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  online April 3, 2013 srcinally published doi:10.1182/blood-2012-09-4570362013 121: 4046-4055   der BomAnne Rafowicz, Mike Williams, Niels Clausen, Rutger A. Middelburg, Rolf Ljung and Johanna G. van Carmen Altisent, Johannes Oldenburg, Beatrice Nolan, Rosario Pérez Garrido, M. Elisa Mancuso,Elizabeth Chalmers, Hervé Chambost, Karin Kurnik, Ri Liesner, Pia Petrini, Helen Platokouki, Samantha C. Gouw, H. Marijke van den Berg, Kathelijn Fischer, Günter Auerswald, Manuel Carcao,  with severe hemophilia A: the RODIN studyIntensity of factor VIII treatment and inhibitor development in children   http://www.bloodjournal.org/content/121/20/4046.full.html Updated information and services can be found at: (762 articles)Thrombosis and Hemostasis   (361 articles)Pediatric Hematology   (2784 articles)Free Research Articles   (3953 articles)Clinical Trials and Observations   Articles on similar topics can be found in the following Blood collections http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests Information about reproducing this article in parts or in its entirety may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#reprints Information about ordering reprints may be found online at: http://www.bloodjournal.org/site/subscriptions/index.xhtml Information about subscriptions and ASH membership may be found online at: Copyright 2011 by The American Society of Hematology; all rights reserved.of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036.Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society For personal use only.on November 3, 2014. by guest www.bloodjournal.orgFrom For personal use only.on November 3, 2014. by guest www.bloodjournal.orgFrom   Regular Article CLINICAL TRIALS AND OBSERVATIONS Intensity of factor VIII treatment and inhibitor development in childrenwith severe hemophilia A: the RODIN study Samantha C. Gouw, 1 H. Marijke van den Berg, 2 Kathelijn Fischer, 2,3 G¨unter Auerswald, 4 Manuel Carcao, 5 Elizabeth Chalmers, 6 Herv´e Chambost, 7 Karin Kurnik, 8 Ri Liesner, 9 Pia Petrini, 10 Helen Platokouki, 11 Carmen Altisent, 12 Johannes Oldenburg, 13 Beatrice Nolan, 14 Rosario P´erez Garrido, 15 M. Elisa Mancuso, 16 Anne Rafowicz, 17 Mike Williams, 18 Niels Clausen, 19 Rutger A. Middelburg, 20 Rolf Ljung, 21 and Johanna G. van der Bom 20,22 for the PedNet and Research ofDeterminants of INhibitor development (RODIN) Study Group 1 Department of Paediatrics, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, The Netherlands;  2 Julius Center for Health Sciencesand Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands;  3 Van Creveldkliniek, University Medical Center Utrecht, Utrecht, TheNetherlands;  4 Gesundheit Nord, Klinikum Bremen Mitte, Prof.-Hess-Kinderklinik, Bremen, Germany;  5 Division of Haematology/Oncology, Hospital for SickChildren, Toronto, Canada;  6 Department of Haematology, Royal Hospital for Sick Children, Yorkhill, Glasgow, UK;  7 Service d’h´ematologie p´ediatrique, Hˆopital La Timone & Aix-Marseille Univ, Marseille, France;  8 Dr. v. Haunersches Kinderspital, University of Munich, Munich, Germany;  9 Hemophilia Center, Departmentof Haematology, Great Ormond Street Hospital for children, London, UK;  10 Department of Pediatrics, Clinic of Coagulation Disorders, Karolinska Hospital,Stockholm, Sweden;  11 St. Sophia Children’s Hospital, Haemophilia-Haemostasis Unit, Athens, Greece;  12 Unitat Hemofilia, Hospital Traumatologica, HospitalVall d’Hebron, Barcelona, Spain;  13 Institut f¨ur Experimentelle H¨amatologie und Transfusionsmedizin, Universit¨atsklinikum Bonn, Bonn, Germany;  14 Departmentof Paediatric Haematology, St. James’s Hospital, Dublin, Ireland;  15 Hospital General Unidad de Hemofilia, Hospitales Universitarios Virgen del Rocio,Sevilla, Spain;  16 Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca’ Granda, OspedaleMaggiore Policlinico, Milan, Italy;  17 Centre R´egional de Traitement de l’H´emophilie et Autres Maladies Bicetre, Service H´ematologique, Paris, France;  18 Departmentof Haematology, The Children’s Hospital, Birmingham, UK;  19 Department of Pediatrics, University Hospital of Aarhus at Skejby, Aarhus, Denmark;  20 Center forClinical Transfusion Research, Sanquin Foundation, Leiden, The Netherlands;  21 Department of Pediatrics and Malm¨o Centre for Thrombosis and Haemostasis,Sk˚anes Universitetssjukhus, Malm¨o, Sweden; and  22 Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands Key Points ã High-dose intensive factor VIIItreatment increases the riskfor inhibitor development inpatients with severehemophilia A.