Immune Tolerance Induction in 28 Children with Hemophilia Awith Inhibitors.
Authors: Callaghan Michael U. , Warrier Indira , Rajpurkar Madhvi , Lusher Jeanne 
Published: April 2020

Abstract
Aim: To study the characteristics, treatment, and outcome of patients with hemophilia with inhibitors who have undergone immune tolerance induction (ITI) at the Children’s Hospital of Michigan over the past 14 years.
Methods: In compliance with local IRB regulations, patient charts and laboratory databases were reviewed and salient data extracted. 28 boys underwent 29 attempts at immune tolerance induction.
Results:
Hemophilia A
26 boys with severe hemophilia A with inhibitors underwent 27 trials of ITI. In this cohort of 26 patients the average age at which patients developed an inhibitor was 22 months and the average age at start of ITI was 5 years 4 months (range 2 months to 17 years 5 months). The average number of exposure days prior to inhibitor development was 10 (1–47). The average time between development of an inhibitor and initiation of ITI was 43 months, with no difference between those who successfully completed ITI and those who did not. Six patients had low titer inhibitors (0.8–6.5 BU) and successfully completed ITI using a modified low dose ITI regimen of factor infusions 3–7 times per week. 20 of the patients with high titer inhibitors (6.4–1280 BU) were treated with daily infusions of 50–200 units/kg/d of factor VIII (FVIII) products. For ITI, 4 patients received high purity plasma derived FVIII (PD-FVIII) and 21 received recombinant FVIII (rFVIII) and one received both. In patients who became tolerized to FVIII, the average time to achieve an inhibitor titer of 0 Bethesda Units (BU) was 211 days. In those who were unable to achieve tolerance, the average length of the trial was 263 days. 21 of the ITI trials employed a central venous catheter and in 5 patients ITI was stopped after removal of the line because of recurrent infections. 14 boys received FEIBA, rFVIIa, or porcine FVIII for bleeding episodes during ITI; 8 of them failed ITI and one is still on therapy. Seven trials of ITI were in Caucasian patients (26 %), 17 in African American (AA) (63 %), and 3 in Middle Eastern patients (11 %). 19 patients achieved complete tolerance (73 %), 6 patients failed (23 %), one failed twice, and one patient continues on therapy. All but 2 patients who successfully completed ITI went on prophylaxis with FVIII. All patients who successfully completed ITI have maintained tolerance with a mean follow-up of 101 months (range 7–168).
Table I: Hemophilia A Failed ITI Successful ITI *One still ongoing Number of trials* 7 (23 %) 19 (73 %) African Americans 7 (41 %) 10 (59 %) Non-AA 0 10 (100 %) Historical Peak Titer (mean) 345 BU 47 BU Titer at Start of ITI (mean) 62 BU 5 BU Peak Titer on ITI (mean) 168 BU 46 BU Age at inhibitor development (mean) 26 months 12 months ITI with PD-FVIII 1 4 ITI with rFVIII 7 15
Hemophilia B
During this time period, 2 boys with severe hemophilia B underwent ITI. Both had severe allergic reactions at the time of inhibitor development; both underwent desensitization successfully but both failed ITI. Both started ITI with plasma derived factor nine at age 15 months. One developed nephrotic syndrome while on ITI.
Conclusions:
Most patients with Hemophilia A were able to achieve and maintain tolerance (73%). Higher titer inhibitors, hemophilia B, younger age at development of inhibitor, AA race and treatment of bleeds with bypass agents or porcine factor while on ITI were risk factors for ITI failures. Loss of central venous access with recurrent infections was also a common reason for ITI failure.