e174
LETTERS TO THE EDITORS
about the available knowledge. Let a well-informed patient decide. Inhibitor formation is a multicausal process and FVIII exposure is undeniably a necessary cause of inhibitors. Despite all efforts of the regulatory authorities it will be impossible to exactly know the immunogenicity of a new product before authorization of the product. The best way to monitor a FVIII product’s immunogenicity is to collect information on all FVIII infusions of a product and to compare inhibitor occurrence between products. A central database with such information, which is under the ownership of patients is the most efficient, fastest and most reliable
References 1 Gouw SC, van der Bom JG, Ljung R et al. Factor VIII products and inhibitor development in severe hemophilia A. N Engl J Med 2013; 368: 231–9. 2 Kessler CM, Iorio A. The Rodin (Research Of Determinants of INhibitor Development among PUPs with haemophilia) study: the clinical conundrum from the perspective of haemophilia treaters. Haemophilia 2013; 19: 351–4. 3 Franchini M, Mengoli C. RODIN and the pitfalls of observational studies. Haemophilia 2013; 19: e315–6. 4 Rosendaal FR, Nieuwenhuis HK, van den Berg HM et al. A sudden increase in factor
way to learn whether a product carries an higher or lower risk of inhibitors. With such a database in place we would have known earlier that Kogenate/Helixate indeed induces more inhibitors than other products.
Disclosures Johanna G. van der Bom has received unrestricted research funding from Bayer, Baxter, CSL Behring and Wyeth. In addition, she has been a consultant to Baxter and Wyeth, and she has been a teacher on educational activities of Bayer. Samantha Gouw has received unrestricted research support and speaking fees from CSL Behring, Novo Nordisk, Wyeth, Baxter and Bayer. Frits R. Rosendaal has no conflict of interest.
VIII inhibitor development in multitransfused hemophilia A patients in The Netherlands. Dutch Hemophilia Study Group. Blood 1993; 81: 2180–6. 5 Vandenbroucke JP, Psaty BM. Benefits and risks of drug treatments: how to combine the best evidence on benefits with the best data about adverse effects. JAMA 2008; 300: 2417–9. 6 Concato J. Study Design and “Evidence” in Patient-oriented Research. Am J Respir Crit Care Med 2013; 187: 1167–72. 7 Ter Avest PC, Fischer K, Mancuso ME et al. Risk stratification for inhibitor development at first treatment for severe hemophilia A: a tool for clinical practice. J Thromb Haemost 2008; 6: 2048–54.
8 Hernan MA, Robins JM. Estimating causal effects from epidemiological data. J Epidemiol Community Health 2006; 60: 578–86. 9 Von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Epidemiology 2007; 18: 800–4. 10 Pahl S, Pavlova A, Driesen J, M€ uller J, P€ otzsch B, Oldenburg J. In vitro characterization of recombinant factor VIII concentrates reveals significant differences in protein content, activity and thrombin activation profile. Haemophilia 2013; 19: 392–8.
Making clinical decisions on the basis of RODIN P. M. MANNUCCI Scientific Direction, IRCCS Ca’ Granda Maggiore Policlinico Hospital Foundation, Milan, Italy
After the commentary of Kessler and Iorio [1] on the results of RODIN [2], I read with interest the spicy rebuttal by van der Bom et al. [3]. A few comments herewith. My main point of disagreement with the Dutch colleagues is when in the subsection Clinical Consequences they suggest, clearly albeit not explicitly, that the so called second-generation factor VIII (FVIII) products should no longer be used clinically, because there are alternative products for the treatment of haemophilia A that are equally effective but safer in terms of inhibitor occurrence. The undersigned thinks that RODIN is a milestone in the search for risk factors for Correspondence: Pier M. Mannucci, Via Pace 9, 20122 Milan, Italy. Tel.: 39 02 55038377; fax: 39 02 50320723; e-mail: [email protected] Accepted after revision 21 December 2013 DOI: 10.1111/hae.12361 Haemophilia (2014), 20, e171--e192
