Jeanne M. Lusher

Recombinant Factor VIII for the Treatment of Previously Untreated Patients with Hemophilia A -- Safety, Efficacy, and Development of Inhibitors

BACKGROUND Although methods of viral attenuation in plasma-derived clotting-factor concentrates have improved, there is still a possibility that such concentrates may transmit certain blood-borne viruses. For this reason, the use of recombinant DNA-derived factor VIII (which is virus-free) to treat hemophilia A has generated considerable interest. METHODS We conducted a multicenter trial in previously untreated children with hemophilia A. They received recombinant factor VIII for all treatment or for prophylaxis and were evaluated at their respective clinics at intervals of no more than three months. RESULTS Between January 1, 1989, and July 1, 1992, 95 patients who could be evaluated received recombinant factor VIII. By September 1, 1992, they had received the concentrate exclusively for 2.4 months to 3.5 years (median, 1.5 years). All responded well, with no treatment failures. A total of 3315 infusions were administered; there were three reports of minor adverse reactions. Inhibitor antibodies to factor VIII developed in 16 of 81 patients tested for them, after a median of nine days of exposure to factor VIII treatment. Inhibitor titers were or became low in 9 of the 16 patients despite continued episodic treatment with the concentrate. Inhibitors disappeared completely in 4 patients and remained at a low level (< 10 Bethesda units) in 5 patients receiving episodic treatment. CONCLUSIONS Transient or low levels of inhibitor, as observed in this study, may represent part of the natural history of hemophilia in infants. In view of the transient nature and lower concentration of the inhibitors detected and the generally satisfactory response to treatment, the benefits of recombinant factor VIII for the treatment of hemophilia seem to outweigh the risks.

Efficacy of prothrombin-complex concentrates in hemophiliacs with antibodies to factor VIII: a multicenter therapeutic trial.

The therapeutic efficacy of prothrombin-complex concentrates in patients with hemophilia and inhibitors (antibodies) to factor VIII has been increasingly debated. We therefore entered 51 hemophiliacs with factor VIII inhibitors into a double-blind randomized crossover study to compare two commercial prothrombin-complex concentrates (Konyne and Proplex) and an albumin placebo. Acute hemarthrosis of the elbow, knee, or ankle was treated with a single dose of a test preparation and assessed six hours later with objective and subjective criteria. In all measurements the concentrates were significantly more effective than the placebo. The data indicate that although prothrombin-complex concentrates, when used in a single dose, are only partially effective in the treatment of joint hemorrhage in hemophiliacs with inhibitors, their continued use for acute hemarthrosis is justified in the absence of any other effective and readily available therapy for this disorder.

Human Recombinant DNA–Derived Antihemophilic Factor (Factor VIII) in the Treatment of Hemophilia A

BACKGROUND Current treatment of hemophilia A, a hereditary disorder affecting approximately 1 in 10,000 males, relies on plasma-derived factor VIII concentrates. We tested the safety and efficacy of a recombinant factor VIII preparation for the treatment of this disorder. METHODS We conducted the investigation in three stages: comparing the pharmacokinetics of plasma-derived and recombinant factor VIII, assessing the efficacy of recombinant factor VIII for home therapy, and assessing its efficacy for major surgical procedures and hemorrhage. A total of 107 subjects with hemophilia, 20 of whom had not been treated previously, enrolled in the investigation. RESULTS The in vivo recovery and elimination half-lives of recombinant factor VIII equaled or exceeded those of plasma-derived factor VIII. Seventy-six subjects participated in a home-treatment program, using recombinant factor VIII for 69 to 807 days (median, 618); home diaries of 56 subjects treated for 5 months were analyzed. Of 540 bleeding episodes, 399 (73.9 percent) required only one treatment with recombinant factor VIII. The projected annual consumption of recombinant factor VIII was similar to that of plasma-derived factor VIII concentrate. Twenty-six subjects received recombinant factor VIII for 22 surgical procedures and 10 serious hemorrhages; hemostasis was excellent in all cases. De novo formation of inhibitors occurred in only 1 of 85 previously treated subjects. Inhibitor antibodies also developed in 6 of 21 children, 20 of whom had not previously been treated; 5 had low levels (less than or equal to 7.5 Bethesda units) despite continued treatment with recombinant factor VIII. There was no evidence of new formation of antibody to foreign proteins, and recombinant factor VIII was well tolerated. CONCLUSIONS Recombinant factor VIII has biologic activity comparable to that of plasma factor VIII and is safe and efficacious for the treatment of hemophilia A.

