MASAC Document 292 - National Bleeding Disorder Clinical Practice Recommendations on the Off-Label Use of Emicizumab for the Treatment of Acquired Hemophilia A

Experts: Ming Y. Lim¹, Peter Kouides², Magdalena D. Lewandowska³, Jonathan C. Roberts^4,5, Amy Dunn⁶

Affiliations:

¹Utah Center for Bleeding & Clotting Disorders at University of Utah Health, Salt Lake City, UT, USA

²Mary M. Gooley Hemophilia Treatment Center, Rochester, NY, USA

³Innovative Hematology/Indiana Hemophilia & Thrombosis Center, Indianapolis, IN, USA

⁴Bleeding & Clotting Disorders Institute, Dills Family Foundation Center for Research at BCDI, Peoria, IL

⁵ Departments of Pediatrics and Medicine, University of Illinois College of Medicine at Peoria, Peoria, IL

⁶Nationwide Children’s Hospital, The Ohio State University College of Medicine, Columbus, OH, USA

TOPIC 1: Emicizumab Use for Acquired Hemophilia A

Background

Acquired hemophilia A (AHA) is a rare, autoimmune disease that occurs due to the development of IgG antibodies against coagulation factor VIII (FVIII), leading to a severe bleeding diathesis with a high morbidity and mortality.^1,2AHA disproportionately affects the elderly population, with about half of reported cases found to be associated with autoimmune diseases, malignancies, and medications.³ The two major goals of management in AHA are to achieve hemostatic control and to eradicate the FVIII inhibitor using immunosuppressive therapies (IST).^1,4

The bypassing agents, recombinant factor VIIa (rFVIIa) and activated prothrombin complex concentrate (aPCC), as well as recombinant porcine FVIII (rpFVIII) can be used for hemostatic control in AHA (See MASAC Document #280 Recommendations Concerning Products Licensed for the Treatment of Hemophilia and Selected Disorders of the Coagulation System). However, these therapies carry disadvantages, including frequent intravenous infusions and increased thromboembolic risk with the use of bypassing agents, and the development of anti-porcine antibodies with rpFVIII.^1,5,6 In addition, until the FVIII inhibitor is eradicated using IST, these individuals remain at high risk of recurrent bleeding requiring frequent hospitalizations for hemostatic control.

Emicizumab is a recombinant, bispecific, monoclonal antibody that bridges activated factor IX (FIXa) and factor X (FX) leading to activation of FX and thrombin generation, thus promoting haemostasis.^7,8. Because of its structure, emicizumab can circumvent the need for FVIII and is not affected by FVIII inhibitors.^9,10 Emicizumab is indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in people of all ages with congenital hemophilia A with and without FVIII inhibitors (See MASAC Document #268 Recommendation on the Use and Management of Emicizumab-kxwh [Hemlibra®] for Hemophilia A with and without Inhibitors).

The efficacy and safety of emicizumab use in the management of AHA have been reported in case reports, case series and two prospective multicenter open-label studies (Table 1).^11-15

Table 1. Published studies on the efficacy and safety of emicizumab in the management of AHA

DVT, deep vein thrombosis; TIA, transient ischemic attack; HTC, hemophilia treatment center

^* One stroke occurred with emicizumab and concomitant recombinant FVIIa use for surgery.

^# One DVT occurred while on maintenance emicizumab dose of 3 mg/kg every other week with a chromogenic FVIII activity level of <1% and no recent use of bypassing agents or recent bleeding. The individual with TIA had no history of stroke or use of antiplatelet or anticoagulant therapy and was on emicizumab monotherapy (with no recent use of bypassing agents). The TIA was not attributed to emicizumab by the treating physician and emicizumab was continued without any dose modifications.

^@ One asymptomatic DVT occurred that was attributed to emicizumab use and resolved on follow-up ultrasonography 7 days later without any treatment.

^% One thrombophlebitis occurred at the site of venous catheter placement at week 1 and was not considered related to emicizumab. One ischemic stroke occurred in the middle cerebral artery in a 79-year-old patient in week 20. This patient had end-stage renal failure and a history of coronary artery disease at study entry. Angiography performed the day after the event showed reperfusion of the middle cerebral artery, and the patient fully recovered.

In the United States, the AHAEmi study, a phase II prospective multicenter open-label study to evaluate the efficacy of emicizumab (6 and 3 mg/kg on days 1 and 2, 1.5 mg/kg weekly) with concurrent immunosuppressive therapy is ongoing (NCT05345197).

Recommendation 1               

• MASAC recommends that given the high morbidity and mortality observed in individuals with AHA due to bleeding complications and immunosuppressive-related adverse events, emicizumab should be considered for bleeding prophylaxis from the time of diagnosis.

