The Dilemma of the Perpetual Previously Untreated Patient with Hemophilia a

BACKGROUND: Inhibitor development is the most dreaded complication of contemporary hemophilia therapy affecting 30 to 40% of previously untreated patients with hemophilia A and typically occurring within 20 to 50 exposure days. The advent of emicizumab has broadened the therapeutic panorama for hemophilia A, especially for persons with inhibitors. However, could the exclusive use of emicizumab in previously untreated patients delay inhibitor development until the second decade of life because of infrequent exposures to rFVIII? Moreover, administration of high-dose, high-intensity rFVIII for breakthrough bleeding events, trauma, or during surgery may accentuate inhibitor development risk (Sharathkumar et al. JTH, 2003).

METHOD: The literature was perused for articles addressing exclusive emicizumab use in previously untreated patients. Additionally, we sought out the advice of physicians on the relevance of exogenous FVIII in persons with hemophilia A and the clinical/psychosocial impact of delayed inhibitor development in previously untreated patients treated exclusively with emicizumab. With this information we propose a therapeutic algorithm for previously untreated patients (Figure 1).

RESULTS: Previously untreated patients treated exclusively with emicizumab may generate enough thrombin to recapitulate a mild hemophilia A phenotype. Real-world data on bleeding patterns showed that 51% (36/70) and 61% (43/70) of prospectively followed patients treated with emicizumab experienced at least one episode of spontaneous or traumatic bleeding event, respectively (Levy-Mendelovich et al. J Clin Med 2021). Patel et al. (J Med Econ, 2019) estimate that inhibitor development may be delayed for approximately 14 years after emicizumab exposure. Mason and Young (Haemophilia 2021) describe 4 infant cases highlighting the treatment challenges confronting families and physicians- 3 chose emicizumab prophylaxis cognizant of the prolonged inhibitor risk and 1 chose rFVIII prophylaxis followed by emicizumab to reduce anxiety regarding inhibitor development. An advisory board comprising physician thought leaders in hemophilia was convened to address the relevance of rFVIII as the foundation of hemophilia A therapy. Figure 1 depicts an algorithm to illustrate 2 therapeutic pathways- 1 using a human cell line-derived FVIII product and the other using emicizumab- and the potential patient-related complications with each therapy. Physician feedback suggests that following the rFVIII pathway the time to inhibitor development is finite and afterward breakthrough bleeding episodes become the major therapeutic concern. Following the emicizumab pathway the time to inhibitor development and high-risk treatment periods (breakthrough bleeding episodes, trauma and surgery) with rFVIII will persist until adolescence. Families and physicians will need to constantly think about inhibitor development and plan for this complication.

CONCLUSION: Our hypothesis that previously untreated patients exposed exclusively to emicizumab (or other non-factor therapies) may experience a protracted timeline to reach 50 exposure days, which may result in a "perpetual" previously untreated patient status. High-risk treatment periods will be inevitable. Factor and non-factor treatment strategies are available each with its respective set of trade-offs, and families and healthcare providers must consider downstream consequences when selecting one strategy over another. Long-term clinical scrutiny and further research are required to resolve issues arising from this new therapeutic paradigm.

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