Guenter Auerswald

Intensity of factor VIII treatment and inhibitor development in children with severe hemophilia A: the RODIN study

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 hemophilia A. This cohort study aimed to include consecutive patients with a FVIII activity < 0.01 IU/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 was associated 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 higher inhibitor risk than low-dose FVIII treatment (aHR, 2.3; 95% CI, 1.0-4.8). Prophylaxis was only associated with a decreased overall inhibitor incidence after 20 exposure days of FVIII. 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, 0.19-2.0 and aHR, 0.85, 95% CI, 0.51-1.4, respectively). In conclusion, our findings suggest that in previously untreated patients with severe hemophilia A, high-dosed intensive FVIII treatment increases inhibitor risk and prophylactic FVIII treatment decreases inhibitor risk, especially in patients with low-risk F8 mutations.

New early prophylaxis regimen that avoids immunological danger signals can reduce FVIII inhibitor development

Summary.  The most problematic complication of haemophilia A treatment is the development of inhibitors to FVIII. The highest risk of developing inhibitors is during the first 20 exposure days (EDs). If the patient can be brought through this high risk period without inhibitor development, the subsequent risk is low. Therefore, as a pilot project, we developed a prophylaxis regimen for the first 20–50 EDs specifically designed to induce tolerance to the administered FVIII and to minimize inhibitor development by avoiding immunological danger signals. Twenty‐six consecutive previously untreated patients (PUPs) with severe haemophilia A were treated with the new prophylaxis regimen and the incidence of inhibitor development in this group was compared with that in a historical control group of 30 consecutive PUPs treated with a standard joint protection prophylaxis regimen (40–50 IU kg−1, three times a week). There were no significant differences between the study and control groups in patient‐related inhibitor risk factors such as ethnicity (all Caucasian), severity of haemophilia (all <1% FVIII), severity of FVIII gene mutation (P < 0.0006) nor in some treatment‐related factors such as product type, age at first exposure, vaccination regimen or the need for surgery. 14 of 30 subjects given standard prophylaxis but only one of the 26 subjects given the new regimen developed an inhibitor (P = 0.0003, odds ratio 0.048, 95% CI: 0.001–0.372). Our results indicate that minimizing danger signals during the first 20 EDs with FVIII may reduce the risk of inhibitor formation. These results should be confirmed in a larger prospective clinical study.

Pharmacokinetics of activated recombinant coagulation factor VII (NovoSeven) in children vs. adults with haemophilia A

Summary.  To establish the pharmacokinetic profile of activated recombinant coagulation factor VII (rFVIIa; NovoSeven®) in children with haemophilia A, and to compare it with the pharmacokinetic profile in adults with haemophilia A.

Health status and health-related quality of life of children with haemophilia from six West European countries

Summary.  A multicentre, international, cross‐sectional study was carried out in the frame of field testing of the first haemophilia‐specific quality‐of‐life (QoL) questionnaire (Haemo‐QoL). The aim of this paper is to describe health status and health care and their impact on QoL in haemophilic children in Western Europe. Children aged 4–16 years with severe haemophilia without inhibitors were enrolled by 20 centres in France, Germany, Italy, the Netherlands, Spain and the United Kingdom. Clinical information was collected by the physicians with a medical documentation form. Health‐related QoL (HRQoL) of children was assessed with Haemo‐QoL, available for three age groups. Clinical data were available in 318 patients, 85.5% with haemophilia A. The mean age at first bleeding was 11 months, at first joint bleed 25 months. Functional joint impairments were found in 11.3%. Prophylaxis treatment was given to 66.7% of children in whom breakthrough bleeds occurred 0.4 times a month compared to 1.1 bleeds in children receiving on‐demand treatment. A significantly higher factor consumption was found only in the two younger age groups of prophylaxis patients compared to on‐demand patients. HRQoL was satisfactory in this cohort: young children were impaired mainly in the dimension ‘family’ and ‘treatment’, whereas older children had higher impairments in the so‐called ‘social’ dimensions, such as ‘perceived support’ and ‘friends’. Health care of children in Western Europe is progressively improving with a large diffusion of home treatment and prophylaxis. This provides a high level of health status and HRQoL, being better in haemophilic adolescents on prophylaxis.

Treatment patterns and cost-of-illness of severe haemophilia in patients with inhibitors in Germany.

