Therapy for acquired hemophilia A primarily involves bleeding management and inhibitor eradication. In addition, there is still a lot of educational work to be done on this rare disease. The congenital form, on the other hand, is better known. There are currently new therapeutic developments in this area. What does the future hold?
Acquired hemophilia A (AHA), with 1.5 cases per million population/year, is a rare but dangerous emergency with high morbidity and mortality and thus great diagnostic and therapeutic relevance, according to Françoise Boehlen, MD, HUG Geneva. In contrast to the congenital form, in the acquired form, neutralizing (mostly IgG) inhibitors are spontaneously produced in the course of an autoimmune disease, which target the endogenous coagulation factor VIII (FVIII) – this predominantly in the C2, more rarely in the A2 domain. The development of autoantibodies may occur due to an out-of-control immune system associated with rheumatologic, inflammatory bowel and other autoimmune diseases, as well as tumors and severe infections or pregnancy. However, the idiopathic form is most common. An interplay between genetic and environmental factors is suspected. Predominantly affected is the older population.
This should be considered in any case of acute or recent onset of spontaneous bleeding symptoms (severe in two-thirds of cases) in elderly or peri- and postpartum patients. The hemorrhages present predominantly subcutaneously, but also as muscular and gastrointestinal hemorrhages, and less commonly urogenital, retroperitoneal, and intracranial. On the laboratory side, a prolonged activated PTT (partial thromboplastin time), which, by the way, can also occur in about 5% in isolation without bleeding, indicates possible factor VIII inhibition – although other causes must be excluded. This is corroborated by a factor administration/plasma exchange experiment (i.e. normal plasma is added to the patient’s plasma and the effect on aPTT is observed), confirmed resp. finally quantified by testing for the antibody (amount of inhibitor in the blood in Bethesda units).
Management of the AHA is based on four basic principles
An update on the evidence and therapy was most recently provided by Kruse-Jarres and colleagues [1]. Four basic principles make up the management of rare disease:
Prevention of bleeding: Educate healthcare professionals and patients, prevent trauma and unnecessary invasive treatments, avoid intramuscular injections, intra-arterial and traumatic punctures, aspirin, NSAIDs and anticoagulants.
Bleeding control: if bleeding is active, treatment must be initiated regardless of inhibitor titer and residual FVIII activity. First-line hemostasis therapy currently consists of recombinant activated coagulation factor VIIa (NovoSeven®) or activated prothrombin complex concentrates (FEIBA®) with factor VIII inhibitor bypass activity. Similar efficacy in terms of bleeding control of over 90% can be assumed, although no direct head-to-head comparisons exist. Therefore, the choice is made based on local availability and experience, prior patient response, and economic considerations. Unfortunately, clear laboratory assays for monitoring the hemostatic effect – in addition to clinical assessment – are currently not established. There is also a potential arterial and/or venous thrombosis risk.
Alternatively, or in the absence of availability and deep inhibitor titers, desmopressin and substitutes such as human factor VIII concentrates or even Obizur®, a recombinant factor VIII lacking the B-domain porcine sequence (rpFVIII) [2], can be used. The latter compound also replaces the missing component and causes measurable FVIII levels and hemostasis in AHA – even at high inhibitor titers. For monitoring, the one-step coagulation test for factor VIII is recommended. Safety considerations include (de novo) inhibitors on rpFVIII and the sometimes very high FVIII levels in some patients. However, thrombotic events, allergic reactions, thrombocytopenias, or other serious adverse events did not occur in the 28 AHA patients studied.
Inhibitor eradication: since spontaneous remission is possible but unpredictable and mortality can be reduced by immunosuppressive therapy, such therapy should be considered in all adult patients with AHA. In the first line, corticosteroids alone or with cyclophosphamide/rituximab may be considered (the latter is not recommended as initial mono-treatment except in the presence of contraindications). Complete, stable remission, i.e., no detectable inhibitor levels, FVIII at >70 IU/dl, and immunotherapy stopped, is achieved in 48%, 70%, and 59%, in the above order, according to registry data [3], with rituximab regimens appearing to take slightly longer to achieve remission. There was no difference in long-term survival. Complications, particularly in the form of infections, are a risk for increased mortality in this older, fragile population. Prospectively, a stepwise approach with corticosteroids alone and addition of cyclophosphamide/rituximab as needed resp. Failure to achieve remission ultimately resulted in a rate of 61% of patients with complete remission after a median of 79 days. Particularly low baseline FVIII activity (<1 IU/dl) negatively affected remission and duration to remission, as well as survival [4]. Recurrences seem to affect patients with IgA autoantibodies against FVIII, but also those with corticosteroid therapy alone more.