• REMARK: In 2021, a survey found that one-third of adult hematologists at US hemophilia treatment centers (HTCs) were already using emicizumab to manage individuals with AHA, with over 70% stating the reason for emicizumab use was for bleeding prophylaxis.¹⁶ This highlights the comfort level of using emicizumab among US HTCs providers given the efficacy and their experience of emicizumab use in congenital hemophilia A.

• REMARK: Due to the theoretical risk of thrombosis particularly in this relatively older age group of individuals with AHA, the hematologist should first assess the individual for the risk of arterial ischemic events based on their atherosclerotic risk profile and for venous thromboembolic events based on hypercoagulable risk factors and subsequently engage in shared decision making using appropriate linguistic and cultural communications. Individualized treatment decisions should occur in collaboration with an HTC.

• REMARK: Pregnancy is a risk factor for AHA with most cases diagnosed after delivery.¹⁷ There are no available data on emicizumab use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. Potential placental transfer of human IgG is dependent upon the IgG subclass and gestational age, generally increasing as pregnancy progresses. The lowest exposure would be expected during the period of organogenesis.^18,19 According to the manufacturer, emicizumab should be used during pregnancy only if the potential benefit for the mother outweighs the risk to the fetus.

• REMARK: Human IgG is known to be present in breast milk. However, it is not known if emicizumab, a humanized monoclonal modified immunoglobulin G4 (IgG4) antibody, is present in breast milk. According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.

TOPIC 2: Emicizumab Dosing for Use in Acquired Hemophilia A

Background

In the scoping review and US case series described above, the dosing for emicizumab use was variable with the majority using the standard emicizumab loading dose conventionally used in congenital hemophilia A (3 mg/kg/week for 4 weeks).^11,12 For the two prospective clinical studies, AGEHA and GTH-AHA-EMI studies, emicizumab was administered subcutaneously at 6 mg/kg on Day 1, 3 mg/kg on Day 2, and 1.5 mg/kg once weekly from Day 8 onward.^13-15 This 1-week accelerated loading regimen was chosen based on pharmacokinetic modelling which found that the effect of emicizumab for preventing bleeds was almost maximized at plasma emicizumab concentrations above approximately 30 μg/mL and that there was a need to rapidly protect from bleeds in the early weeks following diagnosis.¹³ The AGEHA study confirmed that the 1-week loading regimen achieved maximum prophylactic effect of emicizumab (plasma emicizumab concentration >30 μg/mL) by 4 days after starting emicizumab treatment.¹⁴ 

Recommendation 2

• MASAC recommends that in individuals with AHA, the dosing regimen for emicizumab is a loading dose of 6 mg/kg on Day 1, 3 mg/kg on Day 2, and followed by 1.5 mg/kg weekly.

• REMARK: Based on the AGEHA study, this dosing regimen is approved for use in Japan to prevent or reduce the frequency of bleeding episodes in individuals with AHA.²⁰

TOPIC 3: Concurrent Use of Bypassing Agent with Emicizumab

Background

Caution should be undertaken when using bypassing agents to treat bleeding episodes concurrently with emicizumab. Please refer to #4 Caution with dose and duration of bypassing agents in MASAC Document #268 Recommendation on the Use and Management of Emicizumab-kxwh [Hemlibra®] for Hemophilia A with and without Inhibitors for guidance. Specifically, the use of aPCC for breakthrough bleed treatment while on emicizumab should be avoided due to the risk of thrombotic microangiopathy and thromboembolism. AHA disproportionately affects the elderly population who are more likely to have underlying atherosclerotic disease with increased risk of both arterial and/or venous thromboembolism.

Recommendation 3

• MASAC recommends that in individuals with AHA on emicizumab prophylaxis, breakthrough bleeds should be treated with rFVIIa or rpFVIII, and not with aPCC.

TOPIC 4: Laboratory Assay with Emicizumab Use

Background

As emicizumab interferes with aPTT-based assays, including clot-based FVIII activity assays, a chromogenic FVIII assay that uses bovine reagents is required to assay endogenous FVIII activity or the FVIII activity of any additional FVIII concentrate administered. Similarly, a bovine-reagent chromogenic-based inhibitor assay is required to measure FVIII inhibitor titer. Please refer to #6 Recommendations on laboratory assays while on emicizumab in MASAC Document #268.

Recommendation 4.1

• MASAC recommends that in individuals with AHA on emicizumab prophylaxis, only the chromogenic FVIII assay with bovine reagents should be used to monitor endogenous FVIII levels for evaluating AHA remission and to monitor FVIII levels during treatment of bleeding events with rpFVIII.

   

Recommendation 4.2

• MASAC recommends that in individuals with AHA on emicizumab prophylaxis, a bovine-reagent chromogenic-based inhibitor assay should be used to measure FVIII inhibitor titer.

TOPIC 5: Reimbursement

Background

It is well documented that individuals with AHA will require treatment similar to that used for individuals with congenital hemophilia A complicated by inhibitors. Failure to provide adequate reimbursement for these therapies may adversely impact patient care, morbidity, and mortality. 

