Diagnosis and Treatment of Acquired Hemophilia: One Single-Center Experience from PR. China

Objective: To deepen the understanding of the clinical manifestations of acquired hemophilia A for timely and correctly treatment. Methods: The clinical data of the acquired hemophilia A patients diagnosed in the hospital from Jan 2006 to Mar 2021 were retrospectively analyzed, and the relevant literature was reviewed. Results: 17 patients with acquired hemophilia A, male: female =10: 7, median age 61 years (19 to 78 years), were diagnosed and treated in the hospital with the median time from the onset to diagnosis 21 days (2 days to 6 months). Six patients had comorbidity, including hepatitis B carrying, chronic myelomonocytic leukemia, diabetes, hypertension and positive autoantibodies, pemphigoid and gastric cancer, respectively. Other 11 patients were healthy before the onset. All patients had large large ecchymosis of skin, and one case was combined with hematuria, and one case with retroperitoneal hematoma. All patients had APTT extension (45s-144.7s) and the prolonged APTT could not be corrected with normal mixed plasma with and without incubation at 37℃ for 2 hours. FVIII activity was 1% - 8.9% and inhibitor titer 2 - 128 Bu/ml. All patients with bleeding were with prothrombin complex/recombinant activated coagulation factor VII, some of them with pd-coagulation factor FVIII preparations. Inhibitors were removed with prednisone acetate (1 case) + chemotherapy (1 case), prednisone acetate / + CTX (11 cases) + chemotherapy (1 case), prednisone acetate/prednisolone + mabthera (2 cases) + CTX (1 case), respectively. The removal time of inhibitor was from 8 days to 4 years. During the treatment process, two patients developed lower extremity venous thrombosis, and one patient was complicated with lung infection. Conclusion: Patients with unexplained bleeding and prolonged APTT should be conducted normal mixed plasma correction test, coagulation factor activity and inhibitor titer examination. After correctly diagnosis, bypass agents /coagulation factor VIII preparations should be given timely for hemostasis, protocol based on glucocorticoid + CTX/mabthera to remove the inhibitor and symptomatic treatment for patients with primary comorbidity disease at the same time. Disclosures No relevant conflicts of interest to declare.

Orihime Study: Real World Treatment Patterns and Clinical Outcomes of 338 Patients with Acquired Hemophilia a from a Japanese Health Claims Database