Clinical experience with recombinant factor VIIa.

Recombinant factor VIIa (rFVIIa) represents a major therapeutic advance in the treatment of haemophilia patients with inhibitors. The efficacy and safety of rFVIIa has been extensively studied in over 1900 surgical and non-surgical bleeding episodes in over 400 patients with haemophilia A or B (with or without inhibitors) or acquired haemophilia. Of 103 evaluable surgical bleeding episodes, the response to treatment with rFVIIa was considered to be either excellent or effective in 81%, 86% and 92% of major, minor and dental bleeding episodes, respectively. Treatment has been evaluated in 518 serious bleeding episodes and the response was considered either excellent or effective in 62% of muscle, 80% of ear, nose and throat, 88% of central nervous system, 76% of joint, and 75% of internal or retroperitoneal bleeding episodes. An excellent safety profile has also been demonstrated: of 1957 treatments with rFVIIa, only 16 serious adverse events have been reported that were considered to be possibly, but not necessarily, related to treatment.

A randomized, double-blind comparison of two dosage levels of recombinant factor VIIa in the treatment of joint, muscle and mucocutaneous haemorrhages in persons with haemophilia A and B, with and without inhibitors

Recombinant factor VIIa (rFVIIa) was developed to provide an improved procoagulant component capable of ‘by‐passing’ inhibitor antibodies in the treatment of haemophilic patients. The primary objective of this study was to compare the efficacy of two dosage regimens of rFVIIa (given intravenously at periodic intervals) in the treatment of joint, muscle and mucocutaneous haemorrhages in persons with haemophilia A and B with and without inhibitors. The study was designed as a randomized, double‐blind, parellel group, international multicenter trial. Patients were randomly allocated to treatment A: 35 μ kg−1 or B:␣70 μ kg−1, in blocks of 2. Within each block, one patient was assigned to the 35 μ kg−1 dosing regimen and the other to 70 μ kg−1 dose. One hundred and fifty subjects from 20 sites were screened for this study and 116 had baseline assessments. Of these, 84 were treated on the protocol and 32 were not treated in the study, in most cases because they did not return to the clinic with an eligible bleeding episode. One hundred and seventy‐nine bleeding episodes were treated, of which 145 (81%) were acute haemarthroses. Both treatments were efficacious, with 71% having an excellent (59% and 60%) or effective (12% and 11%) response. Overall, the mean and median number of doses given per episode of joint bleeding were 3.1 and 2, respectively. The mean number of doses was 3.1 for the 70 μ kg−1 group and 2.7 for the 35 μ kg−1 group (P value = 0.142). The study concluded that rFVIIa in a dosage of 35 μ kg−1 or 70 μ kg−1 is both safe and reasonably effective in the treatment of joint or muscle haemorrhages in haemophilic patients with inhibitor antibodies to factor VIII or factor IX. It is concluded that the appropriate dose for the treatment of joint and peripheral muscle bleeding in haemophilic patients with inhibitors is 35–70 μ kg−1 given at 2–3 h intervals until haemostasis is achieved.