Summary.  To evaluate current treatment patterns and resource utilization as well as related cost in the management of severe haemophilia patients with inhibitors in Germany, a cost‐of‐illness study was conducted. Generally, data were generated by structured literature search. Missing data were collected by expert interviews. All data were validated by a panel of German experts in haemophilia care. In Germany, immune tolerance therapy (ITT) is first‐line therapy in inhibitor management for children in the initial year after inhibitor development, particularly for high responders (HR). In adult HR patients ITT is applied but to a remarkably lower extent than in children. To treat bleeding episodes, factor VIII (FVIII) is first‐line therapy in low responders (LR). For paediatric HR patients, bleeds are mainly treated with recombinant FVIIa (rFVIIa). In adult HR patients, activated prothrombin complex concentrate (aPCC) and rFVIIa are more equally distributed as treatment options. Treatment costs were calculated for paediatric patients (15 kg) and adult patients (75 kg) from third party payers’ perspective. Cost for ITT ranges from €70 290 (2 months; LR) to €3 812 400 (24 months; with aPCC; HR) in a paediatric patient. For an adult patient ITT cost ranges from €287 500 (6 months; LR) to €17 253 000 (36 months; HR). For on average 12.5 acute bleeds, average annual treatment costs amount to €77 000 for a child and €354 000 for an adult. Assessing the results it has been taken into consideration that ITT can last longer and annual number of bleeds can be extremely higher than on average 12.5 episodes. This indicates more health care resource consumption in some patients.

Prophylaxis in congenital factor VII deficiency: indications, efficacy and safety. Results from the Seven Treatment Evaluation Registry (STER)

Because of the very short half-life of factor VII, prophylaxis in factor VII deficiency is considered a difficult endeavor. The clinical efficacy and safety of prophylactic regimens, and indications for their use, were evaluated in factor VII-deficient patients in the Seven Treatment Evaluation Registry. Prophylaxis data (38 courses) were analyzed from 34 patients with severe factor VII deficiency (<1-45 years of age, 21 female). Severest phenotypes (central nervous system, gastrointestinal, joint bleeding episodes) were highly prevalent. Twenty-one patients received recombinant activated factor VII (24 courses), four received plasma-derived factor VII, and ten received freshfrozen plasma. Prophylactic schedules clustered into “frequent” courses (three times weekly, n=23) and “infrequent” courses (≤2 times weekly, n=15). Excluding courses for menorrhagia, “frequent” and “infrequent” courses produced 18/23 (78%) and 5/12 (41%) “excellent” outcomes, respectively; relative risk, 1.88; 95% confidence interval, 0.93-3.79; P=0.079. Long term prophylaxis lasted from 1 to >10 years. No thrombosis or new inhibitors occurred. In conclusion, a subset of patients with factor VII deficiency needed prophylaxis because of severe bleeding. Recombinant activated factor VII schedules based on “frequent” administrations (three times weekly) and a 90 μg/kg total weekly dose were effective. These data provide a rationale for long-term, safe prophylaxis in factor VII deficiency (clinicaltrials.gov: NCT01269138).

Haemate P/Humate-P for the treatment of von Willebrand disease: considerations for use and clinical experience.

Summary.  von Willebrand disease (VWD) is a heterogeneous bleeding disorder with symptoms in affected patients ranging from mild effects to potentially devastating haemorrhagic events. Desmopressin (DDAVP) and von Willebrand factor/factor VIII (VWF/FVIII) concentrates are the principal treatments. Haemate® P/Humate‐P® is an intermediate‐purity VWF/FVIII concentrate with extensive clinical experience in VWD. This concentrate has been shown to correct haemostatic defects of VWD, with efficacy ratings of good/excellent in nearly all patients treated for bleeding or surgical events. Haemate P/Humate‐P has a high content of the high molecular weight (HMW) VWF multimer fraction, which has been shown to be very effective in achieving haemostasis. The HMW VWF multimer pattern in Haemate P/Humate‐P is more similar to that of normal human plasma (94% for Haemate P/Humate‐P vs. 100% for normal human plasma) than that of other VWF/FVIII concentrates and correlates with functional VWF activities including ristocetin cofactor activity (VWF:RCo) and collagen‐binding activity. The recommended dosing of Haemate P/Humate‐P is based preferentially on VWF:RCo activity, which is approximately twice that of FVIII:C (2.4:1). Haemate P/Humate‐P has been shown to be safe; no serious adverse events or cases of thrombosis have been observed in clinical trials and no documented cases of viral transmission in nearly three decades of clinical use. While DDAVP is effective in a large proportion of VWD patients, it may not provide adequate haemostasis in all situations. In such cases, Haemate P/Humate‐P is an effective replacement concentrate for all types of VWD in both adult and paediatric patients.

Early prophylaxis/FVIII tolerization regimen that avoids immunological danger signals is still effective in minimizing FVIII inhibitor developments in previously untreated patients – long‐term follow‐up and continuing experience