FVIII inhibitor development, being by far the largest study, designed and analysed masterly and written by a distinguished group of experts. However, I believe that its results cannot be considered conclusive and that as such should have no influence as yet on our choice of the FVIII products for replacement therapy; nor, at variance with the title chosen by van der Bom et al. [3], ‘implications for patients with hemophilia A’. In RODIN, the observed crude cumulative incidences of inhibitors with each of the tested FVIII products fell largely within the very wide ranges observed in many smaller studies [4], giving a margin of uncertainty to the increased inhibitor risk of second-generation recombinant FVIII products. For sake of examples of this huge variability, one of the largest earlier studies prospectively done on one of the second-generation products evaluated in RODIN (Kogenate FS, Bayer, Germany) gave one of the lowest inhibitor incidences (15%) [5], whereas the © 2014 John Wiley & Sons Ltd
LETTERS TO THE EDITORS
third-generation product (Advate, Baxter, Austria) taken as reference in RODIN gave, in the frame of a recent prospective study (EPIC), a relatively high incidence of inhibitors that led to the premature interruption of the study. All in all, I applaud the statement made by van der Bom et al. in the subsection Definite Proof and Prior Belief: ‘every decent scientist will agree that a single study cannot provide definite proof. Any finding for any type of study can be the result of chance’. For the latter reason, I fail to grasp why following RODIN the European Medicines Agency (EMA) had chosen, to initiate an enquiry on the risk of immunogenicity of second-generation FVIII products: when, for sake of examples, no such action was taken for similarly striking results, such as for instance the finding by Wight and Paisley [4] that recombinant FVIII products are nearly threefold more inhibitor generating than plasma-derived products, or the report by Aledort et al. [6] that B-domainless recombinant FVIII is nearly sixfold more immunogenic that full-length products in previously treated patients with haemophilia A. Very recently, the Pharmacovigilance Risk
References 1 Kessler CM, Iorio A. The Rodin (Research Of Determinants of Inhibitor Development among PUPs with haemophilia) study: the clinical conundrum from the perspective of haemophilia treaters. Haemophilia 2013; 19: 351–4. 2 Gouw SC, van der Bom JG, Ljung R et al. Factor VIII products and inhibitor development in severe hemophilia A. N Engl J Med 2013; 368: 231–9. 3 van der Bom JG, Gouw SC, Rosendaal FR. Second generation recombinant factor VIII
e175
Assessment Committee of EMA concluded that the available data do not support the views that the so called second-generation FVIII products are more likely to trigger inhibitors than the third-generation product. All in all, I believe that it is premature to change our current policy in the choice of the available recombinant FVIII products that, I agree with the Dutch colleagues, are all equally efficacious in stopping or preventing bleeding. I fully agree with them that physicians should inform persons with haemophilia about solid facts (efficacy) and uncertain perceptions (inhibitor safety), as my colleagues and I did emphasize in a How I Treat article [7]. The choice should not be of the physician only but shared with the patient, truly informed without bias.
Disclosures The author is member of the selection committee of the Bayer Awards, is member of the advisory board of Kedrion Biopharma and has received honoraria for participating at education meetings organized by Novo Nordisk.
and inhibitors risk; interpretation of RODIN study findings and implications for patients with haemophilia A. Haemophilia 2013, doi: 10.1111/hae.12342. 4 Wight J, Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic review. Haemophilia 2003; 9: 418–35. 5 Kreuz W, Gill JC, Rothschild C et al.; International Kogenate-FS Study Group. Full-length sucrose-formulated recombinant factor VIII for treatment of previously untreated or minimally treated young children with severe haemophilia A: results of
an international clinical investigation. Thromb Haemost 2005; 93: 457–67. 6 Aledort LM, Navickis RJ, Wilkes MM. Can B-domain deletion alter the immunogenicity of recombinant factor VIII? A meta-analysis of prospective clinical studies. J Thromb Haemost 2011; 9: 2180–92. 7 Mannucci PM, Mancuso ME, Santagostino E. How we choose factor VIII to treat hemophilia. Blood 2012; 119: 4108–14.
