Drawing First Blood

Continued from page 72

Dr . Young : The other instance when I would prefer plasma-derived products is in patients who have already developed inhibitors . We also use plasma concentrates when we perform immune tolerance induction therapy , in which we give repeated doses of FVIII to try to eradicate inhibitors .

Results from a few case series , mostly international , have suggested that this is another advantage of plasma products : Using a plasma-derived FVIII with vWF in it eradicated inhibitors more effectively than recombinant FVIII . However , these two treatments have never been compared in a head-to-head study .

Dr . Dunn : We also have to be concerned about the high concentrations of vWF present in some plasma products . As the von Willebrand protein accumulates over time in patients who receive these products , it can put patients with bleeding disorders at increased risk of thrombosis – particularly if these agents are being used in high doses or before surgical procedures .

Also , the risk of thrombosis is particularly high in pediatric patients because children have lower volumes of blood than adults . On the other end of the spectrum , older patients with hemophilia who might have cardiovascular disease already have an elevated risk of thrombosis ; that risk will be

even higher if the patients are being treated with plasma FVIII concentrates that have greater vWF levels .

Still , the big problem with the SIPPET study is that plasma-derived concentrates did not eliminate inhibitors . Those patients still developed inhibitors , so there is clearly something about inhibitor development that we don ’ t understand .

Dr . Young : SIPPET was a randomized , controlled trial , and it provided pretty good evidence that the plasma-derived FVIII reduces the risk for inhibitors . Without strong evidence to the contrary , hematologists can argue that using plasma-derived FVIII with vWF may be more effective at eliminating inhibitors than recombinant products .

There also are published case series suggesting that the success rates for immune tolerance therapy are higher than for recombinant FVIII , but again , this hasn ’ t been studied in a head-to-head comparison . Conducting these types of trials is difficult because inhibitors are rare : In the U . S ., only 400 PUPs develop inhibitors each year , and only 30 percent of the entire population of patients with hemophilia develop inhibitors . Assessing therapies in both PUPs and patients with inhibitors is incredibly challenging .

Dr . Dunn : What we really need to figure out is why inhibitors develop in the first place . Then , we could decide if there is something about plasma-derived factor concentrates that have a protective effect against inhibitor development . The lack of knowledge about this complication is one of my biggest concerns . If we don ’ t understand the mechanism of inhibitor formation or who is at risk , how can we choose the best treatment option for a given patient ?

Hemophilia is not a single condition : It ’ s one of the most varied genetic conditions . Inhibitor discordance between monozygotic twins is well documented and indicates that a genetic mutation in and of itself does not predict inhibitor risk . There ’ s more to the story than just a patient ’ s genetic makeup . Learning more about inhibitor development will help us understand who is and isn ’ t at risk for inhibitors .

Of course , another question we can ’ t yet answer is how newer agents for hemophilia will affect these questions . With the recent U . S . Food and Drug Administration approval of emicizumab , the world of hemophilia care is poised to change dramatically . It may render the entire plasma-versusrecombinant debate moot ; we may be able to start patients on emicizumab when they ’ re young and don ’ t have bleeding

complications . In the future , the vast majority of patients with hemophilia might never be exposed to FVIII concentrates .

Dr . Young : I agree and I would predict that , over the coming years , we ’ re going to see factor replacement therapy slowly go away as we transition to subcutaneous therapies . These treatments are much easier to administer than factor replacement products – regardless of the type of concentrate . If we can administer a subcutaneous therapy that requires less frequent dosing , patients will want that option – and families are going to want that for their children .

We ’ re seeing the beginning of the end , so to speak . Factor replacement therapy is not going to disappear next year , but I think over the next five to 10 years , subcutaneous therapies and gene therapies might replace it . ●

REFERENCES

1 . Franchini M . Plasma-derived versus recombinant factor VIII concentrates for the treatment of haemophilia A : recombinant is better . Blood Transfus . 2010 ; 8:292-6 .

2 . Peyvandi F , Mannucci PM , Garagiola I , et al . Source of factor VIII replacement ( PLASMATIC OR RECOMBINANT ) and incidence of inhibitory alloantibodies in previously untreated patients with severe hemophilia A : the multicenter randomized Sippet study . Abstract # 5 . Presented at the 2015 ASH Annual Meeting ; December 6 , 2015 ; Orlando , FL .

3 . Peyvandi F , Mannucci PM , Garagiola I , et al . A randomized trial of factor VIII and neutralizing antibodies in hemophilia A . N Engl J Med . 2016 ; 374:2054-64 .