Factor VIII (FVIII) Trough Levels of Real-World Severe-Type People with Hemophilia a (PwHA) on rFVIII-Fc Prophylaxis: Clinical Correlates and Effects on Perceivable Bleeding Outcomes

Introduction: Extended half-life (EHL) recombinant factor VIII with Fc-fusion protein (rFVIIIFc) has been launched in Taiwan since 2018. In the past, for standard half life (SHL) FVIII prophylaxis in severe-type people with hemophilia A (PwHA), FVIII trough level could be kept as >1% and helpful for prevention of joint bleeding and joint arthropathy. For EHL FVIII prophylaxis for PwHA, it was suggested that trough levels could be kept between 3% and 5% and is more beneficial for stopping subclinical joint bleeding. Clinically, trough levels of PwHA on rFVIIIFc prophylaxis variate greatly, and what is the correlate of trough levels and whether trough levels impact on bleeding outcomes have been seldom discussed. We aimed to study the clinical correlates of trough levels and the effects of trough levels on bleeding for real-world PwHA on rFVIIIFc prophylaxis.

Materials & Methods: Severe-type PwHA were retrospectively enrolled from two hemophilia centers in Taiwan, who switched from rFVIII to rFVIIIFc after 2018. Inclusion criteria were non-inhibitor PwHA, being on rFVIIIFc prophylaxis, having data of trough levels and bleeding frequency. Exclusion criteria were inhibitor patients, PwHA with on-demand therapy, or incomplete data. Bleeding frequency was obtained from bleeding records during study period from December, 2018 to July, 2020, with duration of at least >6 months, which was then annualized as annualized bleeding rate (ABR) and annualized joint bleeding rate (AJBR). Other clinical data were collected, including age, BW, BMI, Hct, ABO blood grouping, endogenous von Willebrand factor (VWF) levels, trough levels and pharmacokinetic data by WAPPS-hemo online. Dose regimen of rFVIIIFc prophylaxis were 30-35 iu/kg/dose every 3 days, 40-50 iu/kg/dose every 4 days, or 55-65 iu/kg/dose every 5 days or weekly as per regulations of National Health Insurance.

Results: There were totally 48 PwHA, 8 boys and 40 adults. The mean age was 34.6±15.9 years (range 8－64). Twenty-one patients were blood-group O, and 29 were non-O. Mean endogenous VWF:Ag was 112.5±54.1% (range 50%－294.7%). Mean endogenous VWF:activity was 103.4±52.3% (range 41.3%－307%). The mean trough level was 3.7±4.5%, range <1%－29.7%. Under rFVIIIFc prophylaxis, mean ABR and AJBR was <2.5 and <2, respectively. PwHA with O and non-O blood group had mean trough levels of 2.0±1.3% and 4.9±5.4%. (p<0.001***) For PwHA with trough level < 1% (n=10) and >1% (n=38), mean half life was 11.9±2.8 and 22.3±5.7 h, respectively. (p<0.001***) By Pearson correlation analysis, rFVIIIFc trough level during prophylaxis was significantly strongly correlated to endogenous VWF:Ag and activity (both P-rank >0.7, P-value<0.001***), significantly moderately correlated to age (P-rank=0.4755, P-value<0.001***), significantly weekly correlated to BMI (P-rank=0.3012, P-value<0.05*), but not correlated to BW and HB. Regarding the impact of trough levels on bleeding outcomes, For PwHA with non-zero bleeding (n=38), the proportion of trough <1% was not significantly higher than that of PwHA with zero bleeding (n=10). For PwHA with non-zero joint bleeding (n=32), the proportion of trough <1% was not significantly higher than that of PwHA with zero joint bleeding (n=16). Among the groups of trough levels of <1% (n=10), >1 and <3% (n=16), >3 and <5% (n=13), and >5% (n=9), there were no significant differences of ABR and AJBR. By Pearson correlation analysis, rFVIIIFc trough level was not significantly correlated to ABR and AJBR. By univariate and multivariate linea regression analysis, rFVIIIFc trough level was not associated with or not a predictor for ABR and AJBR.

Conclusion: Our study showed that for real-world PwHA on rFVIIIFc prophylaxis, trough levels variated hugely, and that trough levels were significantly higher in PwHA with non-O group and longer rFVIIIFc half life, and significantly correlated to endogenous VWF levels, age, and BMI. Meanwhile, our data indicated that between PwHA with non-zero and zero bleeding, the proportion of trough <1% was not significantly different; meanwhile, trough level was not correlated to perceivable bleeding frequency, including ABR and AJBR.