kurnik et al 2010 haemophilia

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ORIGINAL ARTICLE Clinical haemophilia

New early prophylaxis regimen that avoids immunologicaldanger signals can reduce FVIII inhibitor developmentK. KURNIK,* C. BIDLINGMAIER,* W. ENGL, H. CHEHADEH, B. REIPERT and G. AUERSW ALD*Klinikum der Universitat Mu ¨ nchen, Dr. von Haunersches Childrens Hospital, Munich, Germany; Baxter InnovationsGmbH, Vienna, Austria; and Prof. Hess Childrens Hospital, Klinikum Bremen-Mitte, Bremen, Germany

Summary. The most problematic complication of haemophilia A treatment is the development of inhibitors to FVIII. The highest risk of developinginhibitors is during the rst 20 exposure days (EDs).

If the patient can be brought through this high riskperiod without inhibitor development, the sub-sequent risk is low. Therefore, as a pilot project,we developed a prophylaxis regimen for the rst20–50 EDs specically designed to induce toleranceto the administered FVIII and to minimize inhibitordevelopment by avoiding immunological dangersignals. Twenty-six consecutive previously untreatedpatients (PUPs) with severe haemophilia A weretreated with the new prophylaxis regimen and theincidence of inhibitor development in this group wascompared with that in a historical control group of 30 consecutive PUPs treated with a standard jointprotection prophylaxis regimen (40–50 IU kg ) 1 ,three times a week). There were no signicant

differences between the study and control groupsin patient-related inhibitor risk factors such asethnicity (all Caucasian), severity of haemophilia(all <1% FVIII), severity of FVIII gene mutation

(P < 0.0006) nor in some treatment-related factorssuch as product type, age at rst exposure, vaccina-tion regimen or the need for surgery. 14 of 30subjects given standard prophylaxis but only one of the 26 subjects given the new regimen developed aninhibitor ( P = 0.0003, odds ratio 0.048, 95% CI:0.001–0.372). Our results indicate that minimizingdanger signals during the rst 20 EDs with FVIIImay reduce the risk of inhibitor formation. Theseresults should be conrmed in a larger prospectiveclinical study.

Keywords : danger theory, early prophylaxis, FVIIIinhibitors, haemophilia, immunological danger sig-nals, PUPs

Introduction

Today, the most problematic and costly complica-tion of the treatment of haemophilia A that remainsto be overcome is the development of inhibitoryantibodies (FVIII inhibitors) to FVIII replacementtherapy, particularly in previously untreated patients(PUPs). It is now becoming clear that inhibitordevelopment is a complex, multi-factorial immuneresponse involving both patient-specic and treat-ment-related factors [1–3]. It has been shown that

patients with severe defects in the FVIII gene, such aslarge deletions, inversions (most commonly intron 22inversion) and stop mutations are signicantly morelikely to develop inhibitors than are those with moreminor defects such as missense mutations, smalldeletions or insertions and splice site mutations [1].

Severe mutations in the FVIII gene are predicted tocause a complete decit of any endogenous FVIIIproduction. In these circumstances, FVIII cannot bepresented to the immune system during negativeselection of high-afnity autoreactive T cells in thethymus [4,5] and central immune tolerance againstFVIII cannot establish itself. FVIII in FVIII productsthat are given for replacement therapy to patientswho carry such mutations would be seen as a foreignprotein by their immune system. Why some of thesepatients develop FVIII inhibitors while others do notis far from clear. For many years immunologists

Correspondence: Karin Kurnik, PD, MD, Klinikum der Universita ¨tMu ¨nchen, Dr. von Haunersches Childrens Hospital, D-80337Munich, Germany.Tel.: +49 89 5160 2811/2853; fax: +49 89 5160 4453;e-mail: [email protected]

Accepted after revision 7 September 2009

Haemophilia (2010), 16 , 256–262 DOI: 10.1111/j.1365-2516.2009.02122.x

256 2009 Blackwell Publishing Ltd



believed that the immune system’s primary goal wasto discriminate between self and non-self [6,7].Matzinger introduced the concept that the primarydriving force of the immune system is the need todetect and protect against danger [8]. If a foreign or aself-antigen is not dangerous, immune tolerance isthe expected outcome [8]. In recent years, it has beensuggested that the ability of the immune system tosense danger is part of a more general surveillance,defence and repair system that enables multicellularorganisms to control whether their cells are alive ordead and to recognize when micro-organisms intrude[9–12]. Danger is transmitted by various signals thatare associated either with pathogens or with tissueand cell damage [9–12]. Pathogens express pathogen-associated molecular patterns (PAMPS) that arerecognized by pattern recognition receptors such astoll-like receptors (TLR), Nod1-like receptors

