Early Emicizumab Treatment in Acquired Hemophilia A: Impact on Bypassing Agent Use and Length of Hospitalization in an Australian Single-Center Cohort

Recently Franchini et al[1] described the current and potential future treatment landscape for acquired hemophilia A (AHA) highlighting the need for updated management strategies. The authors draw attention to the promising results from several open label studies describing emicizumab use in select patients with AHA. Reported benefits include good hemostatic efficacy, fewer episodes of breakthrough bleeding, earlier hospital discharge, and the potential for delayed or reduced intensity immunosuppressive therapy (IST) with fewer treatment-related adverse events.[2] [3] [4] Emicizumab also has attractive pharmacological properties, given that it is effectively displaced once the inhibitor is suppressed and FVIII levels begin to rise.[5] However, AHA is a rare disorder, with an estimated incidence of around 1.5 per million, and studies are typically limited by small patient numbers, heterogeneity of approach, and absence of a comparator arm. Thus, it is perhaps unsurprising that despite this growing body of clinical evidence, and a European consensus recommendation that it be included in AHA treatment pathways, emicizumab is currently only licensed for use in AHA in Japan.[6]

The Queensland Haemophilia Treatment Centre (HTC) based in Brisbane, Australia, is a tertiary facility servicing a population of approximately 5.5 million. Every patient with newly diagnosed AHA is discussed with the HTC, and all decisions regarding dose and duration of hemostatic therapy are overseen by two hemophilia specialists. We have previously published on the characteristics and outcomes of 24 AHA patients managed at our HTC between 2014 and 2018.[7] In late 2020 we adopted the practice of using emicizumab upfront in AHA patients with “high-risk” features via a cost-sharing arrangement with the manufacturer, Roche Products. We defined high risk according to previously described criteria of FVIII ≤1.0 IU/dL or an inhibitor titer >20 BU/mL,[8] as well as patients with an inhibitor titer >10 BU/mL who had severe bleeding. Applying these criteria retrospectively to our historic (pre-emicizumab) AHA cohort we established a matched comparator group against which relevant outcomes such as bypassing agent use and length of hospitalization could be assessed. Bleeding severity was defined in accordance with previously published criteria.[9] Rebleeding was defined as bleeding at the same site within 2 weeks of successful hemostasis, while new bleeding was defined as bleeding at a new anatomical site, in keeping with definitions used in our historic published cohort.[7] Local human research ethics committee approval was obtained from The Metro North Health Human Research Ethics Committee, Project ID number: 112929.

Out of 24 patients 13 in the historical cohort were retrospectively categorized as high risk. However, 2 of these patients were excluded from further analysis (one received most of the treatment at an external facility with incomplete data provided, the other received porcine FVIII on compassionate grounds, with details published elsewhere).[10] In the emicizumab cohort (December 2020 to August 2024) 10 of 22 patients with newly diagnosed AHA managed at our HTC were categorized as high risk, thereby meeting local eligibility criteria for upfront emicizumab treatment. High-risk patients received IST in accordance with our local protocol, comprising prednisone 1 mg/kg daily, rituximab 100 mg IV weekly for 4 doses, with the addition of oral cyclophosphamide 1 to 2 mg/kg/day in divided doses if a partial response was not observed by week 3 to 4. Demographic and clinical characteristics of the two high-risk groups were similar ([Table 1]).

Table 1 Demographics and baseline characteristics

	Historical cohort (n = 11)	Emicizumab cohort (n = 10)
Age, years—median (range)	73 (55–86)	73.5 (19–86)
Gender
Female, n (%)	4 (36%)	3 (30%)
Male, n (%)	7 (64%)	7 (70%)
Identifiable cause
Idiopathic	6 (55%)	7 (70%)
Autoimmune	3 (27%)	2 (20%)
Malignancy	2 (18%)	1 (10%)
FVIII activity at diagnosis, IU/dL—median (range)	2 (<1–8)	<1 (<1–8)
Inhibitor titer at diagnosis, BU/mL—median (range)	51 (6.3–104)	20 (6.2–870)
Bleeding at presentation
Severe	6 (55%)	7 (70%)
Non-severe	5 (45%)	3 (30%)

Emicizumab dosing, use of recombinant activated factor VII (rFVIIa), bleeding rates, and hospitalization outcomes are summarized in [Table 2]. Patients in the emicizumab cohort received a median total emicizumab dose of 10.35 mg/kg over 3.5 doses; however, regimens were not uniform across the cohort, reflecting variability in product access and evolving practice as new information emerged throughout the study period. Initially patients were dosed according to published congenital hemophilia A loading regimens (3 mg/kg weekly up to a maximum of 4 doses), while patients who developed AHA later in the study period received rapid loading analogous to the protocol described by Shima et al in which 6 mg/kg is given on day 1, followed by 3 mg/kg on day 2, then 1.5 mg/kg weekly.[4] In patients who required rFVIIa both median total dose and duration of treatment were considerably higher in the historical cohort compared with the emicizumab cohort (250.5 mg vs. 52.5 mg, 3 days vs. 1 day). Regardless of whether “standard” (weekly) or “rapid” loading was utilized a cumulative emicizumab dose of 6 mg/kg appeared to be associated with a reduction in rFVIIa requirement, with four patients requiring ongoing rFVIIa after an initial 3 mg/kg emicizumab dose, but only one patient failing to achieve hemostasis after a second 3 mg/kg dose. Furthermore, both rebleeding and new bleeding events were less frequent in the emicizumab cohort, with only one patient experiencing rebleeding at the same site after initial successful hemostasis (compared with four patients in the historical cohort), and two patients experiencing bleeding at a new anatomical site (compared with four patients in the historical cohort). There were no thrombotic events or episodes of thrombotic microangiopathy in either cohort. Delay from AHA diagnosis to first emicizumab dose was common (median 2 days, range 1–6) largely due to the logistical challenges associated with initiation of an off-label therapy, including a requirement to transfer some patients from other centers to facilitate product access. However, despite delays in treatment initiation, the median hospital length of stay was 5.5 days in the emicizumab cohort, with 60% discharged within 7 days, versus a median hospital length of stay of 20 days in the historical cohort, and only 18% discharged within 7 days.

