Predictors of inhibitor eradication by primary immune tolerance induction in severe haemophilia A with high responding inhibitors

Abstract

Background Immune tolerance induction (ITI) is the only proven strategy to eradicate factor VIII inhibitors in patients with haemophilia A (HA). Aim To identify patients and treatment options with the highest chance of inhibitor eradication by primary ITI. Patients and methods In the frame of the Italian ITI Registry, carried out from 1995 to 2015 (last follow‐up 2018), 137 primary ITI courses in severe HA patients (90/137 with poor prognosis) were analysed for predictors of outcome (complete/partial response or failure). Sixty‐six of them (48%) were prospectively evaluated. Results ITI was successful in 91/137 patients (66.4%) and 70 (51.1%) achieved complete response within 11 months (median). Historical peak titres ≤200 BU/ml (P = .033), inhibitor titres ≤5 BU/ml at ITI start (P = .001), peak titres ≤100 BU/ml during ITI (P < .001) and missense mutations and small insertions/deletions of FVIII gene (P = .027) predicted complete inhibitor eradication. A score that considers the cumulative number of these variables predicted complete response with positive predictive values up to .81 at ITI start and .91 during ITI, respectively. Patients who had no bleeding (OR, 3.45, 95% CI: 1.4–8.6) nor other adverse events (OR 2.6, 95%CI: 1.3–5.3) during ITI had higher chances of complete response. During the 120‐month follow‐up (median), 2/70 patients who had achieved complete response relapsed (2.9%). Conclusions This Registry, with a centralized review of outcomes, homogeneous data collection (half of which prospective) and long‐term follow‐up, provides insights for optimizing ITI, with a rationale for further studies in the currently evolving scenario of inhibitor management in HA patients.

Low‐dose immune tolerance induction in children with severe hemophilia A with high‐titer inhibitors: Type of factor 8 mutation and outcomes

“…Peyvandi et al 18 reported that patients with large deletions had the lowest success rate (1/8) of ITI, and a similar finding was revealed that large deletions in F8 were associated with ITI unresponsiveness 7 . The Italian ITI registry observed that small insertions/deletions and missense mutations were linked to complete inhibitor eradication and a shorter time to ITI success 8–9 . This study showed that the patients carrying non–high‐risk mutations associated with inhibitor development were more likely to be successful in ITI and resulted in a shorter time to success.…”

“…7 The Italian ITI registry observed that small insertions/deletions and missense mutations were linked to complete inhibitor eradication and a shorter time to ITI success. [8][9] This study showed that the patients carrying nonhigh-risk mutations associated with inhibitor development were more likely to be successful in ITI and resulted in a shorter time to success. Interestingly, patients carrying high-risk variants were associated with higher inhibitor titers, including historical peak titers, pre-ITI titers, and peak titers during ITI, as well as higher rates of combined immunosuppressive treatment.…”

“…On the other hand, pre‐ITI inhibitor titer, historical peak titer, and peak titer during ITI had no significant impact on the outcomes from our data analysis. However, some studies involving multivariable analysis to evaluate outcomes emphasized the role 9,16,22 . Particularly the inhibitor titer of less than 10 BU/ml at the initiation of ITI, historical peak titer of less than 200 BU/ml, and peak titer of less than 100 BU/ml during ITI were identified as predictors of ITI success 9,22 .…”

“…The predictors of outcome and time to success have been developed based on the available data from ITI registries and other publications. [3][4][5][6][7][8][9] The F8 genotypes are a major risk factor for inhibitor development. [10][11] Based on a review involving dozens of single-and multiple-center cohort studies, Garagiola et al 11 classified F8 mutation types into a high-risk group of inhibitor development (large deletions or insertions in multiple exons and nonsense mutations in the light chain) and non-high-risk group (low-or medium-risk mutations including large deletions or insertions in a single exon, nonsense mutations in the heavy chain, inversions, small deletions or insertions, missense, and splicing-site mutations).…”

“…At present, immune tolerance induction (ITI) is the only strategy to eradicate high‐titer inhibitors for patients by frequent exposure to FVIII concentrates. The predictors of outcome and time to success have been developed based on the available data from ITI registries and other publications 3–9 . The F8 genotypes are a major risk factor for inhibitor development 10–11 .…”