Immune Tolerance Induction Therapy Research Articles

AKATSUKI 48-Week Interim Analysis: Emicizumab and Immune Tolerance Induction in People with Hemophilia A and Factor VIII Inhibitors

Background: Immune tolerance induction (ITI) therapy, for the eradication of factor (F)VIII inhibitors, is indicated for people with hemophilia A (PwHA) with FVIII inhibitors. There are limited data regarding the safety of emicizumab treatment in combination with ITI, particularly regarding thrombotic events (TEs). This study, conducted in Japan, aims to evaluate the safety profile of emicizumab during and immediately after ITI. Methods: AKATSUKI is a Phase IV, open-label, non-randomized, interventional, multicenter study; the methods have been previously published (Matsushita et al. BMJ Open 2022). PwHA with FVIII inhibitors received an approved dose of emicizumab and ITI therapy. Any standard half-life (SHL) FVIII concentrate could be used for ITI, with a dosing regimen of 50IU/kg, three times a week; when using an extended half-life (EHL) FVIII concentrate, 50IU/kg twice a week was permitted. Those who achieved ITI partial success received prophylaxis with emicizumab and a FVIII concentrate starting from the date of their next study visit following investigator confirmation of partial success. Any FVIII concentrate could be used for post-ITI maintenance therapy, given as 50IU/kg once a week for the first 24 weeks followed by 50IU/kg once every 2 weeks for the next 24 weeks, followed by discontinuation of the FVIII concentrate at the investigator's discretion. The primary endpoint was evaluation of adverse events (AEs), with a key focus on TEs, and abnormal laboratory values over time during and immediately after ITI. The main secondary endpoints included number of treated bleeds and the proportion of participants meeting ITI success criteria. Partial success was achieved on the same date that the participant's blood sample showed normal FVIII recovery in addition to the participant receiving a negative FVIII inhibitor titer. Normalized FVIII recovery was defined as a FVIII recovery rate of ≥66% of the predicted value on two consecutive occasions ≥2 weeks apart, and a negative FVIII inhibitor titer was defined as achieving FVIII inhibitor levels of <0.6 BU/mL on two consecutive occasions ≥2 weeks apart. Results: Twelve participants, all of whom were male (median [range] age 2.5 [1-54] years) were included in this interim analysis (evaluation period, median [range]: 437.5 days [224-749]. Data cut-off date: December 22, 2022). Prior to the study, participants had received emicizumab (n=11), ITI (n=9), or both (n=7), and the median (range) duration of ITI in combination with emicizumab was 203.0 (7-1,002) days. Three participants used a SHL FVIII product for their ITI treatment regimen, and nine participants used an EHL FVIII product. Additional baseline characteristics are presented in Table 1. Overall, 30 AEs occurred, none of which were considered emicizumab- or FVIII concentrate-related. Two participants each experienced one serious AE: one case of pneumonia, initially caused by transmission of a viral infection, and one wound hemorrhage, which was recorded as accidental; both recovered. No participants experienced a TE. Three participants reported a total of 10 treated bleeds, all of which were categorized as traumatic and were treated with recombinant activated FVII. At data cut-off, one participant had achieved partial ITI success, having reached a negative inhibitor titer at Week 5 and normalized FVIII recovery by Week 17. This participant was then treated with emicizumab and FVIII concentrate (50IU/kg once a week). No bleeds or AEs were reported for this participant during the observational period. The changes in FVIII inhibitor titer across the study for all participants are presented in Figure 1. Conclusions: At this 48-week interim analysis, no new safety concerns or TEs were reported in PwHA receiving emicizumab and ITI. This study continues to evaluate the safety of emicizumab in conjunction with, and following, ITI therapy in PwHA with FVIII inhibitors.