Table 2 Comparison of rFVIIa use, bleeding events, and duration of hospitalization in the historical and emicizumab AHA cohorts

	Historical cohort (n = 11)	Emicizumab cohort (n = 10)
Total emicizumab dose, mg per kg—median (range)	N/A	10.35 (6–12)
Number of emicizumab doses—median (range)	N/A	3.5 (2–5)
Patients requiring rFVIIa at any stage, n (%)	8 (64%)	6 (60%)
Total rFVIIa dose,a mg—median (range)	250.5 (42–2,277)	52.5 (20–484)
Duration of rFVIIa therapy,a days—median (range)	7.5 (3–33)	1 (1–10)
Rebleeding events, n (%)	4 (36%)	1 (10%)
New bleeding events, n (%)	4 (36%)	2 (20%)
Patients requiring rFVIIa after 3 mg/kg emicizumab, n (%)	N/A	4 (40%)
Patients requiring rFVIIa after 6 mg/kg emicizumab, n (%)	N/A	1 (10%)
Length of hospitalization, days—median (range)	20 (1–44)	5.5 (0–25)
Discharge within 7 days, n (%)	2 (18%)	6 (60%)
Discharge within 21 days, n (%)	7 (64%)	8 (80%)

Abbreviations: AHA, acquired hemophilia A; rFVIIa, recombinant activated factor VII.

Note: ^aPatients who required rFVIIa.

Our results mirror the observations of other open label studies, and demonstrate a trend toward reduction in rFVIIa use and reduced length of hospitalization following initiation of emicizumab in select high-risk AHA patients.[3] [4] [6] Rapid emicizumab loading offers potential for further reduction in rFVIIa requirement, and the AGEHA trial demonstrated that this approach was efficacious, safe, and pharmacologically sound. We transitioned from a “standard” loading to “rapid” loading over the course of our study, but patient numbers were not sufficient to examine any potential dosing effect. Certainly, the most pronounced therapeutic benefit would appear early in the course of AHA for most patients; however, the bleeding risk remains significant until improvement in FVIII levels, and prolonged prophylaxis may be justified in some patients. Notably, due to local funding restrictions, emicizumab was ceased after a maximum of 5 doses in our study despite only one patient achieving a partial remission at that stage (bovine chromogenic FVIII 52 IU/dL), yet new and rebleeding rates were low. It is unclear what endogenous FVIII level in AHA should be reached before emicizumab is ceased. Given that FVIII is known to be a more competitive binder to FIXa/FX further dosing may be futile once endogenous FVIII has recovered to a 20 to 30 IU/dL threshold, and indeed Franchini et al suggest emicizumab be ceased when endogenous FVIII recovers to >30 IU/dL.[1] However, given the unique and complex type 2 inhibitor kinetics observed in AHA patients the effectiveness of measured endogenous FVIII in displacing emicizumab when a measurable inhibitor remains present is unclear.

Whether early use of emicizumab allows for reduced-intensity IST requires further study; however, the results from the GTH-AHA-EMI study, and the recently published updated analysis from the AGEHA study, provide promising data that IST can be deferred in patients with AHA while they are on emicizumab, and this approach may in fact improve overall survival due to fewer infection-related deaths.[3] [4] [11] Unfortunately due to our local funding limitations emicizumab cannot be prescribed for more than a few doses in patients with AHA, so deferring IST is rarely a practical option. Similarly, due to funding restrictions, we adopted a “risk stratification” approach to select patients for emicizumab treatment, being aware that current predictive variables in AHA are associated with time to IST response, not bleeding events.[8] It is well recognized that serious bleeding can occur in “low-risk” AHA patients, and such patients were not excluded from GTH-AHA-EMI or AGEHA clinical trials.[3] [4]

In conclusion, despite accumulating data regarding efficacy and safety, in most countries the use of emicizumab remains unlicensed, and therefore unfunded, for bleed prophylaxis in AHA. It is hoped that our data may add to the growing body of evidence that this approach also has health economic benefits through reduced requirement for bypassing agents and shorter periods of hospitalization, potentially incentivizing the pursuit of specific licensing for this indication. The emergence of new non-factor hemostatic therapies also provides an opportunity for earlier inclusion of AHA patients in other industry-sponsored research cohorts, potentially reducing barriers to licensing applications in future. As clinicians who manage AHA, we should continue to lobby health agencies and advocate for ongoing research of novel therapies to ensure that this group of patients with a rare, but life-threatening disorder have access to products that can potentially reduce bleeding and mortality, shorten the duration of hospitalization, and ultimately improve quality of life.

Authors' Contributions

J.M. and G.P. collected and analyzed the data; G.P., J.R., and J.M. wrote the article; S.C. reviewed the article.

Publication History

Article published online:
17 June 2025

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