Immune Tolerance Induction (ITI) in Adults with Congenital Hemophilia: A Multicenter Experience

Most inhibitors developing in adulthood are low titer inhibitors [Eckhardt 2012], however high titer inhibitors have been described [Kruse-Jarres 2010, Hay 2011]. The role of ITI in the management of adult inhibitors has not been established. Two large registries have suggested that age at ITI initiation could be a predictor of success. The North American ITI registry showed a trend toward a younger age in the ITI success group [DiMichele 2002], while the International ITI group showed a more definitive difference, where patients receiving ITI at age > 20 years had a 40 % success rate compared to a much higher success rate of 70 t0 78% in younger individuals [Mariani 2001]. Prospective therapy trials in an adult congenital hemophilia inhibitor population are difficult to conduct, as the number of patients is limited. The aim of the this multicenter retrospective review was to document our experience in the management of adult hemophilia inhibitor patients with ITI

Twelve hemophilia treatment centers which are part of the Globally Emerging Hemophilia Expert Panel (GEHEP) with centers in Canada, Europe, South Africa and the US, who collectively look after over 3000 hemophilia patients, participated in this study. Each center obtained ethics approval prior to data collection. Retrospective record review was undertaken at each center to identify congenital hemophilia patients treated with ITI as an adult (started at ≥ 17 years of age)and who completed the treatment course between 1980 and 2012. The treatment course was defined as any of the accepted ITI regimens. Treatment success was defined as inhibitor eradication or >66% factor recovery.

Of 21 patients who received ITI as an adult, 71% had partial (<5BU and FVIII was able to be reinstated) or complete success. All patients had hemophilia A and most were severe (One patient in the ITI failure group had a level of 2% and in the success group, one had a level of 1% and on of 3%). Of the 13 patients achieving complete success, 38% relapsed (mean follow up of 9.4 years, range 3 months to 29 years). Age at start of ITI did not seem to be a predictor of success: mean age in the success group was 32.0 years (range 17 –55) and in the failure group was 33.5 years (range 22 – 57). All patients in the failure group were white, where 3 patients in the success group were non-white. The success group included one low responding inhibitor and had an overall lower peak inhibitors (mean 89.75 BU, range 3 – 270 BU) than the failure group (mean 353.8 BU, range 89–600 BU). Fifty percent of the failure patients had received a prior ITI attempt, where only 8% of the success group had. More patients in the failure group had received plasma derived factor VIII product for their ITI (83%) than in the success group (69%) but dosing was not significantly different (mean of 416 units/kg/week in failure group, 455 U/kg/week in success group). Overall, patient who failed stayed on ITI slightly longer (mean 20 months) than the patients who succeeded (mean 16 months).

In this limited series of adult inhibitor hemophilia patients treated with ITI, the success rate was high and comparable to that obtained in the pediatric population. Age at start of ITI did not seem to be a predictor of success, but prior ITI and historical peak inhibitor were negative predictors. Prospective clinical studies are required to expand on these preliminary findings.

Kruse-Jarres:Bayer: Administrative and meeting support Other, Honoraria, Research Funding.