern Med 1973; 79 (01) 84-87
• 68 Laros-van Gorkom BA, Falaise C, Astermark J. Immunosuppressive agents in the treatment of inhibitors in congenital haemophilia A and B--a systematic literature review. Eur J Haematol Suppl 2014; 76 (Suppl. 76) 26-38
• 69 Berntorp E, Astermark J, Carlborg E. Immune tolerance induction and the treatment of hemophilia. Malmö protocol update. Haematologica 2000; 85 (10, Suppl): 48-50 , discussion 50–51
• 70 Albrecht J, Meves A, Bigby M. Case reports and case series from Lancet had significant impact on medical literature. J Clin Epidemiol 2005; 58 (12) 1227-1232
• 71 Collins PW, Mathias M, Hanley J. , et al; UK Haemophilia Centre Doctors' Organisation. Rituximab and immune tolerance in severe hemophilia A: a consecutive national cohort. J Thromb Haemost 2009; 7 (05) 787-794
• 72 Rocino A, Cortesi PA, Scalone L, Mantovani LG, Crea R, Gringeri A. ; European Haemophilia Therapy Strategy Board (EHTSB); European Haemophilia Therapy Strategy Board EHTSB. Immune tolerance induction in patients with haemophilia a and inhibitors: effectiveness and cost analysis in an European Cohort (The ITER Study). Haemophilia 2016; 22 (01) 96-102
• 73 Leissinger C, Josephson CD, Granger S. , et al. Rituximab for treatment of inhibitors in haemophilia A. A phase II study. Thromb Haemost 2014; 112 (03) 445-458
• 74 Casadevall N, Cournoyer D, Marsh J. , et al. Recommendations on haematological criteria for the diagnosis of epoetin-induced pure red cell aplasia. Eur J Haematol 2004; 73 (06) 389-396
• 75 Macdougall IC. Antibody-mediated pure red cell aplasia (PRCA): epidemiology, immunogenicity and risks. Nephrol Dial Transplant 2005; 20 (Suppl. 04) iv9-iv15
• 76 Bennett CL, Cournoyer D, Carson KR. , et al. Long-term outcome of individuals with pure red cell aplasia and antierythropoietin antibodies in patients treated with recombinant epoetin: a follow-up report from the Research on Adverse Drug Events and Reports (RADAR) Project. Blood 2005; 106 (10) 3343-3347
• 77 Verhelst D, Rossert J, Casadevall N, Krüger A, Eckardt KU, Macdougall IC. Treatment of erythropoietin-induced pure red cell aplasia: a retrospective study. Lancet 2004; 363 (9423): 1768-1771
• 78 Link J, Ramanujam R, Auer M. , et al; ABIRISK Consortium. Clinical practice of analysis of anti-drug antibodies against interferon beta and natalizumab in multiple sclerosis patients in Europe: a descriptive study of test results. PLoS One 2017; 12 (02) e0170395
• 79 Sominanda A, Rot U, Suoniemi M, Deisenhammer F, Hillert J, Fogdell-Hahn A. Interferon beta preparations for the treatment of multiple sclerosis patients differ in neutralizing antibody seroprevalence and immunogenicity. Mult Scler 2007; 13 (02) 208-214
• 80 Zarkou S, Carter JL, Wellik KE, Demaerschalk BM, Wingerchuk DM. Are corticosteroids efficacious for preventing or treating neutralizing antibodies in multiple sclerosis patients treated with beta-interferons? A critically appraised topic. Neurologist 2010; 16 (03) 212-214
• 81 Galea I, Ward-Abel N, Heesen C. Relapse in multiple sclerosis. BMJ 2015; 350: h1765
• 82 Cohen JA, Imrey PB, Calabresi PA. , et al; ACT Investigators. Results of the Avonex Combination Trial (ACT) in relapsing-remitting MS. Neurology 2009; 72 (06) 535-541
• 83 Ravnborg M, Sørensen PS, Andersson M. , et al. Methylprednisolone in combination with interferon beta-1a for relapsing-remitting multiple sclerosis (MECOMBIN study): a multicentre, double-blind, randomised, placebo-controlled, parallel-group trial. Lancet Neurol 2010; 9 (07) 672-680
• 84 Pozzilli C, Antonini G, Bagnato F. , et al. Monthly corticosteroids decrease neutralizing antibodies to IFNbeta1 b: a randomized trial in multiple sclerosis. J Neurol 2002; 249 (01) 50-56
• 85 Sorensen PS, Mellgren SI, Svenningsson A. , et al. NORdic trial of oral Methylprednisolone as add-on therapy to Interferon beta-1a for treatment of relapsing-remitting Multiple Sclerosis (NORMIMS study): a randomised, placebo-controlled trial. Lancet Neurol 2009; 8 (06) 519-529
• 86 Hesse D, Frederiksen JL, Koch-Henriksen N. , et al. Methylprednisolone does not restore biological response in multiple sclerosis patients with neutralizing antibodies against interferon-β. Eur J Neurol 2009; 16 (01) 43-47