New Early Prophylaxis Regimen That Avoids Immunological Danger Signals Can Reduce Factor Eight (FVIII) Inhibitor Development Independent From Product Type Used.
Authors: Auerswald Guenter K.H. , Bidlingmaier Christoph , Engl Werner , Chehadeh Heidi , Reipert Birgit M , Kurnik Karin 
Published: October 2019

Abstract 221

Introduction:

Today, the most problematic and costly complication of the treatment of hemophilia A that remains to be overcome is the development of inhibitory antibodies (FVIII inhibitors) to FVIII replacement therapy, particularly in previously untreated patients (PUPs).

Aim of the study:

The highest risk of developing inhibitors to FVIII is during the first 20 exposure days (EDs). If the patient can be brought through this high risk period without inhibitor development, the subsequent risk is low.

We therefore, as a pilot project, developed a prophylaxis regimen for the first 20–50 EDs specifically designed to induce tolerance to the administered FVIII and to minimize inhibitor development.

Patients and Methods:

Twenty-six consecutive PUPs with severe hemophilia A (<1% FVIII) as they appeared in the centers were treated with a once weekly low dose (250 Units) prophylaxis regimen started as soon as venous access allows without a Port-A-Cath. Thereby immunological danger signals were minimized by avoiding giving first FVIII into a bleed or during an infection, and avoiding surgery during the first 20 EDs. The incidence of inhibitor development in the study group was compared with that in a historical control group of 30 consecutive PUPs with severe hemophilia A treated with a standard joint protection prophylaxis regimen of 40–50 IU/kg FVIII three times a week, starting at or after the first joint or other severe bleed. The new prophylaxis regimen was started after a median of 1 FVIII EDs at a median age of 10.7 months compared to the historical control group were high dose prophylaxis was started later after a median of 30 FVIII on demand EDs at a median age of 19 months (p<0.006). Both plasma-derived and recombinant FVIII concentrates were used in 47% and 53% of the patients respectively.

Results:

There were no significant differences between the study and control groups in patient related inhibitor risk factors such as ethnicity (all Caucasian), severity of hemophilia (all <1% FVIII), severity of FVIII gene mutation (p<0.0006) and some treatment related factors such as the type of product, age at first exposure, vaccination regimen, need for surgery. However, 14 of 30 subjects (47%) given standard prophylaxis but only 1 of the 26 subjects (3.8%) given the new regimen developed an inhibitor (p=0.0003, odds ratio 0.048, 95% CI: 0.001 to 0.372). Eight subjects given standard prophylaxis but none of those given the new regimen were high responders (p=0.005, odds ratio for high response 0.00, 95% CI: 0.00 to 0.57).

Conclusion:

Our results indicate that early start of prophylaxis associated with minimizing immunological danger signals during the first 20 exposure days with FVIII may reduce the risk of inhibitor formation even in PUPs with a high risk genetic background independent from the FVIII product type used. Once the patients have developed tolerance to FVIII, usually after about 20 to 50 EDs on the low dose regimen, and venous access permitted, prophylaxis might be changed to the normal three times weekly regimen for optimal protection from joint bleedings. These results need to be confirmed in a larger prospective clinical study.

Disclosures:

Auerswald: Baxter, CSL-Behring and NovoNordisk.: Consultancy, Honoraria, Research Funding. Bidlingmaier:CSL Behring and Bayer : Honoraria. Engl:baxter: Employment. Chehadeh:baxter: Employment. Reipert:baxter: Employment.