Safety and Outcome of Early Start of Emicizumab in Neonates and Infants with Severe Hemophilia Α, a Real-World Experience

The hallmark of severe hemophilia in children is bleeding which varies depending on the age of the child. While intracranial hemorrhage (ICH), circumcision, and venipuncture bleeding are common in neonates, joint and muscle bleeds particularly related to trauma are more common in older children and adolescents. The risk of ICH in neonates diagnosed with hemophilia is 3·5–4·0%, which is 40–80 times higher than expected in the normal population. The risk of ICH after the neonatal period is still high, affecting 3–10% of children with hemophilia on demand treatment and the risk is increased if hemophilia is severe and in hemophilia with inhibitors.

Prophylaxis is the recommended treatment for all patients with severe hemophilia. Emicizumab is a bispecific humanized monoclonal antibody that binds simultaneously to activated FIX and FX mimicking the function of FVIII. Emicizumab widely replaced coagulation factor concentrate (CFC) as the prophylaxis of choice in severe hemophilia A. The HAVEN trials reported a significantly lower bleeding rate in children with severe factor VIII deficiency with or without inhibitors compared with previous factor VIII prophylaxis.

The World Federation of Hemophilia (WFH) recommends starting prophylaxis in children with severe hemophilia before the age of three years. There is no consensus on the ideal time to start emicizumab prophylaxis in newly diagnosed children with hemophilia A. In the PedNet registry, 17 out of 20 (85%) comprehensive hemophilia care centres, started emicizumab before the age of 12 months, however only three centres (10%) started emicizumab before the age of three months.

In our Centre, we adopted a strategy of starting neonates newly diagnosed with hemophilia A on emicizumab prophylaxis as soon as the diagnosis is made, and the family agrees to start prophylaxis. We adopted this strategy in view of the ease of administration of emicizumab via the subcutaneous route compared to intravenous CFC and to reduce the risk of ICH in infants with severe hemophilia A.

The study is approved by the Ethics Committee of Children’s Health Ireland in Crumlin. We retrospectively evaluated 15 children who started emicizumab during infancy. Seven neonates (46.7%) were diagnosed at birth as their mothers were known carriers of severe hemophilia A. The remaining eight infants (53.3%) were diagnosed between the first and 41^st weeks of life (Median 19 weeks). 50% (4 out of 8) infants were investigated due to unusual bruising and prolonged aPTT. The median age at start of emicizumab prophylaxis in our cohort is 13 weeks (2 months), range 1-48 weeks.

After a median follow up of 20.3 months (1-39.7), no child in our cohort developed spontaneous or traumatic bleeds including ICH. Of note, 80% (12/15) of the children in the study have not received CFC since starting emicizumab prophylaxis. One child was given CFC to cover central line removal; the other two children received CFC after head injury. None of the children in the study developed FVIII inhibitors while on emicizumab. Eight children (53.3%) were previously untreated patients (PUPs) and never had CFC before or after start of emicizumab prophylaxis. Apart from mild transient skin reaction in two children, no other side effects were reported from emicizumab prophylaxis. No child stopped emicizumab due to adverse events.

In conclusion, in infants diagnosed with severe hemophilia A, early start of emicizumab as soon as the diagnosis is made and during the first two months of life is a safe, well tolerated and effective strategy to prevent spontaneous as well as traumatic bleeding including ICH. The long-term outcome of very early start of emicizumab is not yet known particularly with regard to development of FVIII inhibitors, bone health and joint health.