Emicizumab prophylaxis in severe hemophilia A with inhibitor: impact on quality of life and musculoskeletal outcomes

Fitri Primacakti Wiharta, Made Citra Saraswati, Dina Clarisa Rumora Abigail, Novie Amelia Chozie

Emicizumab has been acknowledged for its effectiveness in preventing bleeding in patients with hemophilia A developing inhibitors. This report examined the impact of emicizumab prophylaxis on health-related quality of life (HRQoL) and musculoskeletal outcomes in a 10-year-old male with severe hemophilia A and a high titer of factor VIII (FVIII) inhibitor, presenting with hemophilic arthropathy on the right knee and left elbow. He had been unable to walk and was previously treated on-demand with a plasma-derived FVIII concentrate. He received emicizumab prophylaxis for 16 months. HRQoL was evaluated using a hemophilia-specific questionnaire, while musculoskeletal outcomes were assessed using hemophilia early arthropathy detection with ultrasound (HEAD-US) and the hemophilia joint health score (HJHS). During treatment, no breakthrough bleeding occurred, and the patient regained the ability to walk. Emicizumab prophylaxis significantly improved in HRQoL, especially in physical health and sports and and school domains, aligning with bleeding rates, HEAD-US, and HJHS assessments.

 

Keywords

bispecific antibodies, hemophilia A

The development of neutralizing alloantibodies or antibodies against factor VIII (FVIII) inhibitors is the most serious complication of hemophilia treatment, as it makes clotting FVIII concentrates ineffective in controlling bleeding. FVIII inhibitors occur in approximately 25–30% of patients with severe hemophilia A and 5–10% of those with mild or moderate hemophilia.1,2 Recently, the development of non-factor therapies, such as emicizumab, has become more effective and less burdensome for patients with hemophilia A with or without FVIII inhibitors. Clinical trials have demonstrated a favorable safety profile with encouraging outcomes to prevent or reduce the frequency of bleeding.3–6 The current guidelines recommend emicizumab over bypassing agents (BPAs) for prophylaxis in patients with FVIII inhibitors. However, access to this therapy remains limited to middle-income countries.3

The presence of FVIII inhibitors increases morbidity, including musculoskeletal complications and physical limitations that significantly affect patients’ quality of life (QoL).1,4 This concern needs further attention in pediatric patients because excellent physical health is crucial for their growth and development.4 Additionally, it places a burden on their parents or caregivers.7 Here, we present a case of a child with severe hemophilia A and FVIII inhibitor treated with emicizumab prophylaxis. This study aimed to examine its impact on musculoskeletal outcomes and health-related quality of life (HRQoL).

 

 

A 10-year-old male with severe hemophilia A presented with recurrent bleeding in both knee joints and was unable to walk for 1 year. He required a wheelchair and parental assistance for daily activities. He was diagnosed with severe hemophilia A at 11 months of age and had multiple hematomas since birth, as confirmed using factor assays. At 6 years of age, he was first diagnosed with an inhibitor and monitored annually. His previous treatment included on-demand treatment with a plasma-derived (PD) or recombinant FVIII concentrate, based on availability, and a BPA when donations were received from the World Federation of Hemophilia (WFH). Before his joint condition deteriorated, he had no significant disruptions in school or social life and exhibited normal growth and development. He had no other medical conditions or a history of major procedures.

Before initiating emicizumab prophylaxis, written informed consent was obtained from the patient’s legal guardian. Emicizumab was administered subcutaneously at our hospital. He received two cycles of emicizumab; the first cycle involved an initial dose of 3 mg/kg weekly for 4 weeks, followed by a maintenance dose of 3 mg/kg every 2 weeks for 12 months.

We evaluated three outcomes before and after emicizumab treatment: 1) annual joint bleeding rate (AJBR), obtained from medical records and calculated based on the number of joint bleeds per year; 2) musculoskeletal outcomes, evaluated using hemophilia early arthropathy detection with ultrasound (HEAD-US) and hemophilia joint health score (HJHS); and 3) HRQoL, assessed using a hemophilia-specific quality of life (Haemo-QoL) questionnaire (Figure 1).

