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Enhanced Half-Life Recombinant Factor VIII Concentrates for Hemophilia A: Insights from Pivotal and Extension Studies
Di Minno MND, Di Minno A, Calcaterra I, Cimino E, Dell'Aquila F, Franchini M
Seminars in thrombosis and hemostasis. 2020
Abstract
The development of enhanced half-life recombinant factor VIII (EHL-rFVIII) concentrates has improved the management of hemophilia. Furthermore, the chance of maintaining higher trough levels has allowed higher protection from bleeding and, in turn, improved safely performance for certain types of physical activity. The first technology used to improve the pharmacokinetic profile of factor VIII (FVIII) was fusion with the Fc domain of immunoglobulin G. More recently, conjugation to hydrophilic polymers of polyethylene glycol (PEG) has been demonstrated to prolong plasma half-life of FVIII by means of a reduction in clearance of the molecule due to steric hindrance by PEG covering the protein. Here we report results of a systematic review of pivotal studies on EHL-rFVIII concentrates. Significant heterogeneity is observed among different studies on EHL-rFVIII concentrates, and direct comparisons should be avoided. The annualized bleeding rate has ranged between 1.2 and 1.9 in different EHL-rFVIII concentrates, with a progressive further decrease during extension phases of pivotal studies. Zero bleeding was reported by 40 to 45% of patients. Overall, the emerging treatment options seem to be highly effective and safe, associated with a decreased dosing interval to twice weekly or less, which reduces, but does not entirely eliminate, the burden of treatment. Overall, further information is needed from real-life settings to permit differentiation between EHL-FVIII concentrates and for individualizing treatment.
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2.
Assessing options for treating haemophilia with inhibitors
Farrugia A, Hermans C, Franchini M
Haemophilia. 2015;21((3)):307-9.
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3.
Thrombotic adverse events to coagulation factor concentrates for treatment of patients with haemophilia and von Willebrand disease: a systematic review of prospective studies
Coppola A, Franchini M, Makris M, Santagostino E, Di Minno G, Mannucci PM
Haemophilia. 2012;18((3):):e173-87.
Abstract
Thrombotic adverse events (AEs) after clotting factor concentrate administration are rare but the actual rate is unknown. A systematic review of prospective studies (1990-2011) reporting safety data of factor concentrates in patients with haemophilia A (HA), haemophilia B (HB) and von Willebrand disease (VWD) was conducted to identify the incidence and type of thrombotic AEs. In 71 studies (45 in HA, 15 HB, 11 VWD) enrolling 5528 patients treated with 27 different concentrates (20 plasma-derived, 7 recombinant), 20 thrombotic AEs (2 HA, 11 HB, 7 VWD) were reported, including two major venous thromboembolic episodes (both in VWD patients on prolonged replacement for surgery). The remaining thrombotic AEs were superficial thrombophlebitis, mostly occurring at infusion sites in surgical patients and/or during concentrate continuous infusion. The overall prevalence was 3.6 per 10(3) patients (3.6 per 10(4) for severe AEs) and 1.13 per 10(5) infusions, with higher figures in VWD than in haemophilia. Thrombotic AEs accounted for 1.9% of non-inhibitor-related AEs. Thrombosis-related complications occurred in 10.8% of patients with central venous access devices (CVADs) reported in six studies, the risk increasing with time of CVAD use. Data from prospective studies over the last 20 years suggest that the risk of thrombotic AEs from factor concentrate administration is small and mainly represented by superficial thrombophlebitis. These findings support the high degree of safety of products currently used for replacement treatment. Copyright 2012 Blackwell Publishing Ltd.
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4.
Non-thrombotic-, non-inhibitor-associated adverse reactions to coagulation factor concentrates for treatment of patients with hemophilia and von Willebrand's disease: a systematic review of prospective studies
Franchini M, Makris M, Santagostino E, Coppola A, Mannucci PM
Haemophilia. 2012;18((3):):e164-72.