ã In patients with severehemophilia A, factor VIIIprophylaxis decreases inhibitorrisk, especially in patients withlow-risk  F8   mutations. The objective of this study was to examine the association of the intensity of treatment,ranging from high-dose intensive factor VIII (FVIII) treatment to prophylactic treatment,with the inhibitor incidence among previously untreated patients with severe hemophiliaA.ThiscohortstudyaimedtoincludeconsecutivepatientswithaFVIIIactivity < 0.01IU/mL,born between 2000 and 2010, and observed during their first 75 FVIII exposure days.Intensive FVIII treatment of hemorrhages or surgery at the start of treatment wasassociated with an increased inhibitor risk (adjusted hazard ratio [aHR], 2.0; 95%confidence interval [CI], 1.3-3.0). High-dose FVIII treatment was associated with a higherinhibitor risk than low-dose FVIII treatment (aHR, 2.3; 95% CI, 1.0-4.8). Prophylaxis wasonly associated with a decreased overall inhibitor incidence after 20 exposure days ofFVIII. The association with prophylaxis was more pronounced in patients with low-risk  F8   genotypes than in patients with high-risk   F8   genotypes (aHR, 0.61, 95% CI, 0.19-2.0and aHR,0.85, 95% CI,0.51-1.4,respectively). In conclusion,our findingssuggest that inpreviously untreated patients with severe hemophilia A, high-dosed intensive FVIIItreatment increases inhibitor risk and prophylactic FVIII treatment decreases inhibitor risk, especially in patients with low-risk   F8  mutations. ( Blood  . 2013;121(20):4046-4055) Introduction Patients with severe hemophilia A (factor VIII [FVIII] activity , 0.01IU/mL) have a bleeding diathesis characterized by spontaneous joint and muscle bleeding. The current standard of care of childrenwith severe hemophilia A is primary prophylaxis: regular FVIIIinfusions aimed at prevention of joint damage that are started from the  󿬁 rst joint bleeding onward or earlier. 1,2 Most patients with hemophilia do not mount a clinically measur-able immune response toward FVIII. In ; 30% of patients, however,such FVIII antibodies develop, rendering FVIII treatment ineffectiveand impairing the functional status of patients. 3,4 The capacity to develop inhibitors varies from one individual toanother and depends on the interaction of multiple genetic and Submitted September 19, 2012; accepted March 12, 2013. Prepublishedonline as  Blood   First Edition paper, April 3, 2013; DOI 10.1182/blood-2012-09-457036.Presented in abstract form at the XXIII International Society of Thrombosisand Haemostasis Congress, Kyoto, Japan, July 23-28, 2011; and the WorldFederation of Haemophilia World Congress 2012, Paris, France, July 8-12,2012.The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page chargepayment. Therefore, and solely to indicate this fact, this article is herebymarked “advertisement” in accordance with 18 USC section 1734.  ©   2013 by The American Society of Hematology4046 BLOOD, 16 MAY 2013  x  VOLUME 121, NUMBER 20 For personal use only.on November 3, 2014. by guest www.bloodjournal.orgFrom   nongenetic risk factors. The causative  F8  genotype is an important genetic risk factor. 5,6 Other reported genetic risk factors are a familyhistory of inhibitor development, 7 ethnicity, 7 HLA genotype 8,9 andpolymorphisms in immune regulatory genes. 10-14 Nongenetic risk factors for the occurrence of inhibitory anti-bodies arelargelyrelatedtoFVIIItreatment.Ithasbeensuggestedthat this may be partly explained by the immunologic danger theory. 15 According to the immunologic danger theory, inhibitor develop-ment may be in 󿬂 uenced by the extent of tissue damage at the time of FVIII infusions. This model proposes that antigen-presenting cellsneed to be activated by alarm signals to elicit an effective antibodyresponse. 15 Because the FVIII protein itself does not contain  “ alarm signals, ” 16 immune tolerance should occur on exposure to infusedFVIII, unless FVIII is accompanied by alarm signals that trigger thematuration of dendritic cells. 