Real Pandemic World Results of Personalized Prophylaxis of Bleeds in Polish Children and Adolescents with Severe Hemophilia a

Introduction and aim of the study:

In the autumn of 2020, the new nationwide protocol of bleeding prophylaxis in Polish plasma-derived FVIII (pdFVIII) previously treated patients (PTPs) with severe hemophilia A (sHA) was introduced, resulting in the necessity of switching from pdFVIII to recombinant FVIII (octocog-alpha; rFVIII). It created the opportunity to perform the study aiming to:

1. assess the safety of switching from pdFVIII to rFVIII

2. assess the safety and efficacy of pharmacokinetically-based (PK-based) personalized prophylaxis in children and adolescents with severe hemophilia A.

Patients and methods:

A total of one hundred fifty-one patients (median age 166 [93-209] months) receiving prophylaxis with a standard dose (40 U/kg 3 x weekly) of pdFVIII were included in this study. Annualized bleeding rate (ABR) and annualized joint bleeding rate (AJBR) were analyzed for all patients before enrollment. Using myPKFiT application, pharmacokinetic (PK) analysis followed by the selection of optimal (dosing and timing) model of prophylaxis was performed in all patients. All pros and cons of two possible models of prophylaxis (standard-dose rFVIII versus PK-based rFVIII) were discussed with parents/guardians and/or patients leaving the choice to their decision. Episodes of bleeds in two study groups were reported by parents/guardians using e-diaries and verified by local hemophilia treaters. Screening for inhibitor (INH) development was performed every three months and in every case of clinical suspicion. ABR and AJBR were prospectively analyzed again after a minimum follow-up time of 26 weeks with respect to models of prophylaxis and a type of FVIII used. Rates of bleedings were compared using the Student's t-test.

Results: Due to COVID-19 pandemic-related problems, 141/151 (93.4%) patients completed the study. Thirty-four patients decided to continue standard prophylaxis with rFVIII (Group I), whereas one hundred seven were switched to PK-based prophylaxis (Group II). The risk of INH development could be assessed in 137/151 (90.7%) patients. Only 2/137 (1.47%) patients (both on PK-based prophylaxis) developed low-titer inhibitors (0.8 BU/ml after 120 exposure days (EDs) and 1.8 BU/ml after 78 EDs, respectively) with no clinical manifestation and with spontaneous elimination of the inhibitor in both cases. The retrospective analysis of bleeds during last 12 months of standard pdFVIII prophylaxis revealed that patients who decided to continue standard prophylaxis (Group I) had better ABR and AJBR than those who started PK-based personalized prophylaxis (Group II). After a minimum of 26 weeks, ABR and AJBR improved significantly in both groups. There was no significant difference in ABR and AJBR between Group I and Group II during the follow-up period, however the rate of reduction of ABR and AJBR was higher in patients on PK-based personalized prophylaxis (Group II). The prophylaxis results are presented in Figure 1.

Conclusions: 1. Switching from pdFVIII to rFVIII (octocog-alpha) in PTPs with sHA is safe,

2. PK-based personalized prophylaxis may decrease ABR and AJBR in children and adolescents with sHA, especially in those in whom results of previous prophylaxis were unsatisfactory.

Urasinski:Takeda Pharma: Honoraria, Research Funding; Roche Poland: Honoraria, Membership on an entity's Board of Directors or advisory committees; NovoNordisk: Honoraria; Amgen: Honoraria; Phizer: Honoraria; CLS Behring: Honoraria. Paczoska:Takeda: Honoraria. Badowska:TAKEDA: Consultancy. Dakowicz:Takeda: Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria, Speakers Bureau; NovoNordisk: Honoraria, Speakers Bureau. Dobaczewski:Takeda: Consultancy, Honoraria. Latos-Grazynska:Takeda: Consultancy. Karolczyk:Takeda: Other: clinical research. Klukowska:Takeda: Honoraria, Research Funding, Speakers Bureau; Roche: Speakers Bureau; NovoNordik: Honoraria, Speakers Bureau. Koltan:Takeda: Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria, Speakers Bureau; NovoNordisk: Honoraria, Speakers Bureau; CSL Behring: Honoraria; Octapharma: Speakers Bureau; Novartis: Honoraria; JazzPharma: Honoraria; Teva Pharmaceuticals: Honoraria. Wojdalska:takeda: Speakers Bureau. Laguna:Takeda: Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria, Speakers Bureau; NovoNordisk: Speakers Bureau; CSL Behring: Speakers Bureau; Octapharma: Speakers Bureau. Niedzwiecki:Takeda: Honoraria, Research Funding; Roche: Honoraria; NovoNordisk: Honoraria; Octapharma: Honoraria. Pietrys:TAKEDA: Honoraria. Radwanska:Takeda: Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria; NovoNordisk: Honoraria. Ruranska:Takeda: Honoraria, Other: Congress Sponsorship, Research Funding; Roche: Honoraria, Other: Congress Sponsorship. Szczepanski:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Congress Sponsorship; Sobi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Congress Sponsorship; Takeda: Research Funding; Amgen: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Other: Congress Sponsorship; CSL Behring: Other: Congress Sponsorship. Wasinski:Takeda: Honoraria, Research Funding; Roche: Honoraria; NovoNordisk: Honoraria; CSL Behring: Honoraria. Woznica-Karczmarz:TAKEDA: Consultancy, Honoraria; NovoNordisk: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria. Ociepa:Roche: Honoraria, Speakers Bureau; Novartis: Honoraria; Takeda: Honoraria, Research Funding, Speakers Bureau; Jazz Pharma: Honoraria; NovoNordisk: Honoraria.