Kurzfassung: This study is the first to assess prognostic factors in patients with AHA treated according to a uniform immunosuppressive regimen. Residual factor VIII activity and inhibitor concentration at baseline are potentially useful predictors of remission.

Kurzfassung: Acquired hemophilia A (AHA) is a rare autoimmune disorder caused by neutralizing autoantibodies against coagulation factor VIII (FVIII:C). Immunosuppressive treatment may result in remission of disease over a period of days to months. Until remission, patients are at high risk of bleeding and complications from immunosuppression. Prognostic parameters to predict remission and the time needed to achieve remission could be helpful to guide treatment intensity, but have not been established so far. GTH-AH01/2010 was a prospective multicenter cohort study using a standardized immunosuppressive treatment protocol. The primary study endpoint was time to achieve partial remission (PR, defined as FVIII:C activity 〉 50 IU/dl after cessation of any hemotherapy for 〉 24h, and no active bleeding). Secondary endpoints were time to achieve complete remission (CR, defined as PR plus negative FVIII:C inhibitor, steroid tapered to 〈 15 mg/d prednisolone, and cessation of any other immunosuppressive treatment), and overall survival (OS). Enrolment was strictly prospective and only allowed within 7 days of starting immunosuppression. Outcome data were recorded in all patients enrolled. The treatment protocol consisted of prednisolone (100 mg/d from day 1 to the day of PR, then tapered down to 〈 15 mg/d over 5 weeks), oral cyclophosphamide (150 mg/d, from day 21-42, unless PR was achieved), and rituximab (375 mg/m2 weekly for 4 weeks starting on day 43, unless PR was achieved). If AHA was first diagnosed in patients previously on prednisolone 〉 15 mg/d, or equivalent, they received prednisolone (100 mg/d) and rituximab from day 1. If cyclophosphamide was contraindicated, patients received prednisolone (100 mg/d) and rituximab from day 21. One hundred twenty-four patients from 21 treatment centers in Germany and Austria were enrolled between April 2010 and April 2013 (36 months). The patients from two centers not compliant with the treatment protocol were excluded (N=18), as were patients in whom AHA was not confirmed (N=2) or follow-up was too short at the time of this analysis (N=7). The remaining 97 patients from 17 centers were followed for a median of 256 days (interquartile range [IQR] 84-561). Median age was 74 years (IQR 64-82). AHA was associated with other autoimmune disorders (19%), malignancy (12%), pregnancy or puerperium (5%), but was most often idiopathic (66%). The median FVIII:C activity at baseline was 1 IU/dl (IQR 〈 1-3), and the median inhibitor titer was 20 BU/ml (IQR 7.7-78). PR and CR were achieved after a median time of 35 and 102 days, respectively. Patients achieving PR prior to day 21 (N=22) compared with patients not achieving PR within 21 days (N=75) had a higher baseline FVIII:C activity (median 3 vs. 〈 1 IU/dl, p 〈 0.01) and a lower FVIII:C inhibitor (median 12 vs. 29 BU/ml, p 〈 0.05). Multivariate analysis with adjustment for age, sex, underlying disorder, and WHO performance status on admission demonstrated that baseline FVIII:C activity ( 〈 1 IU/dl vs. 〉 =1 IU/dl) had a strong impact on the time to achieve PR (HR 2.76 [95% confidence interval 1.73-4.42] , p 〈 0.001) and CR (HR 2.36 [1.34-4.14], p 〈 0.01). Baseline FVIII:C activity was also a predictor of PR and CR when other cutoffs were used (2 or 3 IU/dl instead of 1 IU/dl), or when it was analyzed as a continuous variable in Cox regression analysis. In contrast, FVIII:C inhibitor titer assessed by the local laboratory did not affect time to PR or CR significantly. OS after 300 days, estimated by the Kaplan Meier method, was 69%. Age, WHO performance status, and FVIII:C activity at baseline were independent predictors of OS. In summary, GTH-AH 01/2010 is the largest prospective study of patients with AHA treated according to a standardized protocol. The study demonstrated a robust effect of baseline FVIII:C activity on the time needed to achieve PR and CR. Baseline FVIII:C activity, together with age and performance status, also affected OS. Therefore, baseline FVIII:C activity may be considered to guide individually tailored immunosuppression in future studies. Disclosures: Tiede: Baxter: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Biotest: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novo Nordisk: Consultancy, Honoraria, Research