Lumbar puncture in haemophilia A: controversy in the management I . B E S H L A W I , * Z . A L L A M K I , * A . R A W A S , * M . S . A B D E L - B A K I † and Y . W A L I * *Pediatric Hematology Unit, Department of Child Health, Sultan Qaboos University Hospital, Muscat, Oman; and †Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, Texas, USA
Haemophilia is the most common X chromosomelinked inherited bleeding disorder [1]. Performance of Correspondence: Dr Yasser Wali, Department of Child Health, Sultan Qaboos University Hospital, PO B 38, PC 123 Muscat, Oman. Tel.: +968 99258692; fax: +968 24141136; e-mail: [email protected] Accepted after revision 10 November 2013 DOI: 10.1111/hae.12343 © 2013 John Wiley & Sons Ltd
lumbar puncture (LP) in people with haemophilia has the potential to cause serious complications including intra-spinal haematoma and spinal cord compression [2]. Here we describe an Arab patient who had severe haemophilia A, with no previous family history of the disease. His genotype is unknown as molecular diagnosis is not feasible in our hospital setting. This patient developed pre–B acute lymphoblastic leukaemia (ALL) at the age of 16 months and was initiated Haemophilia (2014), 20, e171--e192
LETTERS TO THE EDITORS
about the available knowledge. Let a well-informed patient decide. Inhibitor formation is a multicausal process and FVIII exposure is undeniably a necessary cause of inhibitors. Despite all efforts of the regulatory authorities it will be impossible to exactly know the immunogenicity of a new product before authorization of the product. The best way to monitor a FVIII product’s immunogenicity is to collect information on all FVIII infusions of a product and to compare inhibitor occurrence between products. A central database with such information, which is under the ownership of patients is the most efficient, fastest and most reliable
References 1 Gouw SC, van der Bom JG, Ljung R et al. Factor VIII products and inhibitor development in severe hemophilia A. N Engl J Med 2013; 368: 231–9. 2 Kessler CM, Iorio A. The Rodin (Research Of Determinants of INhibitor Development among PUPs with haemophilia) study: the clinical conundrum from the perspective of haemophilia treaters. Haemophilia 2013; 19: 351–4. 3 Franchini M, Mengoli C. RODIN and the pitfalls of observational studies. Haemophilia 2013; 19: e315–6. 4 Rosendaal FR, Nieuwenhuis HK, van den Berg HM et al. A sudden increase in factor
way to learn whether a product carries an higher or lower risk of inhibitors. With such a database in place we would have known earlier that Kogenate/Helixate indeed induces more inhibitors than other products.
Disclosures Johanna G. van der Bom has received unrestricted research funding from Bayer, Baxter, CSL Behring and Wyeth. In addition, she has been a consultant to Baxter and Wyeth, and she has been a teacher on educational activities of Bayer. Samantha Gouw has received unrestricted research support and speaking fees from CSL Behring, Novo Nordisk, Wyeth, Baxter and Bayer. Frits R. Rosendaal has no conflict of interest.
VIII inhibitor development in multitransfused hemophilia A patients in The Netherlands. Dutch Hemophilia Study Group. Blood 1993; 81: 2180–6. 5 Vandenbroucke JP, Psaty BM. Benefits and risks of drug treatments: how to combine the best evidence on benefits with the best data about adverse effects. JAMA 2008; 300: 2417–9. 6 Concato J. Study Design and “Evidence” in Patient-oriented Research. Am J Respir Crit Care Med 2013; 187: 1167–72. 7 Ter Avest PC, Fischer K, Mancuso ME et al. Risk stratification for inhibitor development at first treatment for severe hemophilia A: a tool for clinical practice. J Thromb Haemost 2008; 6: 2048–54.
8 Hernan MA, Robins JM. Estimating causal effects from epidemiological data. J Epidemiol Community Health 2006; 60: 578–86. 9 Von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Epidemiology 2007; 18: 800–4. 10 Pahl S, Pavlova A, Driesen J, M€ uller J, P€ otzsch B, Oldenburg J. In vitro characterization of recombinant factor VIII concentrates reveals significant differences in protein content, activity and thrombin activation profile. Haemophilia 2013; 19: 392–8.
Making clinical decisions on the basis of RODIN P. M. MANNUCCI Scientific Direction, IRCCS Ca’ Granda Maggiore Policlinico Hospital Foundation, Milan, Italy
After the commentary of Kessler and Iorio [1] on the results of RODIN [2], I read with interest the spicy rebuttal by van der Bom et al. [3]. A few comments herewith. My main point of disagreement with the Dutch colleagues is when in the subsection Clinical Consequences they suggest, clearly albeit not explicitly, that the so called second-generation factor VIII (FVIII) products should no longer be used clinically, because there are alternative products for the treatment of haemophilia A that are equally effective but safer in terms of inhibitor occurrence. The undersigned thinks that RODIN is a milestone in the search for risk factors for Correspondence: Pier M. Mannucci, Via Pace 9, 20122 Milan, Italy. Tel.: 39 02 55038377; fax: 39 02 50320723; e-mail: [email protected] Accepted after revision 21 December 2013 DOI: 10.1111/hae.12361 Haemophilia (2014), 20, e171--e192
