Page 2000 - Hematology_ Basic Principles and Practice ( PDFDrive )

1774 Part XI Transfusion Medicine

Recombinant Factor VIII Products AAV8-capsid specific T cells in the peripheral blood. These authors
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Highly purified recombinant factor VIII concentrates have been recently published an update on the long-term outcome of 10 men
licensed in North America, Europe, and Japan since the early 1990s. (22–64 years old) treated with gene therapy using the AAV8 con-
These are either full-length or B domain–deleted molecules (the B struct; the additional four patients received the high dose of the vector
domain is not required for activity in coagulation) that are expressed and had on average 5% factor IX levels, with a decrease in bleeding
in mammalian cell culture (Chinese hamster ovary or baby hamster episodes, sustained over 4 years. 79
kidney cell lines) and are purified using immunoaffinity techniques.
The development of these recombinant products was fueled primarily
by concerns regarding safety of the human blood donor pool and the Plasma/Cryoprecipitate
viral epidemics that occurred within the hemophilia population with
the use of early plasma-derived products. As with highly purified In communities where virally inactivated factor VIII concentrates are
plasma-derived factor VIII concentrates, the first-generation recom- not available, cryoprecipitate provides an effective alternative to
binant products are formulated with added albumin as a stabilizer. therapy with concentrates for hemophilia A and vWD patients.
“Second generation” products (Kogenate FS, Bayer, Refacto, Pfizer) Cryoprecipitate is a small-volume product (10–15 mL) enriched in
have been developed that stabilize the factor VIII molecule with factor VIII, vWF, fibrinogen, fibronectin, and factor XIII. Dosing can
nonprotein excipients. 73–75 Third-generation products (Advate, be calculated assuming approximately 80–150 IU of factor VIII per
Baxter, Xyntha, Pfizer) do not have human proteins or other additives bag of cryoprecipitate (derived from a 450-mL single whole blood
in the cell culture or as a stabilizer. Recombinant production methods donor collection unit). Thus, a typical 1750-IU dose (50% correction
that do not rely on the human plasma resource theoretically should for a 70-kg patient) would require between 10 and 21 bags or units.
provide for unlimited supply. The limitations of cryoprecipitate therapy are (1) lack of a viral
The first long-acting recombinant factor VIII product, Eloctate, inactivation step in manufacture of the component and (2) lack of
Biogen Idec, synthesized in a human embryonic kidney cell line, was convenience, because multiple units must be pooled into a large
US Food and Drugs Administration (FDA) approved in June 2014. volume (≈70–100 mL) for infusion. FFP and whole blood provide
It is a B domain–deleted factor VIII covalently linked to human less desirable alternatives because adequate therapy with both of these
immunoglobulin G1; this Fc fusion protein has extended the half-life products suffers from the limitations described for cryoprecipitate,
of factor VIII: in adults, almost 20 hours, 12–17 years old almost and their use often results in intravascular volume overload. Solvent/
16.5 hours, 6–11 years old about 14.5 hours and 2–5 years old, 12 detergent (S/D)–treated FFP product is available in some countries.
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hours. Almost all of the patients (99%) receiving Eloctate for 6 ABO group–specific S/D plasma is prepared by S/D treatment
months have been able to use the product every 3 days or longer to (TNBP and Triton ×100) of a pool of up to 2500 donors. After
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maintain a factor VIII level 1% to 3%. Eloctate, Biogen Idec, has removal of the solvent and detergent components, 200-mL aliquots
been used on demand, for prophylaxis and in the perioperative are refrozen for infusion.
setting. For prophylaxis, Biogen Idec recommends 50 IU/kg every 4
days and suggests personalizing the dose based on response, 25–65 IU/ Products Available for Treatment of Factor IX
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kg at 3–5 day intervals. The package insert also indicates that
children less than 6 years old, may require more frequent or higher Deficiency
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doses (up to 80 IU/kg). For minor and moderate bleeds, Eloctate
20–30 IU/kg can be given every 24–48 hours; however in children Factor IX Concentrates
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less than 6 years old, Eloctate should be given every 12–24 hours. As with replacement therapy for factor VIII deficiency, intermediate-
For major bleeding episodes, Eloctate 40–50 IU/kg should be given and high-purity products derived from plasma for the treatment of
every 12–24 hours and in children less than 6 years old, Eloctate factor IX deficiency are available, as well as a single recombinant
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should be given every 8–24 hours. Many other long-acting factor factor IX product. All of these concentrates also undergo at least one
VIII products are currently under investigation. viral inactivation or exclusion step in manufacture. The volume of
distribution of factor IX is approximately twice the plasma volume.
This can be explained in part by the affinity of factor IX for type IV
Novel Direction for Factor VIII Deficiency collagen present in the extracellular matrix. Recovery of factor IX
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after infusion is therefore approximately 1%/IU/kg. The recovery
In a phase I, dose escalating study, ACE910, Roche, a humanized observed with recombinant factor IX is approximately 20% lower
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bispecific antibody which binds both IXa and X, essentially mimick- than that observed with plasma-derived factor IX. This is likely
ing how factor VIII functions, was given to patients with severe caused by differences in posttranslational modifications between
hemophilia with (n = 11) and without inhibitors (n = 7); this unique recombinant factor IX and plasma-derived factor IX.
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agent was given subcutaneously weekly and was well tolerated. Intermediate-purity factor IX products are generally purified from
Further testing is needed but the possibility of a weekly subcutaneous plasma using anion-exchange chromatography or calcium or barium
injection would be life altering for patients with factor VIII deficiency, precipitate adsorption. These methods select for proteins that contain
both with and without inhibitors. highly negatively charged epitopes. The vitamin K–dependent (VKD)
coagulation factors, by virtue of their gamma-carboxyglutamic
acid–rich domains, are such proteins; thus, these techniques copurify
Gene Therapy for Factor IX Deficiency varying amounts of the other VKD coagulation factors, factor VII,
factor X, and prothrombin with factor IX. Hence, the products are
A landmark paper was published in December 2011 describing a referred to as prothrombin complex concentrates (PCCs). The levels of
phase 1 trial of the first six patients with severe factor IX deficiency vitamin K proteins in these products vary and can be obtained from
who received one peripheral IV injection of an adeno-associated virus the manufacturer. In addition, the PCCs are contaminated with trace
(AAV) expressing a factor IX gene, at three different doses. This amounts of activated forms of VKD factors. The presence of these
vector was selected as it does not intercalate into the host genome activated factors is the likely explanation for thromboses that have
and a capsid of AAV serotype 8 was added to avoid immunogenicity. occurred with the use of these intermediate-purity products, typically
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Another advantage of using this serotype is the propensity for it to in the setting of postoperative immobility or hepatic dysfunction.
home to the liver. Sixty-seven percent of the patients in the trial no To minimize the risk of thrombosis with the use of PCCs, it is
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longer needed prophylaxis and the other 33% needed less factor. advisable to achieve a peak factor IX level no higher than 50%.
Patients who received the highest dose experienced a transient eleva- Some clinicians add small amounts of heparin to infusions of these
tion of the alanine aminotransferase, between week 7 and 10, which products to prevent thrombosis, and some manufacturers have for-
resolved with prednisolone; this effect correlates with finding mulated PCCs with heparin or antithrombin III.