(NLRs) or Rig-I like receptors (RLRs) that areexpressed on a range of cells of the innate andthe adaptive immune system. Once these receptorsare triggered, several signaling pathways are acti-vated that can induce inammatory responses andthe activation of specic anti-pathogen immuneresponses. Evidence is accumulating that trauma,ischemia and tissue damage can cause inammatoryresponses that are very similar to responses inducedby pathogens [9–12]. Damaged cells release so calleddamage-associated molecular patterns (DAMPs) thatrecruit and activate receptor-expressing cells of theinnate immune system, including dendritic cells,granulocytes, monocytes or eosinophils, and thusdirectly or indirectly promote adaptive immuneresponses [9–12].

Based on the increasing evidence that both patho-gen-associated as well as cell-damage associatedmolecules present danger signals that can stimulateinammatory responses of the innate immune systemand thereby up-regulate antibody responses, weasked whether the prevention of such danger signalsduring treatment with FVIII products could decreasethe risk for the development of FVIII inhibitors inPUPs with severe haemophilia A. We minimized theexposure to immunological danger signals by avoid-ing rst treatment with FVIII in a bleeding situationor during infection, by avoiding surgery during therst 20 exposure days (EDs) and by avoidingvaccinations on the same day as FVIII treatments.Furthermore, any bleeds that did occur were treatedearly by giving higher doses immediately, therebyavoiding long and intensive treatment and shorteningthe time of tissue damage.

Our results indicate that minimizing danger signalsduring the rst 20 EDs with FVIII might indeed

reduce the risk of inhibitor formation. However,these results should be interpreted as hypothesisgenerating and need to be conrmed in a largerprospective clinical study.

Patients and methodsTwenty six PUPs in two centers in Germany withsevere haemophilia A (all <1% FVIII baselineactivity) with a variety of FVIII gene mutations,the majority high risk, were treated with a prophy-laxis regimen designed to induce immune toleranceby avoiding immunological danger signals. Theincidence of inhibitor development in this groupwas compared with that in a historical controlgroup of 30 children treated with a standard jointprotection prophylaxis regimen. To avoid selectionbias both study and control group consists of

consecutive PUPs with severe haemophilia A (<1%FVIII) as they appeared in the respective haemo-philia center during a given time period. Based onthe immunological danger theory and their potentialimpact on FVIII inhibitor development the newprophylaxis regimen was prospectively planned andimplemented as standard of care by January 2001 incenter A (Bremen) and by January 2005 in center B(Munich).

Study aim

The overall risk of developing inhibitors to FVIIIduring the rst 150 EDs is 20–30% for PUPs [13]. Of those developing inhibitors, 50% will do so withinthe rst 20 days and 95% during the rst 50 days[13]. If the patient can be brought through this highrisk period without inhibitor development, thesubsequent risk is low [14].

We therefore decided to test the efcacy inovercoming the high risk of the rst 50 EDs of aprophylaxis regimen specically designed to inducetolerance to the administered FVIII and to minimizeinhibitor development.

Treatment

According to the German haemophilia treatmentguidelines prophylaxis in children with haemophiliais standard of care [15]. Patients in the study groupwere treated with low dose prophylaxis, startingwith 250 IU once a week (corresponds to approx-imately 25 IU kg ) 1 week ) 1 ) as soon as a bleedingtendency manifested, either through soft tissue andmuscle bleeds or a signicant tendency for haemat-omas (Fig. 1). It was also introduced for ‘safety’

NEW REGIMEN CAN REDUCE INHIBITOR DEVELOPMENT 257

2009 Blackwell Publishing Ltd Haemophilia (2010), 16 , 256–262



reasons as bleed prophylaxis after child-felt trauma(i.e. typical head trauma without bleeding signs).Prophylaxis was initiated without insertion of aPort-A-Cath after a minimal number of on-demandFVIII exposures. In patients with early joint bleedsprophylaxis was introduced at the higher frequencyof 25 IU kg ) 1 twice a week, and in those with earlysevere joint or life threatening bleeds at 25–50 IU kg) 1 three times a week. When required bythe severity of the bleeding tendency the frequencywas increased from one per week to two per weekor three per week. For tolerization (as also knownfrom ITI programs in inhibitor patients) it seems tobe important to give prophylactic FVIII dosesalways on the same weekday and to avoid inter-rupting the prophylaxis regimen even when addi-tional on-demand FVIII doses to manage bleeds aregiven.