17 During FVIII treatment of major bleeding or surgery, a patient is exposed to high doses of FVIII incombination with tissue damage and in 󿬂 ammation. According tothe danger theory, substances released from damaged tissue couldactivate antigen-presenting cells, which might subsequently present FVIII antigen with up-regulated costimulatory signals to T lympho-cytes.Thesecellsthenenhanceantibodyformation. 15 Indeed,repeatedhigh-dose FVIII treatment given for major bleeding and surgery hasbeen associated with an increased risk for inhibitor development. 18-21 Low-dose prophylactic FVIII infusions, however, are given in theabsence of tissue damage. Antigen-presenting cells present the FVIIIantigen to T lymphocytes in the absence of costimulatory signals. Thismay cause the induction of immune tolerance by the generation of regulatory T cells from na ¨ ı ve T cells or cause anergy of previouslyprimed T cells. 17 Observations that prophylaxis is associated withareducedriskforinhibitordevelopmentsupportthishypothesis. 18,22,23 However, it is currently unclear whether the timing of the introductionof prophylaxis and the dose and the frequency of prophylactic FVIIIinfusions affect the risk for inhibitor development.We set up a large, international cohort study to examine theassociation of the intensity of treatment with inhibitor incidenceamong previously untreated patients with severe hemophilia A. Westudied high-dose intensive FVIII treatment of bleeds or surgeryand prophylactic FVIII treatment, including the dose, frequency,and time of onset of prophylaxis. Patients and methods Patients We aimed to include consecutive previously untreated patientswith severe hemophilia A (FVIII activity  , 0.01 IU/mL) bornbetween January 1, 2000, and January 1, 2010, diagnosed in oneof the 29 participating hemophilia treatment centers. Patientswho were referred because of the presence of an inhibitor wereexcluded. Approval was obtained from every center  ’ s institutionalreview board. Written informed consent was obtained from theparents or guardians of all participants in accordance with theDeclaration of Helsinki. Data collection Detailed data on potential treatment-related determinants were uni-formly collected in all centers: all administrations of FVIII up to 75exposure days or inhibitor development, including dates of infusion,doses and brands of FVIII products, reasons for treatment, types of bleeding, and surgery. Patients were monitored until the study endpoint, which was either the development of a clinically relevant inhibitor or a cumulative number of 75 exposure days.The determination of clinically relevant inhibitor development was based on all performed inhibitor tests and recovery measure-ments (in case of borderline positive inhibitor test results) in patientswho ever had a positive inhibitor measurement.In the majority of centers (92%), patients were routinely screenedfor inhibitor development after every 1 to 5 exposure days during the 󿬁 rst 20 exposure days and at least every 3 months thereafter. Allcenters closely monitored patients for clinical signs of inhibitor de-velopment and performed inhibitor and recovery testing at anyclinical suspicion of inhibitor development.All data collected were repeatedly checked for completeness andinconsistencies using prespeci 󿬁 edprotocols.Data-monitor visitswereperformed at least annually at each center, including ascertainment of 100% of included and excluded patients, hemophilia diagnosis, and F8  genotype, as well as ascertainment of a minimal 10% of sourcedata on FVIII treatments.Relatively few data were missing (supplemental Methods). For the current analyses, data collected until May 1, 2011, were used. Outcomes The primary outcome of the study was clinically relevant inhibitor development, de 󿬁 ned as at least 2 positive inhibitor titers combinedwith a decreased in vivo FVIII recovery up to the 75th exposureday. 18 A positive inhibitor titer was de 󿬁 ned according to the cutoff leveloftheinhibitorassayusedineachcenter  ’ slaboratory.TheFVIIIrecovery was considered to be decreased when it was less than 66%of the expected FVIII activity level 15 minutes after infusion of FVIII. The expected level of FVIII activity was calculated accordingto Lee et al. 24 The secondary outcome was high titer inhibitor development,de 󿬁 ned as the occurrence of a clinically relevant inhibitor with a peak titer of at least 5 Bethesda Units per mL (BU/mL). 