Factor IX inhibitors and anaphylaxis in hemophilia B

PURPOSE We present clinical and laboratory data on 18 children from 12 hemophilia treatment centers in the United States, Canada, and Europe with the purpose of disseminating information regarding a recently recognized, potentially life-threatening complication of treatment in very young children with hemophilia B. PATIENTS AND METHODS Twelve hemophilia centers from the United States, Canada, and Europe provided clinical information and laboratory data concerning 18 children who had severe allergic reactions to infused factor (F) IX in close association with the development of an inhibitor to FIX. Laboratory testing for establishment of the diagnosis of hemophilia B and inhibitor to FIX was done locally at the centers treating these patients. FIX gene analysis was performed at one of six molecular genetics institutes. RESULTS All 18 children had severe hemophilia B, and in each an inhibitor antibody to FIX developed. The median age at the time of anaphylaxis (or anaphylactoid reaction) was 16 months, and the median number of exposure days to FIX was 11. The FIX inhibitor was detected almost simultaneously with the first occurrence of anaphylaxis in 12 of 18 patients. Maximum inhibitor titers were 4.5-600 Bethesda units (BU), with a median titer of 48 BU. FIX gene analysis, performed in 17 of 18 patients, demonstrated complete deletion of the FIX gene in 10 and major derangements in seven. Immune tolerance induction (ITI) regimens have been attempted in 12 patients, with generally poor responses. Two of the 12 experienced nephrotic syndrome while on ITI. Recombinant FVIIa has been successfully used to treat bleeding episodes in 11 of these children. CONCLUSION Physicians treating young children with hemophilia B should be aware of the potentially life-threatening complication of anaphylaxis. Children with complete gene deletions or major derangements of the FIX gene appear to be at greater risk. Those identified by genotype as being at greater risk may need to receive their first 10-20 treatments in a medical facility equipped for handling such emergencies. Recombinant FVIIa, although not licensed for use in the United States, appears to be the most suitable treatment option for bleeding episodes in such patients.

The safety and efficacy of B‐domain deleted recombinant factor VIII concentrate in patients with severe haemophilia A

BACKGROUND B-domain-deleted recombinant factor VIII (BDDrFVIII) was developed when the B-domain was found to be redundant for maintaining haemostasis. This allows formulation of the final product without albumin added as a stabilizer. METHODS Three multicentre clinical studies and one pharmacokinetic study were conducted in 218 patients to evaluate the safety and haemostatic efficacy of BDDrFVIII. RESULTS Previously treated patients (n = 113; median duration, 1711 days; median exposure days, 385; total 98,096,287 IU infused) rated 97-99% of all infusions as good or excellent efficacy. FVIII inhibitor was noted in one patient in the previously treated patient cohort after 113 exposure days. Among 101 previously untreated patients, responses to BDDrFVIII were rated as excellent or good in 92-95% of infusions (median duration, 1413 days; median exposure days, 148; total 12,636,458 IU infused). Thirty-two previously untreated patients developed inhibitors after a median duration of 12 exposure days (range, 3-49). Sixteen of 32 (50%) patients had low levels (< or = 5 Bethesda units) and 16 had high levels of inhibitors. Inhibitors disappeared in six of 14 (43%) of the high-level and six of eight (75%) of the low-level patients who underwent immune tolerance induction therapy. A total of 42 patients underwent surgery and the overall efficacy of BDDrFVIII was rated as excellent or good for 99.6% of infusions. CONCLUSIONS The results of these clinical studies indicate that BBDrFVIII is safe and effective and has haemostatic activity similar to that of full-length FVIII concentrates.

Frequency of inhibitor development in haemophiliacs treated with low-purity factor VIII