 

 

The radiological approach for joint health status assessment using HEAD-US scoring was performed by musculoskeletal radiologists on the elbow, knee, and ankle joints, with a maximum score of 8 points per joint. Additionally, the HJHS, assessed by physical medicine and rehabilitation experts, evaluates a patient’s joint health status by examining specific features of the six index joints and global gait. The maximum HJHS total score is 124, with higher scores indicating worse joint health status.1

Haemo-QoL was assessed at baseline, after 12 months, and at the end of the second cycle using tools consisting of 13 domains and five open questions. Those domains are “joint bleeds,” “injections,” “physical health,” “feeling,” “view of yourself,” “view of your family,” “view of your friends,” “the support you felt you were receiving,” “view of other people,” “sports and school,” “dealing with hemophilia,” “treatment,” and “overall health.” The questionnaire uses a 6-point Likert scale, with higher scores indicating greater HRQoL impairment. The subscale scores for each domain range from 1 to 5, and the total score ranges from 1 to 45. The transformed scale score is calculated by subtracting the minimum possible raw score from the total raw score, dividing the result by the possible range of raw scores, and multiplying it by 100.

Before emicizumab treatment, the patient experienced joint bleeding 48 times per year. His FVIII inhibitor titer, measured using the original Bethesda assay before prophylaxis initiation, confirmed the presence of a high-titer FVIII inhibitor (5.52 Bethesda unit). Clinically, the patient exhibited restricted knee joint and left elbow movement. The HEAD-US score confirmed hemophilic arthropathy of the right knee and left elbow, with a higher total score aligning with the HJHS score.

During emicizumab prophylaxis, the patient showed clinical, musculoskeletal, and HRQoL improvements, with no breakthrough bleeding or adverse events. By the 2nd week, he could move and extend both legs, and by the 4th week, he could walk without assistance from a wheelchair. The patient also underwent physical exercises performed by physiotherapists to restore joint function. His parents reported that he could participate in physical activities that were previously considered impossible, such as running, cycling, and playing basketball. Haemo-QoL assessments showed significant impairment at baseline, especially in the dimensions of bleeding, physical health, and sports and school (Table 1).

 

 

After 12 months, emicizumab treatment was discontinued due to supply shortages, and prophylaxis was switched to PD of FVIII concentrate (10 IU/kg body weight [BW], twice weekly). In the 3rd week, the patient experienced five bilateral joint bleeding events. After 4 months, additional emicizumab donations were obtained, allowing a second cycle of emicizumab prophylaxis. Owing to limited supply, this cycle was administered without a loading dose, with a maintenance dose of 3 mg/kg BW every 2 weeks for 4 months. The second cycle was assessed using the AJBR, HJHS, HEAD-US, and Hemo-QoL scores at the end of the cycle. The patient showed significant improvement, with no bleeding episodes and similar outcomes observed on the first cycle (Figure 1). Over 16 months of prophylaxis, he experienced no mild side effects, such as injection site reactions, or severe reactions, such as thrombotic events or anti-drug antibody (ADA) formation.

 

 

In this case report, we present excellent results of emicizumab prophylaxis in a pediatric patient with severe hemophilia A and a high FVIII inhibitor titer. Emicizumab, a humanized bispecific antibody, was designed specifically to mimic factor VIIIa activity by simultaneously catalyzing factor X activation through interaction with specific binding sites for factors IXa and X (Figure 2). The emicizumab (ACE910) prophylaxis in patients with hemophilia A with inhibitors (HAVEN) trials, started in 2015, have shown promising safety and efficacy.8,9 During a year of prophylaxis, our patient experienced an AJBR of zero, aligned with HAVEN study findings, which resulted in a very low bleeding rate (annual bleeding rate 0.3 [95% confidence interval: 0.17−0.50]).10 These findings aligned with several pediatric cohort studies of emicizumab prophylaxis, with a lower to zero bleeding rate.11–14

 

 