Introduction: Acquired hemophilia A (AHA) is a rare disorder characterized by severe, spontaneous bleeding caused by autoantibodies against factor (F)VIII (inhibitors). It is known that onset of AHA is triggered by malignancy, autoimmune disease, dermatological disease, and pregnancy/delivery. As the standard therapy, immunosuppressive therapy (IST) should be started immediately to eliminate inhibitors and hemostatic therapy is also necessary in case of bleeding. Many patients require prolonged bed rest because of the bleeding risk; therefore, it is difficult to determine the best time to start rehabilitation. Additionally, the early deaths and high thrombotic rates are frequently reported in AHA. Since it is a rare disorder, the actual situation has not been fully clarified. This study was to describe the epidemiology and clinical practice of AHA in the real world using a large health claims database in Japan. Methods: This was a retrospective observational study using a health claims database provided by Medical Data Vision Co., Ltd. The data period was Apr. 2008-Mar. 2020. Patients who met all of the following criteria were included; patients with disease diagnosis of AHA; patients were hospitalized on the day of AHA diagnosis; and patients had immunosuppressants on/after the date of the first hospitalization. The first date of hospitalization was set as an Index date. Patients with disease diagnosis code of antiphospholipid syndrome, lupus anticoagulant, acquired factor XIII deficiency, acquired von Willebrand disease, or acquired factor V deficiency were excluded. Treatment/procedure patterns (IST, hemostatic therapy, and rehabilitation) and clinical outcome (Activities of Daily Living [ADL], death, and thromboembolism in the hospitalization) in AHA patients were investigated. Results: The study population of 338 patients (214 males: 124 females) was with the mean age of 75.7 (21-96) years. A total of 105 patients (pts) (31.1%) had concurrent diseases, including malignancy (61 pts, 18.0%), autoimmune diseases (40 pts, 11.8%), and dermatological diseases (18 pts, 5.3%). In bypassing agent use (153 pts, 45.3%), recombinant activated factor VII (rFVIIa) was the most frequently used (129 pts, 38.2%) followed by activated prothrombin complex concentrate (aPCC) (36 pts, 10.7%), and plasma-derived factor VIIa and factor X (FVIIa/FX) (14 pts, 4.1%). FVIII agent uses (8 pts) were very few. Median duration of treatment for bypassing agents ranged from 2.5 (FVIIa/FX) to 6.0 (aPCC) days. Steroids alone were used predominantly in the first line for immunosuppression (292 pts, 86.4 %) and oral prednisolone was the most frequently used. The category of rehabilitation most commonly implemented in AHA patients was disuse syndrome (104 pts, 30.8%) followed by locomotor (73 pts, 21.6%) and cerebrovascular (49 pts, 14.5%). Median time (days) from Index date to initiating rehabilitation was 16.5 for disuse syndrome, 23.0 for locomotor, 19.0 for cerebrovascular. In the total ADL scores (Barthel Index) in 196 patients with all 10 items, the proportions of patients with less than 70 points were high at both initial admission and final discharge (47.4% and 38.8%, respectively). The median number of times and length of hospitalization were 1.0 time and 62.0 days, respectively. Of evaluable population (328 pts), thromboembolism during hospitalization was recorded in 15 patients, by type of which disseminated intravascular coagulation (10 pts, 3.0%) was the most frequently recorded. Acute coronary syndrome (3 pts, 0.9%), pulmonary embolism and other (1 pt, 0.3%, each) were fewly recorded. The proportion of deaths during hospitalization was 18.6% (63 pts). Table 1 shows study result summary. Conclusions: This was the first study in a large AHA population using a health claims database in Japan. From an epidemiological point of view, the number of male patients was slightly larger and the mean age was slightly higher compared to the demographics in previous reports. The possible reason is regional variance or data source, whereas, the treatment patterns and the proportion of deaths during hospitalization are mostly aligned with the previous studies. Also this was the first report publishing the data on ADL and rehabilitation in AHA patients. The results showed that it took median 2-3 weeks to start rehabilitation. Further development of treatment strategies to enable early start of rehabilitation is awaited. Figure 1 Figure 1. Disclosures Ogawa: Chugai Pharmaceutical Co., Ltd.: Consultancy. Amano: Chugai Pharmaceutical Co., Ltd.: Consultancy, Speakers Bureau; KM Biologics Co., Ltd.: Research Funding, Speakers Bureau; Bioverativ Inc.: Speakers Bureau; Bayer AG: Speakers Bureau; Shire Plc: Speakers Bureau; Takeda Pharmaceutical Co., Ltd.: Speakers Bureau; Sanofi S.A.: Speakers Bureau; Novo Nordisk A/S: Speakers Bureau; CSL Behring: Speakers Bureau; Pfizer Inc.: Speakers Bureau; Japan Blood Products Organization: Speakers Bureau. Matsuo-Tezuka: Chugai Pharmaceutical Co., Ltd.: Current Employment. Okada: Chugai Pharmaceutical Co., Ltd.: Current Employment. Murakami: Chugai Pharmaceutical Co., Ltd.: Current Employment. Nakamura: Chugai Pharmaceutical Co., Ltd.: Current Employment. Yamaguchi-Suita: Chugai Pharmaceutical Co., Ltd: Current Employment. Nogami: Chugai Pharmaceutical Co., Ltd.: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda Pharmaceutical Co., Ltd.: Honoraria, Research Funding, Speakers Bureau; CSL Behring: Honoraria, Research Funding, Speakers Bureau; Novo Nordisk A/S: Honoraria, Research Funding, Speakers Bureau; Bayer AG: Honoraria, Research Funding, Speakers Bureau; Sanofi S.A.: Honoraria, Research Funding, Speakers Bureau; KM Biologics Co., Ltd.: Honoraria, Research Funding, Speakers Bureau. OffLabel Disclosure: Data on the uses of cyclophosphamide, cyclosporin A, and rituximab for acquired hemophilia may be included in the poster presentation. However, with regard to these drugs, treatments for other diseases may also be included because this study was conducted with a secondary use of a health claims database. Off-label drug use is explained in the poster.

Rituximab Monotherapy Is Effective for Inhibitor Eradication with Concomitant Porcine Factor VIII Followed By Emicizumab for Bleed Control in Acquired Hemophilia a