Recommendation 5.1

• MASAC recommends that reimbursement for treatment for individuals with AHA be the same as for individuals with congenital hemophilia A with inhibitors.

   

Future Research Needs

• The optimal duration of emicizumab prophylaxis in individuals with AHA is not known.
• The efficacy and safety of concurrent anti-fibrinolytic therapy for mucosal-based bleeding is unknown.
• There is no safety data on the use of emicizumab in pregnancy or lactation.

REFERENCES

1. Kruse-Jarres R, Kempton CL, Baudo F, et al. Acquired hemophilia A: updated review of evidence and treatment guidance. Am J Hematol.2017;92(7):695-705.

2. Poston J, Kruse-Jarres R. The role of emicizumab in acquired hemophilia A. Hematology Am Soc Hematol Educ Program. 2023 Dec 8;2023(1):24-30

3. Konstantinov K, Dolladille C, Gillet B, et al. Drug-associated acquired hemophilia A: an analysis based on 185 cases from the WHO pharmacovigilance database. Haemophilia. 2023 Jan;29(1):186-192.

4. Tiede A, Collins P, Knoebl P, et al. International recommendations on the diagnosis and treatment of acquired hemophilia A. Haematologica. 2020;105(7):1791-1801.

5. Amano K, Seita I, Higasa S, et al. Treatment of acute bleeding in acquired haemophilia A with recombinant activated factor VII: analysis of 10-year Japanese postmarketing surveillance data. Haemophilia. 2017;23(1):50-58.

6. Tiede A, Klamroth R, Scharf RE, et al. Prognostic factors for remission of and survival in acquired hemophilia A (AHA): results from the GTHAH 01/2010 study. Blood. 2015;125(7):1091-1097.

7. Kitazawa T, Igawa T, SampeiZ, et al. A bispecific antibody to factors IXa and X restores factor VIII hemostatic activity in a hemophilia A model. Nat Med. 2012;18(10):1570-1574.

8. Sampei Z, Igawa T, Soeda T, et al. Identification and multidimensional optimization of an asymmetric bispecific IgG antibody mimicking the function of factor VIII cofactor activity. PLoS One. 2013;8(2):e57479.

9. Oldenburg J, Mahlangu JN, Kim B, et al. Emicizumab prophylaxis in hemophilia A with inhibitors. N Engl J Med. 2017;377(9):809- 818.

10. Mahlangu J, Oldenburg J, Paz-Priel I, et al. Emicizumab prophylaxis in patients who have hemophilia A without inhibitors. N Engl J Med. 2018;379(9):811-822.

11. Thomas VM, Abou-Ismail MY, Lim MY. Off-label use of emicizumab in persons with acquired haemophilia A and von Willebrand disease: A scoping review of the literature. Haemophilia. 2022 Jan;28(1):4-17.

12. Poston JN, Bryan C, von Drygalski A, et al. Real-world impact of emicizumab and immunosuppression on acquired hemophilia A: a multicenter US cohort. Blood Adv. 2024 Nov 26;8(22):5896-5905. 

13. Shima M, Amano K, Ogawa Y, et al. A prospective, multicenter, open-label phase III study of emicizumab prophylaxis in patients with acquired hemophilia A. J Thromb Haemost. 2023 Mar;21(3):534-545.

14. Shima M, Suzuki N, Nishikii H, et al. Analysis Results from the AGEHA Study: Emicizumab Prophylaxis for Acquired Hemophilia A with or without Immunosuppressive Therapy. Thromb Haemost. 2025 May;125(5):449-459. 

15. Tiede A, Hart C, Knöbl P, et al. Emicizumab prophylaxis in patients with acquired haemophilia A (GTH-AHA-EMI): an open-label, single-arm, multicentre, phase 2 study. Lancet Haematol. 2023 Nov;10(11):e913-e921. 

16. Poston JN, Al-Banaa K, von Drygalski A, et al. Emicizumab for the Treatment of Acquired Hemophilia a: A Multicenter US Case Series. Blood 2021; 138 (Supplement 1): 496.

17. Knoebl P, Marco P, Baudo F, et al. Demographic and Clinical Data in Acquired Hemophilia A: Results From the European Acquired Haemophilia Registry (EACH2). Journal of Thrombosis and Haemostasis 10, no. 4 (2012): 622–631

18. Palmeira P, Quinello C, Silveira-Lessa AL, Zago CA, Carneiro-Sampaio M. IgG placental transfer in healthy and pathological pregnancies. Clin Dev Immunol. 2012;2012:985646.

19. Pentsuk N, van der Laan JW. An interspecies comparison of placental antibody transfer: new insights into developmental toxicity testing of monoclonal antibodies. Birth Defects Res B Dev Reprod Toxicol. 2009 Aug;86(4):328-44.

20. https://www.chugai-pharm.co.jp/english/news/detail/20220620170002_928.html