25 Determinants  Intensive FVIII treatment.  Intensive FVIII treatment was evalu-ated by peak treatment moments, surgical procedures, durationbetween exposure days, and dose of FVIII product. Peak treatment moments and surgical procedures.  “ Peak treatment moments ”  were de 󿬁 ned as episodes of treatment withFVIII for bleeding or surgery on at least 3, 5, or 10 consecutivedays.Westudied “ surgicalprocedures ” forwhichreplacementtherapylasting at least 3 consecutive days was given. 18 The correspondingtime-dependent variables were de 󿬁 ned as the  “ after peak treatment moment  ”  or   “ after surgical procedure. ”  Duration between exposure days.  “ Duration between exposuredays ”  was the measure for frequency of exposures; it was de 󿬁 ned asthe period between each exposure day and 5 exposure days beforethis exposure day.  Dose of FVIII product.  To study the association betweeninhibitor occurrence and the  “ dose of FVIII product, ”  we calculatedat each time point the mean FVIII dose per kilogram bodyweight of the previous 5 exposure days.Because prophylaxis in 󿬂 uences these factors to a large extent, theanalyses of duration between exposure days and the dose of FVIIIproduct were performed in patients who were treated on demand only.  Prophylaxis.  Ascertaining the moment when prophylaxis wastruly started is not always clear-cut, because of venous accessproblems or lack of cooperation of the child. Therefore, we de 󿬁 nedprophylaxis in 2 ways, analogous with the analysis of randomized BLOOD, 16 MAY 2013  x  VOLUME 121, NUMBER 20 FVIII TREATMENT AND INHIBITORS IN HEMOPHILIA A 4047 For personal use only.on November 3, 2014. by guest www.bloodjournal.orgFrom   controlled trials: the  “ per-protocol analysis ”  and  “ intention-to-treat analysis. ”  Regular prophylaxis.  First, the  “ per-protocol analysis ”  wasused to study the effect of regular prophylaxis on inhibitor devel-opment. Prophylactic FVIII infusions were all infusions of FVIIIgiven to prevent bleeding. The start of regular prophylaxis wasde 󿬁 ned as the moment on which at least 3 consecutive prophylacticFVIII infusions had been given within a period of at least 15 days. Itseffect was compared with on-demand treatment, which was de 󿬁 nedas FVIII treatment without any prophylactic FVIII exposures. From the moment that at least 1 prophylactic infusion was given, until thecriteria of regular prophylaxis were met, patients were categorizedinto a residual group, which was not included in the comparison.This analysis was designed to assess the maximal effect of prophylactic FVIII infusions.  Intention to start prophylaxis.  Second, in the  “ intention-to-treat analysis, ” weassessedtheeffectoftheintentiontostartprophylaxisoninhibitor development, regardless of any delays or failures to start regular prophylaxis. This analysis was designed to estimate the effect of a prophylactic treatment regimen in clinical practice, including anysurgeryforvenousaccessneededtoaccomplishprophylaxis.Withthisanalysis, we aimed to avoid potential overestimation of the effect of prophylaxis. Because the intention to start prophylaxis was not registered as such, we de 󿬁 ned it as the moment when either at least 1 prophylactic infusion was given or at the time of any surgicalprocedures to facilitate venous access (implantation of a centralvenous access device or creation of an arteriovenous  󿬁 stula).We assumed that after prophylaxis was started, its effect continued during the period up to the 75th exposure.  Dose and frequency of prophylaxis.  To investigate the effect of the dose and frequency of FVIII infusions in prophylaxis, regular prophylaxis was categorized into 4 arbitrarily de 󿬁 ned categories of prophylaxis: (1) once a week, less than 30 IU/kg/infusion; (2) once a week, more than 30 IU/kg/infusion; (3) more than once a week, lessthan 30 IU/kg/infusion; and (4) more than once a week, more than30 IU/kg/infusion. On-demand treatment was the reference. Start of prophylaxis.  