Introduction: Even though episodic replacement of clotting factor concentrate (CFC) at doses ranging from 1000-2000 IU/kg/year does alter the natural bleeding profile of patients with hemophilia in a way that can prevent long term musculoskeletal damage (Poonnoose et al, Haemophilia, 2017), it continues to be widely used around the world because most patients do not have access to standard dose prophylaxis with 30-40 IU/kg of CFC 2-3 times/week. We have prospectively evaluated the effectiveness of prophylaxis at lower doses in minimally treated young children with severe hemophilia.
Patients & methods: Minimally treated children, between 3-7 years, with severe hemophilia A (FVIII <1%) with no inhibitors and with a HJHS score of <5 were offered the opportunity to be included in the program. Their bleeding rate over the 6 months period prior to study entry was documented. Prophylaxis was administered with a plasma derived FVIII concentrate (KLOTT, Kedrion, Italy) at a dose of 10-15 IU/kg two times/week. Supervised administration of CFC was carried out in the clinic for all these patients. Only peripheral venous access was used to administer CFCs to all patients. All bleeding was documented with special emphasis on joint or muscle bleeds which were defined as per ISTH SSC criteria (Blanchette et al, JTH, 2014) along with any other critical bleeding. Inhibitors were monitored every 5-10 exposures. Clinical assessment was done with the hemophilia joint health score (HJHS).
Result: The outcome of treatment with this protocol in 26 children is included in this report. Their median age was 5 years. All patients had a HJHS score of <5 at study entry. The median number of exposures to CFC prior to study entry was 4 (range: 0-314). The median annualized bleeding rate (AdBR) among these patients prior to prophylaxis was 3 (range: 1-5). On prophylaxis with a median dose of 16 IU/kg twice weekly, the median AdBR was 0 (range: 0-3) at a median follow-up of 8 months (range: 4-10). No patient had any target joint at study entry or during the course of the study. No patient had any muscle or CNS bleed during this period. Two patients developed transient inhibitors (low titer 1.1 BU & 2.5 BU, respectively) after 7 and 17 exposures. These resolved within 4-12 weeks with continuing prophylaxis and have remained negative since. None of the other patients developed inhibitors after a median of 70 exposures (range: 35 to 90). One patient withdrew from the prophylaxis program after 11 doses while 1 patient missed two prophylaxis doses. Other than these, there has been complete compliance with all prophylaxis doses so far.
Conclusion: Data from this prophylaxis program shows that even at low doses of ~15 IU/kg 2x/week, which is similar to that used for episodic treatment at many centers around the world, the AdBR very can be brought down significantly to <3 / year, a level at which major improvements in long term musculoskeletal outcome in hemophilia can be expected. These data further support the concept that lower dose prophylaxis therefore must immediately replace episodic treatment where ever possible and dosage further optimized to reduce bleeding in each individual patient to a level which will give the best long term results.
Srivastava: Bayer Healthcare, Shire, Novo Nordisk, Roche Genentech, LFB: Other: Educational grants / Advisory Board / Grants Review / Data Monitoring Committee, Research Funding.
Asterisk with author names denotes non-ASH members.