During this ‘tolerization’ period, immunologicaldanger signals were minimized by avoiding givingrst FVIII in a severe bleeding situation or duringan infection, avoiding surgery during the rst 20EDs, avoiding giving vaccinations on the same dayas FVIII and giving all vaccinations subcutaneouslyrather than intramuscularly. Any bleeds that didoccur were treated early by giving a higher thanthe prophylactic dose immediately, thereby avoid-ing long or intensive treatment. Patients in thestudy group were tested for inhibitors every 3–4EDs.

Patients in the control group were treated with astandard joint-protection prophylaxis regimen of 40–50 IU kg ) 1 FVIII three times a week, starting ator after the rst joint or other severe bleed. Pleasenote that some of the patients in the control group

(n = 8) developed their inhibitors already during on-demand therapy before they entered a standardprophylaxis program. The vaccination guidelineshave been the same for both the study and thecontrol group.

Statistical analysis

Differences in inhibitor development between thestudy group and the historical control group wereanalysed by Fisher’s exact test and odds ratios (OR).

The effect of potential determinants on inhibitorrisk such as FVIII gene mutation and type of product(recombinant vs. plasma-derived FVIII) was evalu-ated for the two groups in a logistic regressionmodel.

Differences between the two study groups of treatment-related parameters such as median EDsbefore prophylaxis and age at start of prophylaxiswere assessed by Wilcoxon test.

Results

Fifty six of the 58 subjects studied had more than100 EDs to FVIII therapy. Data from these wereanalysed for inhibitor development and both patient-related and treatment-related factors which mighthave affected inhibitor development.

There were no signicant differences between thestudy and control groups in any patient-relatedfactors (Table 1), nor in the majority of treatment-related factors (Table 2). In a logistic regressionmodel for inhibitor development with factors forstudy group (standard vs. new regimen prophylaxis),genetic risk for inhibitor development (low vs. high),

1 x weekly25 lU kg –1

When bleeding pattern requests:2 x 25 lU week –1 3 x 25 lU week –1

Fig. 1. Treatment scheme for PUPs receiving the new prophylaxis regimen.

25 8 K. KURNIK et al.

Haemophilia (2010), 16 , 256–262 2009 Blackwell Publishing Ltd



and type of factor concentrate (recombinant vs.plasma-derived), only the type of prophylaxis regi-men had a signicant effect ( P = 0.005). Logisticregression analysis was not performed for the risk of high responder inhibitors due to lack of events inpatients given the new regimen.

There were however highly signicant differencesbetween groups for the prophylaxis-related factors:age at start of prophylaxis and the number of EDsbefore the introduction of prophylaxis (Table 3).Whereas the new prophylaxis regimen was startedafter a median of 1 FVIII EDs at a median age of 10.7 months compared to the historical controlgroup were high dose prophylaxis was started later

after a median of 30 FVIII on-demand EDs at amedian age of 19 months ( P < 0.006).

Age at start of prophylaxis was available for 23 of the 30 subjects in the standard prophylaxis group andall 26 subjects given the new regimen. The median ageat start of prophylaxis was 19 months (range 0.8–87)for those given standard prophylaxis and10.7 months(range0.5–24.5) for those given thenewregimen. Thisdifference is highly signicant ( P < 0.0006).

Standard prophylaxis had been introduced after amedian of 30 EDs (range 1–innity) whereas the newregimen was introduced after a median of 1 ED(range 0–14). This difference too is highly signicant(P < 0.0001).

Table 1. Patient-related risk factors for inhibitor development in the study group compared with the control group.

Control group(standard prophylaxis regimen)

(n = 30)

Study group(new prophylaxis regimen)

(n = 26)Statistical

signicance

Demographics – BremenBorn between March 1995–December 2000 January 2001–July 2007 Not signicantEthnicity All Caucasian ( n = 15) All Caucasian ( n = 13)Demographics – MunichBorn between January 2002–September 2004 January 2005–October 2007 Not signicantEthnicity All Caucasian ( n = 15) All Caucasian ( n = 13)Genetic factorsSeverity of haemophilia A All <1% FVIII activity All <1% FVIII activity Not signicantFVIII mutation type*:High risk (%) 24 (80) 18 (69) Not signicantLow risk (%) 5 (17) 8 (31) Not signicantUnknown (%) 1 (3)

*Categorization of genetic risk according to Oldenburg J, Pavlova A. Genetic risk factors to inhibitors against FVIII and IX. Haemophilia2006; 12 (Suppl. 6): 1–8.