Funding; Biogen Idec: Consultancy; CSL Behring: Consultancy, Honoraria, Research Funding. Off Label Use: Prednisolone, cyclophosphamid, and rituximab for immunosuppression in acquired hemophilia. Klamroth:Bayer: Honoraria, Research Funding; Baxter: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Novo Nordisk: Honoraria, Research Funding. Gottstein:Novo Nordisk: Honoraria; Baxter: Honoraria. Holstein:Baxter: Honoraria, Speakers Bureau. Scharf:CSL Behring: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Biotest: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria; Baxter: Consultancy, Honoraria, Research Funding. Huth-Kühne:SRH Kurpfalz Hospital and Hemophilia Center: Consultancy, Employment, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Greil:Roche: Consultancy, Honoraria, Research Funding. Miesbach:Novo Nordisk: Consultancy, Honoraria, Research Funding; Baxter: Consultancy, Honoraria, Research Funding. Trappe:Roche: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau, Travel Other; AMGEN: Research Funding, Travel, Travel Other; CSL Behring: Honoraria, Research Funding, Speakers Bureau, Travel, Travel Other; Mundipharma: Research Funding, Travel, Travel Other; Takeda: Consultancy, Research Funding, Travel Other; Novartis: Consultancy, Research Funding, Travel, Travel Other; Novartis: Research Funding, Travel Other; Cellgen: Travel, Travel Other. Knoebl:Novo Nordisk: Consultancy, Honoraria; Baxter: Consultancy, Honoraria.

Kurzfassung: Background: Acquired hemophilia A (AHA) is a severe bleeding disorder that requires fast and accurate diagnosis as it occurs often unexpectedly in previously healthy men and women of every age. The Nijmegen-modified Bethesda assay (NBA) is the diagnostic gold standard detecting neutralizing anti-FVIII autoantibodies, but is not widely available, not ideal to quantify the complex type 2 inhibitors seen in AHA, and suffers from high inter-laboratory variability. Objectives: To assess the diagnostic and prognostic value of FVIII binding antibodies as detected by a commercial ELISA (Hyphen Biomed/Coachrom) compared with the NBA. Methods: Samples and clinical data were available from 102 patients with AHA enrolled in the prospective GTH-AH 01/2010 study. Controls were matched for gender and age. Diagnostic cut-offs were determined by receiver-operator curve (ROC) analysis on training and validation sets, assigned by 1:1 randomization, and by classification and regression tree (CRT) analysis. Prognostic value was assessed by Cox regression analysis of time to partial remission. Results: Anti-FVIII IgG above the 99th percentile ( 〉 15 AU/ml) revealed high sensitivity (1.0, 95% confidence interval [CI] 0.92-1.0) and specificity (1.0, CI 0.92-1.0) to diagnose AHA. The likelihood of achieving remission was strongly related to antibody concentration (anti-FVIII IgG 〈 100 AU/ml: 1.0; 100- 〈 1000 AU/ml: 0.40; ≥1000 AU/ml: 0.21). This association was stronger than that between NBA inhibitor titer and likelihood of remission. Conclusion: Although the NBA is the gold standard for demonstrating neutralizing antibodies in AHA, the detection of FVIII-binding antibodies by anti-FVIII IgG ELISA is similarly sensitive and specific to diagnose AHA. In addition, anti-FVIII IgG provides important prognostic information. Disclosures Tiede: CSL Behring: Consultancy, Honoraria, Research Funding; Baxter: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Investigator, Research Funding; Biotest: Consultancy, Honoraria, Research Funding; Leo Pharma: Consultancy, Honoraria; SOBI: Consultancy, Honoraria; Boehringer Ingelheim: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novo Nordisk: Consultancy, Honoraria, Research Funding; Biogen Idec: Consultancy, Honoraria; Coachrom: Research Funding; Octapharma: Other: Investigator, Speakers Bureau. Geisen:Roche Diagnostics International AG, Switzerland: Research Funding; Baxalta: Honoraria; Bayer: Research Funding; Novo Nordisk: Consultancy, Honoraria. Nowak-Göttl:Bayer: Consultancy; LFB: Consultancy; Octapharma: Consultancy. Eichler:CSL Behring: Consultancy, Research Funding; Biotest: Consultancy, Research Funding; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxter: Consultancy, Research Funding; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Klamroth:Bayer, Baxter, CSL Behring, Pfizer, Novo Nordisk, and Octapharma: Honoraria, Research Funding, Speakers Bureau; Biogen and SOBI: Honoraria, Speakers Bureau. Huth-Kühne:Biotest: Consultancy; Baxalta: Consultancy; CSL: Consultancy; Bayer: Consultancy.