Abstract
In the last three decades there have been dramatic improvements in the availability and quality of treatment for people with inherited coagulation disorders. Indeed, the improvement of methods of purification and viral inactivation for plasma-derived coagulation factor concentrates first and then the development of products utilizing recombinant DNA technology have greatly improved the life expectancy of hemophiliacs, which has progressively become similar to that of males in the general population. Nowadays, the most frequent complication of factor replacement therapy for hemophilia is the development of inhibitors. However, no studies so far have systematically analysed the type and incidence of other adverse reactions following the administration of coagulation factor concentrates. The aim of this systematic review was to screen the published literature data to evaluate the types and frequencies of non-thrombotic-, non-inhibitor-associated adverse reactions to coagulation factor concentrates in patients with hemophilia A, hemophilia B and von Willebrand's disease. On behalf the European Haemophilia Safety Surveillance System (EUHASS), a systematic review of the prospective studies published in the last 20 years was performed using electronic databases and article references. Both severe and mild adverse events following infusion of coagulation factor concentrates are relatively rare in patients with inherited coagulation disorders; the most common events are of an allergic type. There are no differences in the rate of adverse events caused by plasma-derived or recombinant products. On the whole, these data confirm the high degree of safety of the products currently used for replacement therapy. Copyright 2012 Blackwell Publishing Ltd.
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5.
Cumulative inhibitor incidence in previously untreated patients with severe hemophilia A treated with plasma-derived versus recombinant factor VIII concentrates: a critical systematic review
Franchini M, Tagliaferri A, Mengoli C, Cruciani M
Critical Reviews in Oncology-Hematology. 2012;81((1):):82-93.
Abstract
Inhibitor development represents currently the most serious and challenging complication of clotting factor replacement therapy. A number of studies have analyzed the impact of the type of factor VIII (FVIII) replacement therapy (plasma-derived versus recombinant concentrates) on inhibitor development in hemophilia A patients with conflicting results. In order to shed light on this controversial issue, we performed a systematic review and meta-analysis on the published prospective studies evaluating the incidence rate of inhibitors in previously untreated patients (PUPs) with severe hemophilia A. Data from a total of 800 patients enrolled in 25 prospective studies published between 1990 and 2007 were included in this review. The quality of the studies was evaluated using two different systems: the Newcastle-Ottawa Scale (NOS) and STrengthening the Reporting of OBservational studies in Epidemiology (STROBE). Overall, the inhibitor incidence rate did not differ significantly between recipients of plasma-derived and recombinant FVIII concentrates (weighted means: 21%; 95% CI, 14-30 versus 27%; 95% CI, 21-33). Similarly, high titer inhibitors did not differ significantly between patients treated with plasma-derived (weighted means: 14%; 95% CI, 8-25) or recombinant FVIII concentrates (weighted means: 16%; 95% CI, 13-20). Thus, the main conclusion of this systematic review performed using selective criteria is that the type of FVIII product (i.e. plasma-derived versus recombinant FVIII concentrates) does not seem to influence the inhibitor rate in PUPs with severe hemophilia A.
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6.
The use of recombinant activated FVII in postpartum hemorrhage
Franchini M, Franchi M, Bergamini V, Montagnana M, Salvagno GL, Targher G, Lippi G
Clinical Obstetrics and Gynecology. 2010;53((1):):219-227.
Abstract
Severe bleeding remains a leading cause of morbidity and mortality in obstetrics. The first-line standard treatment of massive postpartum hemorrhage (PPH) includes medical measures directed at improving uterine tone, replacement of lost intravascular volume, blood and coagulation factors, and surgical or invasive procedures. Recently, a number of case reports or case series have reported the successful 'off-label' use of recombinant activated factor VII (rFVIIa) in PPH unresponsive to conventional treatments. In this review, a critical analysis of the published literature on the use of rFVIIa in severe PPH was performed. Overall, a total of 272 PPH women were collected among the largest case series and/or international registries. No randomized controlled trials have been conducted in this area. Currently, the literature data suggest that, at a median dose of 81.5 mug/kg, rFVIIa is effective in stopping or reducing bleeding in 85% of the cases. Finally, on the basis of the evidence from the literature and on own experience, we included some recommendations and an algorithm on the therapeutic role of rFVIIa in the management of PPH.
