Successful Control of Refractory Inhibitors in Children with Hemophilia a Using Multiple Agent Immune Modulation.
Authors: Manco-Johnson Marilyn J. , Wagner Lori , Recht Michael , Knoll Christine , Geraghty Susan J. , Pounder Elizabeth , Goldenberg Neil A. 
Published: April 2020

Abstract
BACKGROUND: Development of inhibitory antibodies that limit replacement therapy with factor VIII (FVIII) is one of the most difficult complications of hemophilia A. Although 70–90% of children achieve immune tolerance (IT) with regular FVIII therapy, children with refractory inhibitors remain a challenge to manage.
METHODS: Boys with hemophilia A were evaluated for the development and treatment of inhibitors (COMIRB 97–178). Children with refractory inhibitors following failure of IT or failure to achieve &lt;10 Bethesda Units (BU) to start IT were treated on a salvage therapy clinical care protocol, shown on Table 1, if they had experienced bleeding events that were lifethreatening or requiring hospitalization.
Table 1: Immune Modulation Protocol employed for Compassionate Care
Throughout Protocol FVIII 100-200 U/kg IV daily Months 1 and 3 Rituximab 375/m2 IV once weekly x 4 Months 5 through 10 Cyclophosphamide 500-1000 mg/m2 IV once monthly Month 11 to sustained tolerization x 1 year, then taper as tolerated over 6 months. Mycophenylate mofetil 400-600 mg/m2/dose orally twice daily;&#x2028; Pneumocystis prophylaxis with Trimethoprim/Sulfamethoxazole twice weekly Persistent/Refractory Inhibitor Repeat course of Rituximab (once weekly x 4 more doses)
RESULTS: Six children were treated on this protocol; results are shown on Table 2.
Table 2: Results of Salvage Therapy Protocol for Refractory FVIII Inhibitors.
Patient Peak Titer (BU) Current Titer (BU) Time on Protocol Current Therapy Den 1 175.4 0.5 23 months Mycophenylate mofetil, FVIII Den 2 5600 1.1 13 months Mycophenylate mofetil, FVIII Den 3 17.4 0.1 7 months Mycophenylate mofetil, FVIII Phx 1 1206 1.9 12 months Rituximab, Mycophenylate mofetil, FVIII Phx 2 180 115 12 months Rituximab, Mycophenylate mofetil, FVIII Phx 3 204.8 2.1 5 months Rituximab, Mycophenylate mofetil, FVIII
Two children (Den 1 and Den 3) achieved a negative BU (0.2, 0.1, respectively) after 9 and 4 months of therapy although Den 1 had a relapse to 1.5 BU at 17 months and required further Rituximab. All children have experienced decreased bleeding and pain, and no child required further hospitalization for bleeding complications. CD 20 cell counts decreased to near zero in all treated children but no child experienced reduction in CD 20 count for more than 6 months beyond cessation of rituximab therapy. One child (Phx 1) had transient neutropenia (ANC=350) for which mycophenylate mofetil was withheld and decreased immunoglobulins (IgG ≥ 100 mg/dL) for which IGIV was infused. No child had infection related to neutropenia or lymphopenia. This protocol has been well-tolerated and no major adverse events have occurred.
CONCLUSION: These findings provide the first evidence that multiple agent immune modulatory therapy consisting of intravenous rituximab and cyclophosphamide followed by oral mycophenylate mofetil may be safe and effective to reduce BU titers and improve clinical status in children with hemophilia A and refractory inhibitors. Future clinical trials are needed to confirm and extend these observations and to explore other strategies for IT.