Successful of Immune Tolerance Induction (R-ITI) with Simoctocog Alfa (rhFVIII) in Hemophilia a Patients and High-Titer Inhibitors
Authors: Zanon Ezio , Pasca Samantha , Marino Renato , Molinari Angelo Claudio 
Published: October 2019

Abstract
Backgroud: The appearance of inhibitors (INH) is the most serious complication in hemophilia A (HA) patients. The primary objective is their eradication. Usually the primary ITI was performed with the same concentrate causing INH development, but which replacement factor to be use in case of ITI-R is still debatable. We report two successful cases of ITI-R with simoctocog alfa (rhFVIII) performed in two different Italian Hemophilia Centers, while three other cases are still ongoing. Case Report: Case-1: Adult man with moderate HA who developed INH after surgery and concomitant switch to another concentrate (octocog-alfa 2nd gen). The patient refused the ITI treatment immediately after the inhibitors appearance, and was then put on prophylaxis with bypassing agents for several months. First ITI was then started with pdFVIII/vWF at 200 IU/kg/day, inhibitor titer reached its historical peak (134 BU/ml) two months later and progressively decreased to 15 BU/ml, but without ever disappearing. This ITI was stopped after nineteen months. A second ITI was then tried with high dose regimen of morocotocog-alfa, but also in this case the mean INH titer remained steadily high (21 BU/ml) and this treatment was considered failed after fifteen months from the onset. A new ITI-R was then started when the INH titer was 74 BU/ml, with simoctoctocog-alfa (rhFVIII), at 200 IU/kg/day. INH progressively decreased and 7 months later disappeared (<0.6 BU/ml). Subsequent laboratory analysis confirmed this value. Case-2: A child, with severe hemophilia A, diagnosed at 12 months, was initially treated with moroctocog alfa only on demand, but he developed a transient low titer inhibitor (3 BU/ml) after 18 exposure days (ED), subsequently disappeared. At age of 42 months the young child was put on prophylaxis at dosage of 40 IU/kg three times a week. One year later he developed a new low titer inhibitor. A first ITI was then started with morocotocog alfa 100 IU/kg/day, reduced to 50 IU/kg three times a week when the inhibitor disappeared. Subsequently the ITI dose was increased to 200 IU/kg/day due to inhibitor recurrence and to frequent bleeds. During this treatment the inhibitor titer reached its historical peak of 103 BU/ml. This ITI was considered failed after 57 months of treatment. An ITI Rescue was then started with simoctocog alfa 200IU/kg/day, at the onset of this treatment the inhibitor titer was 2.8 BU/ml, it reached a peak of 10 BU/ml two months later, and disappeared 22 months from the start of ITI-R. During treatment with simoctocog alfa no haemorrhagic events were reported. Conclusions: Our cases showed that simoctocog alfa (rhFVIII) can be an important option in treating patients with HA and high-titer INH who previously underwent one or more failed ITI. Our cases proved the efficacy of this concentrate in two very poor risk patients. This result may suggest the use of simoctocog alfa also for first-line ITI, more real-world data are requested to confirm it. Important results are now awaited by the remaining three ITI-R still ongoing in three other Italian Hemophilia Centers. Backgroud: The appearance of inhibitors (INH) is the most serious complication in hemophilia A (HA) patients. The primary objective is their eradication. Usually the primary ITI was performed with the same concentrate causing INH development, but which replacement factor to be use in case of ITI-R is still debatable. We report two successful cases of R-ITI with simoctocog alfa (rhFVIII) performed in two different Italian Hemophilia Centers, while three other cases are still ongoing. Case Report: Case-1: Adult man with moderate HA who developed INH after surgery and concomitant switch to another concentrate (octocog-alfa 2nd gen). The patient refused the ITI treatment immediately after the inhibitors appearance, and was then put on prophylaxis with bypassing agents for several months. First ITI was then started with pdFVIII/vWF at 200 IU/kg/day, inhibitor titer reached its historical peak (134 BU/ml) two months later and progressively decreased to 15 BU/ml, but without ever disappearing. This ITI was stopped after nineteen months. A second ITI was then tried with high dose regimen of morocotocog-alfa, but also in this case the mean INH titer remained steadily high (21 BU/ml) and this treatment was considered failed after fifteen months from the onset. A new ITI-R was then started when the INH titer was 74 BU/ml, with simoctoctocog-alfa (rhFVIII), at 200 IU/kg/day. INH progressively decreased and 7 months later disappeared (<0.6 BU/ml). Subsequent laboratory analysis confirmed this value. Case-2: A child, with severe hemophilia A, diagnosed at 12 months, was initially treated with moroctocog alfa only on demand, but he developed a transient low titer inhibitor (3 BU/ml) after 18 exposure days (ED), subsequently disappeared. At age of 42 months the young child was put on prophylaxis at dosage of 40 IU/kg three times a week. One year later he developed a new low titer inhibitor. A first ITI was then started with morocotocog alfa 100 IU/kg/day, reduced to 50 IU/kg three times a week when the inhibitor disappeared. Subsequently the ITI dose was increased to 200 IU/kg/day due to inhibitor recurrence and to frequent bleeds. During this treatment the inhibitor titer reached its historical peak of 103 BU/ml. This ITI was considered failed after 57 months of treatment. An ITI Rescue was then started with simoctocog alfa 200IU/kg/day, at the onset of this treatment the inhibitor titer was 2.8 BU/ml, it reached a peak of 10 BU/ml two months later, and disappeared 22 months from the start of ITI-R. During treatment with simoctocog alfa no haemorrhagic events were reported. Conclusions: Our cases showed that simoctocog alfa (rhFVIII) can be an important option in treating patients with HA and high-titer INH who previously underwent one or more failed ITI. Our cases proved the efficacy of this concentrate in two very poor risk patients. This result may suggest the use of simoctocog alfa also for first-line ITI, more real-world data are requested to confirm it. Important results are now awaited by the remaining three R-ITI still ongoing in three other Italian Hemophilia Centers.

Disclosures
No relevant conflicts of interest to declare.