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7.
A critical review on the use of recombinant factor VIIa in life-threatening obstetric postpartum hemorrhage
Franchini M, Franchi M, Bergamini V, Salvagno GL, Montagnana M, Lippi G
Seminars in Thrombosis and Hemostasis. 2008;34((1):):104-12.
Abstract
The objective of this review was to evaluate and summarize the current literature on the unlicensed use of the novel agent recombinant activated factor VII (rFVIIa) in the management of major postpartum hemorrhage. After a systematic electronic search without temporal limits on MEDLINE, EMBASE, OVID and SCOPUS, the bibliographic references of all retrieved studies and reviews were additionally assessed for further reports of clinical trials. Unpublished works were also identified by searching abstracts from the most eminent conferences on this topic. In total, there were 31 studies that fulfilled our inclusion criteria. These studies incorporated 118 cases of massive postpartum hemorrhage treated with rFVIIa. The median age of the patients was 31.4 years, and cesarean section appeared to increase the risk of postpartum hemorrhage. At a median dose of 71.6 mug/kg, rFVIIa was reported to be effective in stopping or reducing bleeding in nearly 90% of the reported cases. Based on the evidence from the literature, we give some recommendations on the use of rFVIIa in massive postpartum hemorrhage. Nevertheless, although these reports suggest the potential role of rFVIIa in treating massive postpartum hemorrhage refractory to standard therapy, we advise particular caution in interpreting these results, as they are derived from few and uncontrolled studies. Further evidence is needed using well-designed clinical trials to better assess the optimal dose, the effectiveness, and the safety of rFVIIa in such critical bleeding conditions.
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8.
Potential role of recombinant activated factor VII for the treatment of severe bleeding associated with disseminated intravascular coagulation: a systematic review
Franchini M, Manzato F, Salvagno GL, Lippi G
Blood Coagulation & Fibrinolysis. 2007;18((7):):589-93.
Abstract
Recombinant activated factor VII (rFVIIa) is a novel hemostatic agent, originally developed for the treatment of hemorrhage in hemophiliacs with inhibitors, which has been successfully used recently in an increasing number of nonhemophilic bleeding conditions. In the present systematic review we report the existing literature data on the use of this hemostatic agent in severe bleeding, unresponsive to standard treatment, associated with disseminated intravascular coagulation. A total of 99 disseminated intravascular coagulation-associated bleeding episodes treated with rFVIIa were collected from 27 published articles: in the majority of the cases, the underlying disorder complicated by disseminated intravascular coagulation was a postpartum hemorrhage, while in the remaining cases it was a cancer, trauma, sepsis or liver failure. Although limited, the data available suggest that rFVIIa could have a potential role in this clinical setting. Large randomized trials are needed, however, to confirm the preliminary results and to assess the safety and dosing regimens of this agent in refractory bleeding associated with disseminated intravascular coagulation.
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9.
The potential role of recombinant activated FVII in the management of critical hemato-oncological bleeding: a systematic review
Franchini M, Veneri D, Lippi G
Bone Marrow Transplantation. 2007;39((12):):729-35.
Abstract
Recombinant activated factor VII (rFVIIa) is an hemostatic agent that was originally developed for the treatment of hemorrhage in patients with hemophilia and inhibitors. However, in the last few years rFVIIa has been employed with success in a broad spectrum of congenital and acquired bleeding conditions. In this systematic review we present the current knowledge on the use of this drug in patients suffering from hemato-oncological disorders, which are quite commonly complicated by severe hemorrhage. On the whole, data in the literature suggest a potential role for rFVIIa in the management of bleeding unresponsive to standard therapy in patients with hematological malignancies, including those undergoing bone marrow transplant. However, the vast majority of the currently available data are derived from uncontrolled studies including single cases or small series of patients. Thus, further trials with larger numbers of patients are needed to establish the most appropriate doses and timing of rFVIIa and to assess its efficacy and safety in this setting.