Prompt immune tolerance induction at inhibitor diagnosis regardless of titre may increase overall success in haemophilia A complicated by inhibitors: experience of two US centres

Abstract

Current guidelines recommend delaying the start of immune tolerance induction (ITI) until the inhibitor titre is <10 Bethesda units (BU) to improve success. This study was conducted to evaluate ITI outcome relative to time to start ITI from inhibitor detection irrespective of inhibitor titre. Data were retrospectively collected from two U.S. haemophilia treatment centres (HTCs) on subjects with severe/moderate factor VIII (FVIII) deficiency with inhibitors who underwent ITI. Outcomes were defined pragmatically: success--negative inhibitor titre and ability to use FVIII concentrate for treatment/bleed prevention; partial success--inhibitor titre 1 to <5 BU with ability to use FVIII concentrate for treatment of bleeding; failure--ITI ongoing >3 years without achieving success/partial success, or ITI discontinuation. Fifty-eight subjects were included; 32 of 39 (82%) with high-responding inhibitor (HRI) achieved success, 7 failed. HRI subjects were subdivided based on ITI start time: 23/39 subjects started within 1 month of detection and 22/23 (96%) achieved success. Of these 23, 13 started ITI with an inhibitor titre ≥10 BU; all were successes. Eleven of 39 HRI subjects had an interval >6 months until ITI start; 7 (64%) achieved success. Time from inhibitor detection to ITI start may play a critical role in outcome. A titre ≥10 BU at ITI start did not influence outcome in subjects when ITI was initiated within 1 month of detection. Prompt ITI should be considered a viable therapeutic option in newly identified patients with inhibitors regardless of current inhibitor titre.

Toward optimal therapy for inhibitors in hemophilia

“…28 More recently, Nakar et al reported that successful tolerance (defined in this study as a negative inhibitor titer and the ability to use fVIII for the treatment of bleeding episodes) was achieved in 13 patients with severe hemophilia A who started ITI within 1 month of inhibitor detection despite pre-ITI titers .10 BU/mL (median 25 BU/mL, range 265 BU/mL), raising doubt as to the necessity of delaying ITI. 31 In patients with high-responding inhibitors, there have been several predictors of success identified in registries and cohort studies and used in subsequent clinical trials of ITI (Table 2). [32][33][34] Race has been proposed as a risk factor, but its independent effect is unclear.…”

Inhibitors: A Need for Eradication?

“…One obvious benefit of starting ITI immediately is that it avoids the possibility of breakthrough bleeds while waiting to start ITI. A recent study suggests that the success of ITI may be improved by starting therapy immediately [9]. …”

Successful immune tolerance induction using turoctocog alfa in an adult haemophilia A patient

“…The patient showed no signs of immune deficiency and received no immune-suppressive therapy. In this case, prompt ITI after the onset of inhibitor development may have improved the chances of treatment success [18].…”