Clinical studies evaluating highly purified monoclonal-antibody-derived and recombinant-DNA-derived clotting factor concentrates in previously untreated (PUPS) severe factor VIII (FVIII) deficient haemophilia patients, have documented an increased frequency of inhibitors compared with that seen in patients who have received less pure products. However, a valid comparison of inhibitor frequency in patients treated with pure and less pure products has not been possible because appropriate studies have not been done in PUPS treated with the less pure products. To determine the frequency of inhibitor development in PUPS treated solely with less pure plasma-derived products (specific activities < 5 FVIII U/mg protein), we reviewed the records of all haemophilia patients born between 1975 and 1985 and treated with such products at any of seven centres. 89 patients with severe FVIII deficiency (< 1%) were observed and tested for inhibitors from birth to 5 years old or until 30 bleeding episodes had been treated. 25 of the 89 patients developed inhibitors (28%), and 21 of these 25 were high-titre responders (> 5 Bethesda units). This frequency of inhibitor development is greater than that reported in patients treated with monoclonal FVIII products, but the latter patients may not have been followed as long as the patients in our report. Our data may make possible a meaningful comparison with the frequency of inhibitor development in PUPS treated solely with recombinant-DNA-derived FVIII.

Intracranial and extracranial hemorrhages in newborns with hemophilia: a review of the literature.

PURPOSE Intracranial hemorrhage (ICH) and extracranial hemorrhage (ECH) in newborns with hemophilia were reviewed with respect to incidence, anatomic location, clinical presentation, and relationship to the mode of delivery and type of hemophilia. MATERIALS AND METHODS A MEDLINE search from 1964 to 1996 of all reports of neonatal hemophilia and head bleeds in children from birth to 1 month old was performed. ICH was defined as any bleed occurring within the cranial cavity, and ECH was defined as hemorrhage occurring outside of the cranial cavity, including subgaleal and cephalhematoma. The mode of delivery, type and severity of hemophilia, and clinical presentation were also noted. RESULTS One hundred two newborns with hemophilia and cranial bleeds were described in 33 publications. The cumulative incidence of ICH and ECH was 3.58% in 5 studies that reported the total newborn population or that examined birth records. The type of hemophilia was reported for 40 of 102 newborns and was hemophilia A in 87%. The mode of delivery was recorded in 46% (47 of 102) of the patients. Of these, 13% had cesarean delivery, and 87% were delivered vaginally (40% had spontaneous vaginal delivery, and 47% had vaginal delivery with vacuum extraction or forceps). There were 109 episodes of ICH and ECH (65% were ICH, 35% were ECH, and 5.8% were a combination of both). Common clinical features of ICH and ECH included anemia, hypotension, shock, and lethargy. However, only patients with ICH were reported to have neurologic deficits (15%) and late neurologic sequelae (38%). CONCLUSION In neonates with hemophilia and cranial bleeds, ICH occurs more often and is often associated with late neurologic deficits.

Perinatal management of newborns with haemophilia

The dawn of potentially curative strategies for haemophilia, advances in gene diagnosis and the availability of safer clotting factor concentrates for treatment and prophylaxis make it imperative that newborns with haemophilia be appropriately diagnosed and managed. They can then avoid the crippling consequences of haemophilia and avail themselves of a better quality of life. Additionally, once a diagnosis has been made, the infant’s parents should be provided with information concerning haemophilia, what to look for, when to seek medical advice and how to care for the child. Haemophilia A and B are X-linked bleeding disorders and can present with haemorrhage in the neonatal period. The genes for factor (F) VIII and F IX are located at the tip of the long arm of chromosome X. Haemophilia occurs in 1:5000 male births, affects all racial groups and is worldwide in distribution. Approximately 80‐85% of cases are haemophilia A (F VIII deficiency) and 15‐20% are haemophilia B (F IX deficiency). Based on plasma levels of F VIII or IX coagulant (F VIII:C or F IX:C), which usually correlate with disease severity, haemophilia is classified as mild (. 5% to , 40%), moderate (1‐5%) or severe (, 1%). Roughly twothirds of newly diagnosed infants have a family history of haemophilia, whereas one-third have no family history of haemophilia and are referred to as sporadic cases. Haemophilia in these infants is usually as a result of a mutation that arose in the infant’s mother or in one of the maternal grandparents. The most common genetic alteration is an inversion mutation (commonly referred to as the ‘flip tip’ mutation). This accounts for 45% of cases of severe haemophilia A, and 90% of the mothers of such patients are carriers (Antonarakis et al, 1995).