Table 2. Treatment-related risk factors forinhibitor development in the study groupcompared with the control group.

Control group(standard prophylaxis

regimen)(n = 30)

Study group(new prophylaxis

regimen)(n = 26)

Statisticalsignicance

Product typerFVIII (%) 16 (53) 15 (58) Not signicantpdFVIII (%) 14 (47) 11 (42)Age at rst exposureMedian (months) 9.8 8.1 Not signicantRange (months) 0.1–22 0–21Reason for rst

exposureBleed (%) 21 (70) 12 (46) Not signicant:

P = 0.103Safety (%) 9 (30) 14 (54)Total EDs* >100 >100 Not signicantSurgeryWithin the rst 20 EDs 3 2 Not signicantVaccinationGiven i.m. 1 All no Not signicantGiven on a FVIII day All no All no

*As on August 2009.





Fourteen of the 30 subjects given standard pro-phylaxis and one of the 26 subjects given the newprophylaxis regimen developed an inhibitor. Thedifference between the groups was highly signicant(P = 0.0003, OR 0.048, 95% CI: 0.001–0.372)(Table 4).

Eight subjects given standard prophylaxis but none

of those given the new regimen were high responders.The difference between groups was again signicant(P = 0.005, OR for high response 0.00, 95% CI:0.00–0.57) (Table 4). Inhibitors in the control groupdeveloped after a median of 11 EDs (range: 3–170EDs) which is well in agreement with a recentinternational study [16].

The cumulative inhibitor incidence in the studygroup on the new prophylaxis regimen was reducedby 95% (OR 0.048) as compared to the controlgroup on a standard protocol ( P = 0.0003, 95% CI:0.001–0.372) (Fig. 2).

As a post-hoc analysis, these results should beinterpreted as hypothesis generating. Conrmation ina prospectively planned, historically controlled studywould be warranted.

Discussion

It may be considered that the overall risk of developing an inhibitor reects the level of dangersignals perceived by the patient’s immune system. It

is not, therefore, surprising that on-demand treat-ment which is, by denition, given in the presence of bleeding should cause inhibitor development morefrequently than prophylaxis.

The value of prophylactic factor replacementtherapy in the prevention of severe joint bleeds andarthropathy is now well established [17], and is

increasingly being adopted as the standard approachto treatment of haemophilia A. However, even inthose countries, such as Sweden, where prophylaxisis virtually universal there has been no reduction inthe overall incidence of inhibitors in PUPs [18]. Theprophylaxis regimens employed have been designedfor joint protection, with relatively high doses of concentrate such as 50 IU kg ) 1 three times per week.Because they are usually introduced at or just afterthe rst signicant joint bleed, the FVIII is beingintroduced at a time when there are strong immuno-logical danger signals present, to an immune systemwhich has already been ‘primed’ by previous on-demand therapy. Therefore, prophylaxis might starttoo late to prevent inhibitor formation.

An effective prophylactic regimen for the treatmentof PUPs without the development of inhibitors musttake into account and avoid known danger signals,such as bleeding associated with tissue damage,immunological challenges such as vaccination, orinfection. This would permit the immune system todevelop tolerance to the foreign protein in a ‘non-

Table 3. Prophylaxis-related factors forinhibitor development in the study groupcompared with the control group.

Control group(standard prophylaxis

regimen)(n = 30)

Study group(new prophylaxis

regimen)(n = 26)

Statisticalsignicance

Age at start of prophylaxis (n = 23) (n = 26)Median (months) 19 10.7 Highly signicant:

P < 0.0006Range (months) 0.8–87 0.5–24.5EDs before prophylaxisMedian 30 1 Highly signicant:

P < 0.0001Range 1–innity 0–14

Table 4. Inhibitor development in thestudy group compared with the controlgroup.

Control group

(standard prophylaxisregimen)(n = 30)

Study group

(new prophylaxisregimen)(n = 26)

Statistical

signicance

Inhibitors (%) 14 (47) 1 (3.8) Highly signicant:P = 0.0003

OR 0.048 (95% CI:0.001–0.372)

High responders (%) 8 (27) 0 Highly signicant :P = 0.005

OR of high response0.00 (95% CI:

0.00–0.57)

Low responders (%) 6 (20) 1 (3.8)





threat’ situation. The results of this study demonstratethat this approach with an early start of low doseprophylaxis once weekly might have the capacity todramaticallyreducethe incidence of inhibitors, even in

high-risk patients, from the normally expected level,which in PUPs has been around 30% [1,13].