Potential Predictive Biomarkers for the Development and Outcomes of Inhibitors in Hemophilia A Patients

Introduction Inhibitor development poses a significant challenge in the treatment of hemophilia A (HA). Approximately 30% of HA patients develop inhibitors in response to FVIII infusion therapy. While the risk is highest early in treatment days, patients are at risk throughout their lifetime. Regardless of certain known risk factors, the lack of biomarkers for inhibitor development hampers efforts to prevent their occurrence. Since inflammation is a well-known risk factor, one of our goals is to identify potential biomarkers among inflammatory cytokines. Another focus is glycosylation-related biomarkers, which has drawn great attention in biomarker discovery of various diseases including cancers. By analyzing the association of cytokines and plasma glycosylation with inhibitor formation, this research aims to provide valuable references for clinical care. Methods Plasma samples from 60 HA patients, and 23 healthy donors were analyzed to detect the levels of G-CSF, IFN-γ, IL-1β, IL-2, IL-6, IL-8, IL-10, IL12p70, IP-10 and TNF. The HA samples were divided into inhibitor negative (InhNeg, BU < 0.6, n = 26) and inhibitor positive (InhPos, BU ≥ 0.6, n = 34) groups. A predictive model of inhibitor development was established using logistic regression analysis. To investigate the correlation between cytokine levels and high inhibitor titers, the inhibitor-positive samples were further categorized into good risk (< 10 BU, n = 14) and poor risk (≥ 10 BU, n = 20) groups based on immune tolerance induction therapy prognosis. Total plasma N-glycans were released, methylated, and analyzed by using MALDI-TOF MS/MS. A synthesized N-glycan was spiked in to quantify each glycoform. The study evaluated the correlation between HA sample groups and various glycosylation ratios, including for sialylation, core-fucosylation, galactosylation and galactose. The cut-off value of each glycosylation ratio was based on the median of the inhibitor-negative group. Results The adjusted odds ratio of inhibitor development for elevated G-CSF, IL-6 and decreased IL-10 were 2.84 (95% CI: 1.45-8.48; p = 0.021), 1.50 (95% CI: 1.14-2.42; p = 0.069), and 0.28 (95% CI: 0.10-0.61; p = 0.006), respectively in HA patients. Among InhPos HA patients, the levels of G-CSF, IL-2, IL-6, IL-8, and IL-10 in poor risk group were significantly higher than in good risk group (p-value < 0.05, ANOVA). Since aging also causes glycosylation changes, we analyzed adult (≥ 18 years old, n = 31) and pediatric (< 18 years old, n = 17) HA patients separately. Among analyzed glycan ratios, 80% of adult HA patients with inhibitors had a higher core-fucosylation ratio. All pediatric patients with inhibitors had significant lower sialylation and higher galactosylation ratios. Strikingly, pediatric patients with inhibitors exhibited around 2-fold higher core-fucosylation than those without inhibitor. Conclusion Our finding of elevated levels of G-CSF and IL-6 along with decreased levels of IL-10 associated with the presence of inhibitors, suggests the potential for prediction of inhibitor development. Moreover, high levels of G-CSF, IL-2, IL-6, IL-8 and IL-10 in patients with high inhibitor titers (≥ 10 BU, poor risk group) but not in good risk group imply they could be explored in future studies as prognostic factors in immune tolerance therapy. Glycan ratios can also hold promise as biomarkers including higher core-fucosylation in adult patients. Additionally, significant lower sialyation, higher galactosylation and core-fucosylation ratios indicate higher possibility of inhibitor development in pediatric patients.

Factor IX administration in the skin primes inhibitor formation and sensitizes hemophilia B mice to systemic factor IX administration

BackgroundFactor IX inhibitor formation is the most serious complication of replacement therapy for the bleeding disorder hemophilia B, exacerbated by severe allergic reactions occurring in up to 60% of patients with inhibitors. Low success rates of immune tolerance induction therapy in hemophilia B necessitate the search for novel immune tolerance therapies. Skin-associated lymphoid tissues have been successfully targeted in allergen-specific immunotherapy. ObjectivesWe aimed to develop a prophylactic immune tolerance protocol based on intradermal administration of FIX that would prevent inhibitor formation and/or anaphylaxis in response to replacement therapy. MethodsWe measured FIX inhibitor, anti-FIX immunoglobulin G1, and immunoglobulin E titers using the Bethesda assay and enzyme-linked immunosorbent assay after 4 weeks of twice-weekly intradermal FIX or FIX-Fc administration followed by 5 to 6 weeks of weekly systemic FIX injections in C3H/HeJ hemophilia B mice. We also measured skin antigen-presenting, follicular helper T, and germinal center B cell frequencies in skin-draining lymph nodes after a single or repeat intradermal FIX administration. ResultsIntradermal administration enhanced FIX inhibitor formation in response to systemic administration. We further found that intradermal administration alone triggers inhibitor formation, even at a low dose of 0.4 IU/kg, which is 100-fold lower than the intravenous dose of 40 IU/kg typically required to induce inhibitor development in hemophilia B mice. Also, intradermal administration triggered germinal center formation in skin-draining lymph nodes and sensitized mice to systemic administration. Factor IX–Fc fusion protein did not modulate inhibitor formation. ConclusionIntradermal FIX administration is highly immunogenic, suggesting that the skin compartment is not amenable to immune tolerance induction or therapeutic delivery of clotting factors.