FVIII inhibitor development, being by far the largest study, designed and analysed masterly and written by a distinguished group of experts. However, I believe that its results cannot be considered conclusive and that as such should have no influence as yet on our choice of the FVIII products for replacement therapy; nor, at variance with the title chosen by van der Bom et al. [3], ‘implications for patients with hemophilia A’. In RODIN, the observed crude cumulative incidences of inhibitors with each of the tested FVIII products fell largely within the very wide ranges observed in many smaller studies [4], giving a margin of uncertainty to the increased inhibitor risk of second-generation recombinant FVIII products. For sake of examples of this huge variability, one of the largest earlier studies prospectively done on one of the second-generation products evaluated in RODIN (Kogenate FS, Bayer, Germany) gave one of the lowest inhibitor incidences (15%) [5], whereas the © 2014 John Wiley & Sons Ltd
LETTERS TO THE EDITORS
third-generation product (Advate, Baxter, Austria) taken as reference in RODIN gave, in the frame of a recent prospective study (EPIC), a relatively high incidence of inhibitors that led to the premature interruption of the study. All in all, I applaud the statement made by van der Bom et al. in the subsection Definite Proof and Prior Belief: ‘every decent scientist will agree that a single study cannot provide definite proof. Any finding for any type of study can be the result of chance’. For the latter reason, I fail to grasp why following RODIN the European Medicines Agency (EMA) had chosen, to initiate an enquiry on the risk of immunogenicity of second-generation FVIII products: when, for sake of examples, no such action was taken for similarly striking results, such as for instance the finding by Wight and Paisley [4] that recombinant FVIII products are nearly threefold more inhibitor generating than plasma-derived products, or the report by Aledort et al. [6] that B-domainless recombinant FVIII is nearly sixfold more immunogenic that full-length products in previously treated patients with haemophilia A. Very recently, the Pharmacovigilance Risk
References 1 Kessler CM, Iorio A. The Rodin (Research Of Determinants of Inhibitor Development among PUPs with haemophilia) study: the clinical conundrum from the perspective of haemophilia treaters. Haemophilia 2013; 19: 351–4. 2 Gouw SC, van der Bom JG, Ljung R et al. Factor VIII products and inhibitor development in severe hemophilia A. N Engl J Med 2013; 368: 231–9. 3 van der Bom JG, Gouw SC, Rosendaal FR. Second generation recombinant factor VIII
e175
Assessment Committee of EMA concluded that the available data do not support the views that the so called second-generation FVIII products are more likely to trigger inhibitors than the third-generation product. All in all, I believe that it is premature to change our current policy in the choice of the available recombinant FVIII products that, I agree with the Dutch colleagues, are all equally efficacious in stopping or preventing bleeding. I fully agree with them that physicians should inform persons with haemophilia about solid facts (efficacy) and uncertain perceptions (inhibitor safety), as my colleagues and I did emphasize in a How I Treat article [7]. The choice should not be of the physician only but shared with the patient, truly informed without bias.
Disclosures The author is member of the selection committee of the Bayer Awards, is member of the advisory board of Kedrion Biopharma and has received honoraria for participating at education meetings organized by Novo Nordisk.
and inhibitors risk; interpretation of RODIN study findings and implications for patients with haemophilia A. Haemophilia 2013, doi: 10.1111/hae.12342. 4 Wight J, Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic review. Haemophilia 2003; 9: 418–35. 5 Kreuz W, Gill JC, Rothschild C et al.; International Kogenate-FS Study Group. Full-length sucrose-formulated recombinant factor VIII for treatment of previously untreated or minimally treated young children with severe haemophilia A: results of
an international clinical investigation. Thromb Haemost 2005; 93: 457–67. 6 Aledort LM, Navickis RJ, Wilkes MM. Can B-domain deletion alter the immunogenicity of recombinant factor VIII? A meta-analysis of prospective clinical studies. J Thromb Haemost 2011; 9: 2180–92. 7 Mannucci PM, Mancuso ME, Santagostino E. How we choose factor VIII to treat hemophilia. Blood 2012; 119: 4108–14.
Lumbar puncture in haemophilia A: controversy in the management I . B E S H L A W I , * Z . A L L A M K I , * A . R A W A S , * M . S . A B D E L - B A K I † and Y . W A L I * *Pediatric Hematology Unit, Department of Child Health, Sultan Qaboos University Hospital, Muscat, Oman; and †Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, Texas, USA
Haemophilia is the most common X chromosomelinked inherited bleeding disorder [1]. Performance of Correspondence: Dr Yasser Wali, Department of Child Health, Sultan Qaboos University Hospital, PO B 38, PC 123 Muscat, Oman. Tel.: +968 99258692; fax: +968 24141136; e-mail: [email protected] Accepted after revision 10 November 2013 DOI: 10.1111/hae.12343 © 2013 John Wiley & Sons Ltd
lumbar puncture (LP) in people with haemophilia has the potential to cause serious complications including intra-spinal haematoma and spinal cord compression [2]. Here we describe an Arab patient who had severe haemophilia A, with no previous family history of the disease. His genotype is unknown as molecular diagnosis is not feasible in our hospital setting. This patient developed pre–B acute lymphoblastic leukaemia (ALL) at the age of 16 months and was initiated Haemophilia (2014), 20, e171--e192
