Emicizumab prophylaxis among infants and toddlers with severe hemophilia A and inhibitors—a single‐center cohort

Abstract

Background: Emicizumab is a bispecific antibody that bridges factor IXa and factor X to restore hemostasis in patients with hemophilia A (HA). Its efficacy and safety have been proven in multicenter trials. However, real world data regarding its use in very young children are currently lacking. Ancillary test results for monitoring emicizumab's hemostatic effect and their clinical correlations are scarce. Methods:Children with HA and inhibitors treated by emicizumab were prospectively followed at our center. Laboratory follow-up included rotational thromboelastometry (ROTEM) and thrombin generation (TG), prior to and during treatment.Results: Eleven children whose median age was 26 months were treated by emicizumab and followed for a median of 36 weeks. During follow-up, none experienced hemarthrosis or any other spontaneous bleeds. For 7/11 patients, emicizumab prophylaxis was sufficient to maintain hemostasis without additional supplemental therapy. Only 4/11 patients were occasionally treated with recombinant activated FVII for trauma. Two minor surgeries were safely performed without supplemental therapy while another procedure was complicated by major bleeding. TG parameters improved for all patients, correlating with their clinical status. Interestingly, the lowest TG values were obtained for patients experiencing bleeding episodes, while ROTEM parameters in all patients were close to the normal range. Conclusions:This study confirms the safety and efficacy of emicizumab in reducing bleeds in young children with HA with inhibitors, including infants. However, surgeries warrant caution as emicizumab prophylaxis may not be sufficient for some procedures. TG may more accurately reflect the hemostasis state than ROTEM in pediatric patients treated with emicizumab. K E Y W O R D Semicizumab, hemophilia A, inhibitors, ROTEM, thrombin generation

Emicizumab prophylaxis in patients with haemophilia A with and without inhibitors

“…In the last several years, novel therapeutics have been evaluated in clinical trials, among which the bispecific monoclonal antibody, emicizumab, has been licensed for the prevention of bleeding in children and adults with haemophilia with and without inhibitors. Recent studies indicate emicizumab is safe and effective for prophylaxis in infants with haemophilia A 15,16 and in immune tolerance induction (ITI) in inhibitor patients, 16,17 and, while costly, is cost-effective in those with inhibitors. 13,14 Whether bleed frequency and bleed severity, long-term joint health and quality of life are comparable to that achieved with factor VIII, therefore, remains unknown.…”

“…13,14 Whether bleed frequency and bleed severity, long-term joint health and quality of life are comparable to that achieved with factor VIII, therefore, remains unknown. Recent studies indicate emicizumab is safe and effective for prophylaxis in infants with haemophilia A 15,16 and in immune tolerance induction (ITI) in inhibitor patients, 16,17 and, while costly, is cost-effective in those with inhibitors. 18 Yet, there is limited experience with emicizumab in breakthrough bleeding rates and surgical hemostasis in those with and without inhibitors.…”

<p>Clinical Evidence and Safety Profile of Emicizumab for the Management of Children with Hemophilia A</p>

“…In both case series, no spontaneous bleeds were reported for up to 52 weeks after initiation of QW emicizumab prophylaxis in a total of 15 male HA children with high-titer FVIII-inhibitors. 37,38 In the phase 3 HAVEN 2 trial, enrolling 88 HA children (2-12 years of age) with high-titer FVIII-inhibitors, 68 patients received the QW dosing regimen for a median efficacy period of 57.6 weeks (range 17.9-92.6). Among them, 94.7% had zero treated bleeds, and 72.3% experienced zero bleeds, whether they were treated or not.…”

“…Most treated bleeds observed in these studies were traumatic bleeds, with half of them being joint bleeds, which resolved after few injections of BPA. 32,37,38 When comparing to other dosing regimens used in the HAVEN 2 study, we can notice that the Q4W dosing regimen performed less well than both QW and Q2W dosing regimens in terms of pharmacokinetic profile, which resulted in lower efficacy over bleeding prevention (Table 1; Figure 1). 32 Interestingly, studies revealed that emicizumab prophylaxis considerably reduced target joints.…”

“…In all studies available to date, no target joint developed in HA pediatric patients with FVIII-inhibitors who had no target joint at baseline, including 12 patients <2 years of age. 32,37,38 In addition, among 38.6% of patients who met criteria for target joint at baseline in the HAVEN 2 study, all 45 target joints resolved after 52 weeks of emicizumab prophylaxis. 32 The markedly better efficacy of emicizumab prophylaxis over BPA treatment for bleeding prevention and the reduction of target joints supports the use of this drug in patients who have developed FVIIIinhibitors and who failed ITI.…”