OC 44.2 Developing Humanized Mouse Models as a Testing Platform for Immune Tolerance Induction Therapy for Antibody-Positive Hemophilia a Patients

OC 44.2 Developing Humanized Mouse Models as a Testing Platform for Immune Tolerance Induction Therapy for Antibody-Positive Hemophilia a Patients

Coagulation factor VIII regulates von Willebrand factor homeostasis invivo

BackgroundCoagulation factor VIII (FVIII) and von Willebrand factor (VWF) circulate as a noncovalent complex, but each has its distinct functions. Binding of FVIII to VWF results in a prolongation of FVIII’s half-life in circulation and modulates FVIII’s immunogenicity during hemophilia therapy. However, the biological effect of FVIII and VWF interaction on VWF homeostasis is not fully understood. ObjectivesTo determine the effect of FVIII in VWF proteolysis and homeostasis in vivo. MethodsMouse models, recombinant FVIII infusion, and patients with hemophilia A on a high dose FVIII for immune tolerance induction therapy or emicizumab for bleeding symptoms were included to address this question. ResultsAn intravenous infusion of a recombinant B-domain less FVIII (BDD-FVIII) (40 and 160 μg/kg) into wild-type mice significantly reduced plasma VWF multimer sizes and its antigen levels; an infusion of a high but not low dose of BDD-FVIII into Adamts13+/- and Adamts13-/- mice also significantly reduced the size of VWF multimers. However, plasma levels of VWF antigen remained unchanged following administration of any dose BDD-FVIII into Adamts13-/- mice, suggesting partial ADAMTS-13 dependency in FVIII-augmented VWF degradation. Moreover, persistent expression of BDD-FVIII at ∼50 to 250 U/dL via AAV8 vector in hemophilia A mice also resulted in a significant reduction of plasma VWF multimer sizes and antigen levels. Finally, the sizes of plasma VWF multimers were significantly reduced in patients with hemophilia A who received a dose of recombinant or plasma-derived FVIII for immune tolerance induction therapy. ConclusionOur results demonstrate the pivotal role of FVIII as a cofactor regulating VWF proteolysis and homeostasis under various (patho)physiological conditions.

Early immune tolerance induction is a unique predictor of favorable outcomes in hemophilia A children with intron 22 inversion and high-responding inhibitors

BackgroundThe predictors of immune tolerance induction (ITI) outcomes in hemophilia A (HA) patients with the same F8 genetic background have not yet been evaluated, although the F8 genotype is strongly associated with ITI response. This study aims to explore the predictors of ITI outcomes in the same F8 genetic background by focusing on intron 22 inversion (Inv22) patients with high-responding inhibitors. MethodsHA children with Inv22 and high-responding inhibitors who received low-dose ITI therapy over 24 months were included in this study. ITI outcomes were centrally assessed at the 24th month of treatment. The predictive ability of clinical variables to identify ITI success was determined using the receiver operating characteristic (ROC) curve, and the predictor of ITI outcomes was analyzed on the multivariable Cox model. ResultsAmong the 32 patients investigated, 23 (71.9 %) achieved success. In univariate analysis, interval time from inhibitor diagnosis to ITI start (interval-time) was significantly associated with ITI success (P = 0.001); however, inhibitor titers showed no significance (P > 0.05). The interval-time demonstrated a good predictive value for ITI success with the area under the ROC curve of 0.855 (P = 0.002), and the cutoff value was 25.8 months (sensitivity, 87.0 %; specificity, 88.9 %). In the multivariable Cox model which considered success rate and time to success, interval-time was the only independent predictor (<25.8 months vs. ≥25.8 months, P = 0.002). ConclusionsThe interval-time was first identified as a unique predictor of ITI outcomes in HA patients with high-responding inhibitors under the same F8 genetic background (Inv22). An interval-time of <25.8 months was associated with increased ITI success and reduced time to success.