Toassesstheeffectofstartingprophylaxisearly,wede 󿬁 ned “ startofprophylaxis < 15ED ”  asthe startofregular prophylaxis before a cumulative number of 15 or fewer exposuredays of on-demand treatment. Fifteen exposure days was chosenbecause this was the median number of exposure days at whichpatients started prophylaxis. Prophylaxis exposure days before a cumulative number of 15 or fewer exposure days were comparedwith on-demand treatment days. In these analyses, all prophylaxisexposure days of patients who started prophylaxis after their   󿬁 rst 15exposure days were censored. Varying prophylaxis effect.  The cumulative inhibitor incidencecurves for patients receiving prophylaxis and patients treated ondemand showed that the difference between these patients onlyoccurred later during treatment. For this reason, we also estimatedthe values of the HR allowing it to vary during 75 exposure days.The period of 1 to 75 exposure days was categorized into arbitrarilyde 󿬁 ned periods (1-10, 11-20, 21-30, 31-40, and 40-75 days). Effect of prophylaxis in patients with high-risk andlow-risk genotypes Prophylaxis may have a different effect in patients, dependent ontheir   F8  genotype. To investigate this, we assessed the relationshipbetween prophylaxis and inhibitor development according to thepresence of a high-risk or low-risk   F8  genotype. High-risk   F8  genemutations were large gene deletions, nonsense mutations, and intron1and 22 inversions;low-risk   F8 genemutations weresmalldeletionsand insertions, missense mutations, and splice site mutations. Sensitivity analyses of prophylaxis Several sensitivity analyses on the effect of prophylaxis wereperformed. The methods and results are described in supplementalmaterial. Data analyses We used survival analysis methods with the cumulative number of exposure days as the time variable instead of calendar time(pooled logistic regression). This method accounts for varying risksaccording to the cumulative number of exposure days, and itsinterpretation is similar to that of a Cox regression, with exposuredaysastime-variable andtime-dependentcovariates. 26 Patientswhohad not yet reached the study end point were included in theanalyses and were censored at the last exposure day. In the analyseswith  “ high titer inhibitor development  ”  as the outcome, censoringoccurred at the last exposure day in noninhibitor patients and at thelast exposure day at inhibitor development in patients with low titer inhibitors.HRsare interpretedas relativerisksthroughoutthe study.Crude as well as adjusted hazard ratios (aHRs) are presented. TheaHRs for time- 󿬁 xed determinants (treatment-related factors at the  󿬁 rst exposure) and associations assessed in patients treated on demandonly(FVIIIdoseanddurationbetweenexposuredays)werecalculatedusing multivariable pooled logistic regression models. We usedmarginal structural models with an inverse probability of treatment weighting to adjust the associations between time-varying determi-nants and inhibitor development for confounders. 27 We adjusted for possible determinants that could have confounded the speci 󿬁 cassociations studied, independent of their statistical signi 󿬁 cance inunivariate analyses.S.G. and J.G.v.d.B. analyzed the data. All authors have accessto the primary data. Role of the funding source TheRODINStudywassupportedbyunrestrictedresearchgrantsfrom Bayer Healthcare and Baxter Bioscience. The companies did not havea role in the study design, data collection, data analysis, or the writingof this manuscript. As agreed in the contracts, the companies receiveda copy of this manuscript 2 weeks before submission. Results Patient characteristics Figure 1 presents an overview of the study population. In thisstudy, 576 patients were included on whom detailed exposure data were available. The baseline and treatment characteristics arepresented in supplemental Table 1 and Table 1. Inhibitor development The overall cumulative incidence of inhibitors was 32.0% (95% CI,28.1-35.9). The cumulative incidence of high titer inhibitor devel-opment was 22.2% (95% CI, 18.7-25.8) (Figure 2).Of the 179 patients with inhibitors, 118 (65.9%) had high titer inhibitors and 61 (34.1%) had low titer inhibitors. Table 2 summarizesthe characteristics of the patients with inhibitors.Inhibitor development  4048 GOUW et al BLOOD, 16 MAY 2013  x  VOLUME 121, NUMBER 20 For personal use only.on November 3, 2014. by guest www.bloodjournal.orgFrom 
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