Introduction Acquired hemophilia A (AHA) is a rare bleeding disorder in which acquired auto-antibodies to endogenous Factor VIII (FVIII) resulting in decreased FVIII activity. AHA can lead to life-threatening bleeding, with effective treatment requiring both immunosuppressive therapy (IST) and bypassing agents such as recombinant activated Factor VII (rFVIIa) or activated prothrombin complex concentrates (APCC) (Tiede et al. Haematologica 2020). Some, including our group, have begun using emicizumab as well (Knoebl et al. Blood 2020). IST is required for inhibitor eradication, but regimens are heterogenous and have not been systematically compared in the literature. While there is no standard of care IST in these patients, most patients in the literature receive multiple agents, including corticosteroids, mycophenolate mofetil, cyclosporine, and/or rituximab in combination. We report in a prospective cohort that for IST, rituximab monotherapy is an effective strategy. An updated treatment algorithm is offered that has been effective for treatment of these patients at our institution, which adds emicizumab therapy after initial bleed control. Methods We analyzed clinical, pharmacy, and laboratory data from 24 patients treated with rpFVIII at the University of North Carolina for AHA from July 2015 to June 2021. All patients were initially treated according to our previously established dosing algorithm with recombinant porcine FVIII, and the last five patients have received emicizumab after initial factor dosing (see Figure 1). 17 of the patients who received rituximab and were followed at our center subsequently attained inhibitor eradication, six of those received only rituximab therapy. Investigational review board approval was obtained for our data collection and analysis. Patients who did not receive rituximab, failed to reach an inhibitor level <0.5 BU, or who were lost to follow up were excluded from the analysis. For patients that fit the inclusion criteria, the time between date of the first rituximab infusion and the date of inhibitor eradication was calculated. Results All patients in our cohort who we followed until inhibitor eradication (17 of 24 patients) had eradication of inhibitors after a median of 143 days from initiation of immunosuppression. For patients treated with rituximab monotherapy for inhibitor eradication (6 of 17), this goal was reached in a median of 134.5 days (range 76-191 days). For those who received agents in addition to rituximab and have reached inhibitor eradication to date (9 of 17 patients), median days from initiation of immunosuppression to inhibitor eradication was 137.5 days (range 11-485) (P = 0.43 on Mann-Whitney test). Patients were treated as previously reported by our group per an algorithm that starts recombinant porcine FVIII without waiting for a porcine inhibitor and at lower than FDA recommended dosing. Subsequent doses for bleed control are titrated according to one-stage, clot based FVIII activity. This report also includes 5 new patients who, after initial bleed control per our algorithm, were initiated on emicizumab while awaiting inhibitor eradication. There was no correlation between time to rituximab initiation and time to inhibitor eradication in both those who received rituximab monotherapy and those who had multiple IST agents. There was also no significant difference in initial inhibitor titer between groups with median initial inhibitor titer of 104 BU in the rituximab monotherapy group, and 70 BU in the multiple IST agents group (see Figure 3). Conclusions Rituximab monotherapy appears to be an effective strategy for inhibitor eradication in acquired hemophilia A. In the context of bleed treatment with porcine factor, followed by emicizumab, a standardized, algorithmic approach can be effectively employed for these patients. Though any patients have inhibitor recurrence, as is described in the literature, with emicizumab available, bleeding can be avoided with regular monitoring. Emicizumab given while re-eradicating an inhibitor can prevent morbidity of this disease. Figure 1 Figure 1. Disclosures Ellsworth: Takeda: Other: Salary supported as part of NHF-Takeda Clinical Fellowship Award. Key: Uniqure: Consultancy, Other: Participation as a clinical trial investigator; Grifols: Research Funding; Takeda: Research Funding; BioMarin: Honoraria, Other: Participation as a clinical trial investigator; Sanofi: Consultancy. Ma: Accordant: Consultancy; Takeda: Honoraria, Research Funding. OffLabel Disclosure: Emicizumab is not approved for use in Acquired Hemophilia A and this represents an OFF LABEL use of the drug.

A Healthy Volunteer-Derived, Factor VIII-Neutralized, Acquired Hemophilia a-Mimetic Plasma Produces Similar Pharmacodynamic Responses of Emicizumab to Those in Patients with Congenital Hemophilia a with or without Inhibitors