The WFH guidelines recommend annual evaluation and documentation of each patient’s musculoskeletal and overall health.1 The HJHS is one of the most reliable tools for detecting early signs of joint damage and monitoring the progression in children and adolescents. The HAVEN study reported positive effects of emicizumab on joint health, including meaningful improvements in the HJHS and physical health domain scores from the Haemo-QoL Assessment Instrument for Children and Adolescents Short Form.15,16 In our patient, the HJHS score gradually improved with ongoing prophylaxis (Figure 1), which is relevant to patient health outcomes in activities of daily living and participation in physical activities. This improvement was apparent from the 2nd week and persisted until the last week of the prophylactic regimen. The HRQoL assessment also showed a significant improvement in physical health at 6 months of evaluation, which yielded unexpected results when compared to HAVEN 3 and HAVEN 4, where improvements were observed in the 73rd week.16

Early structural changes in the joints are best assessed using magnetic resonance imaging or ultrasonography.1,16 Our center utilizes the HEADUS scoring system, which is a fast and affordable radiological examination. Higher HEAD-US scores indicate more severe joint abnormalities in the joints.17 This patient had documented hemophilic arthropathy of the right knee and left elbow owing to recurrent bleeding before prophylaxis. Although prophylaxis cannot reverse existing joint damage, it reduces bleeding frequency and enhances the QoL. Although his HEAD-US results were higher, other outcomes such as the HJHS examination, AJBR score, and clinical symptoms showed different results (Figure 1). Due to the unplanned second cycle, baseline conditions before starting the second cycle were unavailable; however, a comparison of the 4-month gap without emicizumab and the second cycle showed a reduced AJBR from 15 to zero, showing improvement during emicizumab prophylaxis.

Children receiving prophylaxis exhibit better HRQoL than those on on-demand treatments. Moreover, emicizumab has been associated with further improvement over baseline.7,18 Our experience confirms significant improvement, with lower HRQoL scores at 12 months after the first cycle and 4 months after the second cycle. Owing to the observed deterioration upon discontinuation of emicizumab followed by PD with FVIII concentrate administration, we recommend careful planning and continuity of administration when starting emicizumab prophylaxis.19,20

In our patient, the second cycle of emicizumab was initiated without a loading dose because of a limited donation supply. Low-dose emicizumab without 4-week loading doses has been evaluated in a case series of six patients with hemophilia A, showing a decreased bleeding rate, improvement in swollen target joints, and better QoL scores, such as Haemo-QoL and the Canadian Hemophilia Outcomes-Kids Life Assessment Tool.21 Further research is needed on the safety and efficacy of this approach, specifically for patients with inhibitors. Low-dose emicizumab may be a cost-effective treatment option in developing countries. A study in India found that the direct cost of low-dose emicizumab was lower (USD 6,000) than the standard dose (USD 15,000), with significant outcomes relative to the FVIII prophylaxis group.22

As a recommended long-term prophylactic treatment for patients with hemophilia A, emicizumab requires continuous evaluation of its safety and efficacy. Studies have demonstrated good safety signals, notable efficacy in improving joint health and QoL, and significantly lower bleeding rates.6 Thrombotic microangiopathy and thromboembolic events reported in HAVEN trials were linked to high-dose administration of activated prothrombin complex concentrate (aPCC). Thus, the study recommended that aPCC be discontinued at least 24 hours before emicizumab prophylaxis. In our case, the patient did not receive aPCC before or during emicizumab prophylaxis, which resulted in good drug tolerance and favorable results. Although plasma concentration analysis was not performed for emicizumab, no clinical signs of reduced efficacy were observed in our patient. The potential development of ADAs remains a concern, as they may reduce the plasma concentration of emicizumab and neutralize its therapeutic effect.11,19,20

Subcutaneous administration of emicizumab at infrequent intervals is an easy and minimally invasive option, especially in pediatric patients (Figure 3).5,23 However, its high cost limits its wide availability in Indonesia. Given its tolerability and efficacy, our report suggests that the Indonesian government should provide access to emicizumab to manage hemophilia. Further research on emicizumab prophylaxis is required, especially in the Indonesian population receiving low doses of emicizumab, as reported in India.

 

 

Objective evidence of treatment outcomes is required to optimize prophylactic treatment. For patients with hemophilia A and FVIII inhibitors, the WFH recommends a chromogenic Bethesda assay using bovine reagents to monitor the inhibitor titer level because emicizumab interferes with the measurement of FVIII.1 However, owing to the unavailability of bovine reagents in our center, the inhibitor titer could not be evaluated, and clinical monitoring remained the primary approach.

 

 

 

 

 

 

 

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