of 100%. Thus, it is likely that this amino acid substitution might modify fibrinogen function. Cys227 is located in the D domain of fibrinopeptide B and involved in the formation of a disulphide bridge with Cys161 residue of the c chain (Cys227–Cys161). The substitution of cysteine at amino acid position 227 with phenylalanine residue causes the rupture of a disulphide bond, giving rise to an aromatic ring, as shown by a molecular modelling analysis (Figure 1, panel b). In another Italian series previously published by our group [5] among the four afibrinogenemic patients described, three carried an FGA mutation already present in database and 1 novel in the FGG. All showed severe bleeding episodes, requiring treatment with fibrinogen concentrate and/or plasma and blood transfusions. All those patients had clinically important haemorrhagic events. The FGB mutations are quite rare, when compared with the majority found in FGA [6]; they are of a particular interest, because it is well known that the synthesis of the Bb chain is the ratelimiting step in the production of mature protein [7]. Usually missense mutations are not often associated with afibrinogenemia, most of them being associated with hypofibrinogenemia (see http:// www.hgmd.cf.ac.uk/). Thrombotic events occurred in CAF patients who received factor concentrates [8]. However, although Pt1 was taking prophylactic infusions of fibrinogen, his plasma fibrinogen levels were undetectable soon after arterial thromboses. Thrombotic events unrelated to infusions of fibrinogen in such patients have been previously described [9,10] and do not still have an explanation. It has been suggested that, in the absence of fibrinogen, the small traces of thrombin usually formed, remain longer in the circulation as no absorption on circulating fibrinogen occurs [10]. Pt2 showed a spontaneous intracerebral bleeding and carried a substitution (Cys227Phe) in D domain of fibrinopeptide B. The observation of clinical histories of two probands confirms that CAF may go undetected until adulthood. Data from the literature and patients herein presented suggest that a primary prophylactic administration of fibrinogen should be considered with caution. On the contrary, prophylactic doses may be of help in CAF patients after traumatic events to prevent haemorrhagic complications.

PRO-PACT: retrospective observational study on the prophylactic use of recombinant factor VIIa in hemophilia patients with inhibitors.

INTRODUCTION Hemophilia patients with inhibitors have frequent bleeding episodes and often develop hemophilic arthropathy which is in contradistinction to non-inhibitor patients for whom prophylaxis prevents joint disease. Recently, two prospective trials have demonstrated that secondary prophylaxis with bypassing agents in inhibitor patients offers benefit by reducing bleeding episodes. This report describes the clinical experience of secondary prophylaxis in a large population of inhibitor patients. PATIENTS/METHODS This retrospective, observational study was performed by abstracting data from medical records of patients in whom secondary prophylaxis with rFVIIa was prescribed. Data were collected by professional medical record abstractors and included patient demographics, dosing regimens, bleeding events, and healthcare resource utilization. Data analysis was descriptive and included sensitivity analyses. RESULTS Data from 86 patients from 14 countries were collected. The primary outcome measure (% reduction in bleeding) was 46% (95% CI, -54.0 to -38.2) in patients with at least one bleeding episodes prior to starting prophylaxis and 52% (95% CI, -60.7 to -43.3) in patients with at least one bleeding episode per month prior to starting prophylaxis. A variety of subanalyses were performed, including among age and bleed location; the results for pediatric patients, adults, target and non-target joint bleeds categorizations were similar to the overall primary outcome. CONCLUSIONS The results in this large observational study are similar to those from the previously reported prospective study of prophylaxis with rFVIIa in inhibitor positive patients, although this study represents a more typical inhibitor population who utilized prophylaxis in the clinical setting. As such, prophylaxis should be considered a potentially effective therapy in hemophilia patients with inhibitors.

Experience of Advate rAHF-PFM in previously untreated patients and minimally treated patients with haemophilia A

Summary We report a prospective trial of 55 previously untreated patients (PUPs) and minimally treated patients (MTPs) with severe/moderately severe haemophilia A (baseline factor VIII [FVIII] ≤2%) treated with a single FVIII replacement product. It was the objective of this study to evaluate the immunogenicity, efficacy, and safety of rAHF-PFM (Advate ® ). Ondemand or prophylactic treatment regimens were determined at the discretion of the investigator. rAHF-PFM was also permitted for perioperative management. There were 633 bleeding episodes (BEs), including 517 treated, and 466 rated for efficacy. Haemostatic efficacy was considered excellent/good in 93% of 466 rated treatments. Of 517 treated BEs, 463/517 (90%) were managed with one (356/517 [69%]) or two infusions (107/517 [21%]). There were 27 surgeries. Intraoperative (n=22) and postoperative (n=25) haemostatic efficacies were considered excellent or good in 100% of rated surgeries. Related serious adverse events (SAEs) were inhibitor development in 16/55 (29.1%) subjects who received at least one infusion of rAHF-PFM. Nonserious, related adverse events (AEs) were few in number (14 in eight subjects). The odds ratio (OR [95% Confidence Interval, CI]) of developing inhibitors was significantly higher in subjects with a family history of inhibitor (4.95 [1.29–19.06]), non-Caucasian ethnicity (4.18, [1.18–14.82]), and intensive treatment at high dose (4.5 [1.05–19.25]) within ≤20 exposure days (EDs). In conclusion, rAHF-PFM was safe and effective for the management and perioperative coverage of PUPs/MTPs with severe/moderately severe haemophilia A. This report supports previous findings from studies in which family history of inhibitor, non-Caucasian ethnicity, and high intensity treatment were associated with high risk of inhibitor development.