INTRODUCTION: Emicizumab is a bispecific antibody that mimics the cofactor function of activated factor VIII (FVIIIa) and is currently indicated for routine prophylaxis of bleeds in patients with congenital hemophilia A (PwCHA) regardless of factor VIII (FVIII) inhibitor status. Given its mechanism of action, the treatment response of emicizumab is expected to be similar between PwCHA and patients with acquired hemophilia A (AHA; PwAHA). However, it has not been well evidenced. We aimed to address this question by elucidating whether a healthy volunteer (HV)-derived, FVIII-neutralized, AHA-mimetic plasma produces similar pharmacodynamic (PD) responses of emicizumab to those in PwCHA. METHODS: In the phase I-I/II studies of emicizumab (Blood 2016;127:1633-41; N Engl J Med 2016;374:2044-53; Blood Adv 2017;1:1891-9; Haemophilia 2021;27:81-9), 40 Japanese HVs, 24 Caucasian HVs, 11 Japanese PwCHA with inhibitors (PwCHAwI), and 7 Japanese PwCHA without inhibitors (PwCHAwoI) were enrolled to receive emicizumab or placebo. These studies were conducted in accordance with relevant ethical standards as previously reported. Plasma samples were collected before first administration of the study drug, and they were spiked with emicizumab at 0, 0.3, 3, 30, or 300 μg/mL for HVs or 0, 3, or 300 μg/mL for PwCHA in combination with two anti-FVIII neutralizing antibodies (VIII-2236, anti-A2 type 1 inhibitor; VIII-9222, anti-C2 type 2 inhibitor) at approximately 300 μg/mL each (termed "ex vivo spiked plasma") for the measurement of activated partial thromboplastin time (APTT) and activated factor XI-triggered thrombin generation (TG). Separate plasma samples were collected before and after first administration (termed "in vivo exposed plasma") to be used for measuring APTT and TG, with ex vivo FVIII neutralization for HVs or without for PwCHA, as well as emicizumab concentration. Due to the difference in the given dosing regimens, observed plasma emicizumab concentrations did not largely overlap between HVs and PwCHA (up to 5.92 μg/mL as mean maximum concentration in HVs versus 10.3 to 120 μg/mL as mean steady-state trough concentration in PwCHA), which precluded simple comparison of the concentration-response (C-R) relationships between HVs and PwCHA in the in vivo exposed plasma. To overcome this limitation, nonlinear mixed-effect ("population") modeling was performed to analyze the C-R data from the ex vivo spiked plasma from HVs for APTT and TG each, and the developed population PD (PopPD) models were used to simulate C-R relationships in HVs over a wide range of plasma emicizumab concentration for comparison with those observed in the in vivo exposed plasma from PwCHA. RESULTS: In the ex vivo spiked plasma, the observed C-R relationships of APTT and TG were similar among Japanese HVs, Caucasian HVs, Japanese PwCHAwI, and Japanese PwCHAwoI, indicating similar FVIIIa-mimetic activity of emicizumab between HVs and PwCHA under the artificial FVIII-depleted condition ex vivo. The developed PopPD models adequately described the C-R data from HVs which were used for the model development. In the in vivo exposed plasma (Figure), the observed C-R relationships of APTT and TG were similar between Japanese HVs and Caucasian HVs as well as between Japanese PwCHAwI and Japanese PwCHAwoI. The observed C-R relationships in HVs were well captured by the PopPD model-based simulations despite these data being not directly used for the model development, which demonstrated the ability of the ex vivo data to be extrapolated in vivo. The PopPD models also well captured the observed C-R relationships in PwCHA, suggesting similar FVIIIa-mimetic activity of emicizumab between HVs and PwCHA in vivo. Some deviating observations from the PopPD model-based simulations might be attributed to the residual activity of given coagulation factor products, e.g., relatively short APTT and promoted TG at a plasma emicizumab concentration of 0 μg/mL (before first administration) in PwCHAwoI prior treated with FVIII prophylaxis. CONCLUSIONS: A HV-derived, FVIII-neutralized, AHA-mimetic plasma produced similar PD responses of emicizumab to those in PwCHA with or without inhibitors. Given its potential nature of mimicking AHA, i.e., coexistence of FVIII and multiple inhibitors including a type 2 one, the findings derived using this plasma may suggest similarity in the treatment response of emicizumab between PwCHA and PwAHA. Figure 1 Figure 1. Disclosures Yoneyama: Chugai Pharmaceutical Co., Ltd.: Current Employment, Patents & Royalties: Inventor of patents related to anti-FIXa/FX bispecific antibodies. Tokuda: Chugai Pharmaceutical Co., Ltd.: Current Employment. Soeda: Chugai Pharmaceutical Co., Ltd.: Current Employment, Patents & Royalties: Inventor of patents related to anti-FIXa/FX bispecific antibodies. Saito: Chugai Pharmaceutical Co., Ltd.: Current Employment. Shima: BioMarin Pharmaceutical Inc.: Membership on an entity's Board of Directors or advisory committees; Bayer AG: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk A/S: Honoraria, Speakers Bureau; Takeda: Research Funding; CSL Behring: Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd.: Membership on an entity's Board of Directors or advisory committees; Chugai Pharmaceutical Co., Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Inventor of patents related to anti-FIXa/FX bispecific antibodies, Research Funding, Speakers Bureau; Sanofi S.A.: Speakers Bureau; Fujimoto Seiyaku: Consultancy, Speakers Bureau. OffLabel Disclosure: Emicizumab for acquired hemophilia A