It remains difcult to judge which parameters of the new prophylaxis regimen were of major inuenceon inhibitor development: the low number of on-demand exposures before prophylaxis, the lowdose/frequency of the prophylaxis regimen, theyoung age at start of prophylaxis or a combinationof some or of all of them. The avoidance of rst FVIIIexposure during a severe bleeding episode might be adirect protector from inhibitor development whereasthe age, however, might play only an indirect role as

the earlier prophylaxis is started the more likely thePUP can reach >50 ‘tolerizing’ EDs without the needfor intensive treatment due to a severe joint bleed.

However future studies will have to evaluate thesignicance of single treatment-related factors andfurther rene the optimal regimen for inducingimmunotolerance.

We are aware of the fact that our results can onlybe considered as hypothesis generating and need tobe conrmed in a larger prospective clinical study.

Our results also suggest that early introduction of FVIII is a more satisfactory way of avoiding inhibi-tors than attempting to delay the use of FVIII, forexample by treating bleeds with rFVIIa [19]. Startingwith prophylaxis early in life, in our study at amedian age of 10.7 months, was not associated withan increased inhibitor risk, a nding that is well inline with other recent studies [20,21].

A low dose, escalating regimen may also provide abetter long-term outcome for patients, with lessfrequent joint bleeds and better joint scores, due tothe earlier start on prophylaxis. The benecial effecton joint outcomes is hard to explain, since a weeklyprophylaxis regimen cannot maintain FVIII levels

above 1%. Nevertheless, benet from a regimensimilar to ours has been demonstrated in a 10-yearstudy into the Canadian tailored primary prophy-laxis regimen [22]. This regimen differs from ourproposed regimen in using higher doses, introducingprophylaxis only after a joint bleed has occurred andstepping up only after inadequacy of dosage isdemonstrated by several joint bleeds or developmentof a target joint. This benecial effect should be thesubject of further study.

As well as its key role in preventing inhibitordevelopment, the new prophylaxis regimen offers anumber of other advantages. With once a weekadministration, it is not necessary to insert a Port-A-Cath, thereby avoiding surgery. If the initial dosageproves inadequate, it may still be possible to avoid theneed for a Port-A-Cath by increasing the individualdose rather than the frequency of dosing. Avoiding the

need for a Port-A-Cath is probably a major advantagefor the induction of immune tolerance to FVIIIbecause any surgical procedure is likely to be associ-ated with some form of tissue damage together withthe generation of danger signals.

Once weekly administration is also simpler forparents, requiring only one visit to the haemophiliacenter each week, so that concordance is easier toachieve with a consequent improvement in control.

There is also a pharmacoeconomic benet in thatlower doses and less frequent treatments can allowconsiderable cost savings compared with standardprophylactic regimens.

Conclusions

Summarizing our results, we conclude that early startof prophylaxis associated with minimizing immuno-logical danger signals during the rst 20 EDs withFVIII should be considered for future therapy of patients with severe haemophilia A to reduce the riskof inhibitor formation. Once the patients havedeveloped tolerance to FVIII, usually after about20–50 EDs on the low dose regimen, and venousaccess permitted, prophylaxis might be changed tothe normal three times weekly regimen for optimaljoint protection (Fig. 1).

Acknowledgements

The authors thank Baxter for support in develop-ment of this manuscript. The Munich centre thanksMartin Olivieri and Susan Jenkins for valuablesupport on patient care and data collection. It alsoacknowledges greatly the work of the coagulationlaboratory of Prof. Dr W. Schramm. The Bremen

Fig. 2. Cumulative inhibitor incidence with increasing number of EDs: control vs. study group.





centre thanks Dr Julia Johne and Dr David Overbergfor intensive support on data collection.

Disclosures

G. Auerswald, K. Kurnik and C. Bidlingmaier havebeen reimbursed for attending and/or speaking atand/or organizing several symposia on the behalf of several pharmaceutical industries.

K. Kurnik received funding for research by Baxter,CSL Behring, Bayer, Wyeth/Pzer; C. Bidlingmaierby CSL Behring, Bayer, and Wyeth/Pzer, and G.Auerswald by Baxter, CSL-Behring and NovoNor-disk.

B. Reipert, W. Engl and H. Chehadeh are Baxteremployees.

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