Treatment of the underlying disease/condition: Of the above factors that may be associated with AHA, pregnancy accounts for approximately one-tenth of cases, often being the first pregnancy (recurrences in second pregnancies then relatively rare) and symptoms may continue to occur days to months after delivery. The prognosis is good, and the rate of spontaneous remissions is relatively high at over 60%. Nevertheless, even with an AHA during pregnancy, therapy with corticosteroids alone should be considered to prevent the potential harm of hemorrhage to both mother and child.
Emicizumab – new substance on the horizon
What place the new hemostatic agents such as emicizumab, fitusiran, etc. will have in the AHA’s therapeutic spectrum in the future is currently unclear. Prof. Dr. med. Manuela Albisetti from the University Children’s Hospital Zurich went into more detail about their role in congenital hemophilia. Treatment has made great strides in recent decades – from cryoprecipitates in the 1960s to the first factor concentrates derived from human plasma to today’s genetically engineered, so-called recombinant (also long-acting) products. The repeated i.v. infusions, the immunogenicity, i.e. inhibitor formation (in about 30% with severe hemophilia A – with the mentioned long-acting concentrates, however, at least in previously treated patients no longer a problem), and the immune tolerance induction with a failure rate of about 20% and corresponding costs represent limitations of the current hemophilia treatment. Alternative approaches such as FVIII mimetics, inhibition of physiological anticoagulants, or gene therapy are therefore of great research interest. Various approaches are now in phase III clinical development or have already been approved in some cases.
One of the most promising new agents is emicizumab (already approved in the US and Europe for prophylaxis in children and adults with hemophilia A and inhibitors; currently under review at Swissmedic). It is a bispecific antibody that replaces the function of FVIII by binding coagulation factors IXa and X. Emicizumab is not expected to induce inhibitors against FVIII due to its lack of structural homology to FVIII, nor is it expected to be affected by the possible presence of such inhibitors. It is administered subcutaneously once a week.
The “open-label” HAVEN 1 trial [5] included patients aged 12 years and older with hemophilia A and Inhibitors previously treated episodically (group A and B) or prophylactically (group C) had received bypass preparations. In the primary endpoint, treated bleeding, prophylaxis with emicizumab (group A) of the comparison group without prophylaxis (group B) as superior: A total of 2.9 such events occurred annually with the agent, compared with 23.3 without, a significant difference of 87% (p<0.001). Results were consistent across subgroups – as well as in secondary endpoints such as spontaneous bleeding or joint hemorrhage. 63% vs. 6% suffered from no corresponding bleeding at all during the study period. Emicizumab also performed significantly better compared with prophylaxis with bypass preparations (group C) (79 percent reduction in bleeding rate, p<0.001). Adverse events are mainly reactions at the injection site. Antibodies against the active substance did not form in any patient. Thrombotic microangiopathies were evident in three patients previously treated with high cumulative doses of aPCC for several days (because of breakthrough bleeding). After aPCC stop, the situation improved rapidly. Two other patients suffered from thrombotic events.
The results of HAVEN 2 with children under twelve years of age have not yet been published, but were presented at the ISTH Congress in Berlin 2017. The mean annual rate of treated bleeding here was 0.4, with nearly 95% of participants showing no such bleeding at all (median observation time 12 weeks). Again, substantial bleeding reduction was found with emicizumab versus bypass prophylaxis. In all cases, the rates with the bispecific antibody tended toward 0. Thromboembolism or thrombotic microangiopathies were not observable, nor were antibodies to the active substance.
“In general, new approaches that are not based on a direct replacement of the missing factor are highly welcome – especially for inhibitor patients. The question is: Is immune tolerance induction then still needed at all, or what role do the new agents take in hemophilia patients who have not (yet) developed inhibitors? What about previously untreated individuals and what safety signals will we still see in the long term? These are all questions that will need to be answered in the future,” the speaker concluded.
Source: Swiss Oncology & Hematology Congress, June 27-29, 2018, Zurich.
Literature:
- Kruse-Jarres R, et al: Acquired hemophilia A: Updated review of evidence and treatment guidance. Am J Hematol 2017 Jul; 92(7): 695-705.
- Kruse-Jarres R, et al: Efficacy and safety of OBI-1, an anti-haemophilic factor VIII (recombinant), porcine sequence, in subjects with acquired haemophilia A. Haemophilia 2015; 21: 162-170.
- Collins P, et al: Immunosuppression for acquired hemophilia A: results from the European Acquired Haemophilia Registry (EACH2). Blood 2012 Jul 5; 120(1): 47-55.
- Tiede A, et al: Prognostic factors for remission of and survival in acquired hemophilia A (AHA): results from the GTH-AH 01/2010 study. Blood 2015 Feb 12; 125(7): 1091-1097.
- Oldenburg J, et al: Emicizumab Prophylaxis in Hemophilia A with Inhibitors. N Engl J Med 2017 Aug 31; 377(9): 809-818.
InFo ONCOLOGY & HEMATOLOGY 2018; 6(4) – published 7/7/18 (ahead of print).
