Outcome of the Japanese Immune Tolerance Induction (ITI) Registry and Predictors of Successful ITI (2015)

Abstract [Background] Immune tolerance induction (ITI) therapy is the only therapeutic approach that can eradicate factor (F)VIII and FIX inhibitors in patients with hemophilia A (HA) and B (HB), respectively. Although results of several retrospective cohort studies have been published, predictors of successful outcome are still debated. Nonetheless, little information is so far available in terms of large ITI cohort in non-Caucasian countries. [Aim] In this study, we performed a retrospective cohort study on ITI therapy carried out for Japanese hemophilia patients with inhibitors to understand the status of practice on this therapy in Japan and to study the predictors of successful outcome. [Methods] As of March 31, 2015, the registry of ITI therapy in Japanese hemophilia patients had received reports on 155 HA patients (140 severe type, high responder 69.1%) and 7 HB patients (7 severe type, high responder 42.5%) who have undergone this therapy from 45 hospitals including Hemophilia Treatment Centers since 2000. The ITI outcome was centrally reviewed. The success of ITI was defined as an undetectable inhibitor for 2 successive measurements, and the salvage ITI was defined as any rescue ITI regimen by using von Willebrand factor-containing FVIII concentrates. [Results] Among the completed ITI courses, the overall success rate of ITI therapy was 71.2% (94/132) and 83.3% (5/6) for HA and HB patients, respectively. Cumulated ITI success rates of 50% and 80% for HA patients were achieved at 1.6 and 4.3 years after the inhibitor diagnosis, and 0.6 and 2.3 years after the initiation of ITI, respectively. Significant predictors for success of ITI in HA were (i) low responding inhibitors (success 35/37 (94.5%)) compared to high responding inhibitors (59/93 (63.4%); p &lt;0.0001), (ii) shorter intervals from inhibitor diagnosis to the initiation of ITI (success (S): 1.85±3.52 vs failure (F): 3.38±3.77 years; p =0.02), (iii) lower historical peak titers on pre-ITI (S: 24.9±55.2 vs F: 132±295 BU/ml; p =0.04), and (iv) lower peak inhibitor titers on-ITI (S: 72.4±231 vs F: 916±1,307 BU/ml; p &lt;0.01). However, outcome was not significantly different (p =0.77) between high dose regimens (&gt;90 IU/kg, 7 days/wk) and low dose regimens (&lt;75 IU/kg, 3 days/wk). Also, either FVIII products (plasma-derived or recombinant) at the initiation or the insertion of central venous access devise (CVAD) did not affect the outcome (p =0.32 and 0.85). Although the outcome prediction was difficult for HB because of low number of the cases registered, success rate was much higher than those of previous reports. The success rate of salvage ITI was 50% (6/12) for HA. The significant predictive parameter for outcome was only the age at the initiation of salvage ITI (p =0.03). The inhibitor relapsed in 6 cases, and all cases were HA patients (4.5% 6/140). In 86 cases with insertion of CVAD, the catheter-related infection was complicated in 21 cases (12.9%). [Conclusion] This study underscores the importance of initiating the ITI as early as possible after the diagnosis of inhibitor and the low response of inhibitor titer before and during the ITI to maximize the success of the treatment for Japanese hemophilia patients. Disclosures Nogami: Chugai: Membership on an entity's Board of Directors or advisory committees; Bayer, NovoNordisk, Baxalta, Chugai, Kaketsuken, Pfizer, Biogen: Honoraria; Bayer, Novo Nordisk, Baxalta. Biogen: Research Funding. Taki:Biogen, Baxalta, Bayer, Novo, Pfizer: Honoraria; Biogen, Baxalta, NovoNordisk, CSL-Behring, Kaketsuken, Chugai: Research Funding. Matsushita:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Biogen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; CLS-Behling: Research Funding; Japan Blood Products Organization: Honoraria, Research Funding; Kyowa-Kirin: Honoraria, Research Funding; Octapharma AG: Honoraria; Sysmex: Speakers Bureau; Seamens: Speakers Bureau; Nihon Pharmaceutical: Honoraria, Research Funding, Speakers Bureau; Kaketsuken: Honoraria, Research Funding, Speakers Bureau; Asahi Kasei Pharma: Honoraria, Research Funding, Speakers Bureau; Eisai: Research Funding; Novartis Pharma: Honoraria, Speakers Bureau; Bayer Healthcare: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novo Nordisk Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Chugai Pharmaceutical Co., Ltd.: Research Funding. Hanabusa:Novo Nordisk, Baxalta, Bayer, Pfizer, Biogen, and KaketsuKen: Honoraria; Novo Nordisk, Baxalta, KaketsuKen, and Biogen: Membership on an entity's Board of Directors or advisory committees. Shima:Pfizer: Honoraria, Research Funding; Kaketsuken: Honoraria; Biogen: Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; Baxalta: Honoraria, Research Funding.