Low-dose immune tolerance induction therapy in severe hemophilia a children in China: Starting earlier resulted in better inhibitor eradication outcomes

BackgroundShorter interval-time from inhibitor detection to starting immune tolerance induction (ITI) might predict better ITI outcomes for severe Hemophilia A (SHA) patients with high-risk-inhibitors. However, the prediction-impact of interval-time for these patients on low-dose ITI strategy remained unclear. ObjectivesTo explore the relationship between interval-time and low-dose ITI outcomes in Chinese SHA children with high-risk-inhibitors. MethodsThis was a single-center, retrospective study on SHA children with high-risk-inhibitors (each with immediate pre-ITI inhibitor titer>10 Bethesda Units/mL) undergoing low-dose ITI strategy for ≥24 months. ITI outcomes and their predictive factors were evaluated at the 24th month treatment for each patient. The predictive ability of interval-time on ITI success was determined using receiver operating characteristic (ROC) curve. ResultsAmong 47 patients investigated, 34 (72.3 %) achieved success. Independent predictor for ITI-outcome on multivariate analysis included the interval-time (p = 0.007) and peak inhibitor-titer (p = 0.011). Shorter interval-time predicted ITI success [cut-off value = 22.3 months, area under ROC-curve (AUC) = 0.701] and early-ITI success within 12 month (cut-off value = 9.4 months AUC = 0.704). Linear regression analysis suggested each month interval-time delay delayed success by 0.1552 month. Unlike the interval-time, peak inhibitor-titer had no success-predictive value in high-peak inhibitor-titer patients on ITI with immunosuppressants. ConclusionsInterval-time represented a strong predictive value for outcomes in our low-dose ITI strategy for SHA patients with high-risk-inhibitors. Shorter interval-time was associated with higher success rate and earlier success achievement. The respective interval-time cut-off values were 22.3 months for ITI success and 9.4 months for early-success.

Immune tolerance against infused FVIII in hemophilia A is mediated by PD-L1+ Tregs.

A major complication of hemophilia A therapy is the development of alloantibodies (inhibitors) that neutralize intravenously administered coagulation factor VIII (FVIII). Immune tolerance induction therapy (ITI) by repetitive FVIII injection can eradicate inhibitors, and thereby reduce morbidity and treatment costs. However, ITI success is difficult to predict and the underlying immunological mechanisms are unknown. Here, we demonstrated that immune tolerance against FVIII under nonhemophilic conditions was maintained by programmed death (PD) ligand 1-expressing (PD-L1-expressing) regulatory T cells (Tregs) that ligated PD-1 on FVIII-specific B cells, causing them to undergo apoptosis. FVIII-deficient mice injected with FVIII lacked such Tregs and developed inhibitors. Using an ITI mouse model, we found that repetitive FVIII injection induced FVIII-specific PD-L1+ Tregs and reengaged removal of inhibitor-forming B cells. We also demonstrated the existence of FVIII-specific Tregs in humans and showed that such Tregs upregulated PD-L1 in patients with hemophilia after successful ITI. Simultaneously, FVIII-specific B cells upregulated PD-1 and became killable by Tregs. In summary, we showed that PD-1-mediated B cell tolerance against FVIII operated in healthy individuals and in patients with hemophilia A without inhibitors, and that ITI reengaged this mechanism. These findings may impact monitoring of ITI success and treatment of patients with hemophilia A.

Protocol and Primary Analysis of Lome: A Randomized Trial of Low- Versus Intermediate-Dose Immune Tolerance Induction with Recombinant Factor VIII (Omfiloctocog alfa, SCT800) in China

Background: Although the cohort and registry data support low-dose (LD; 50 IU/kg once every other day) and intermediate-dose (MD; 100 IU/kg daily) immune tolerance induction (ITI) are almost equally effective in inducing tolerance in people with severe hemophilia A, with inhibitors (PwHI)1-3, there has been no prospective randomized trials, especially in China. Here, we present the protocol and results of the primary analysis in LOME (ChiCTR2200056603). Methods LOME is a multicenter, prospective, randomized comparison of LD and MD ITI, in severe hemophilia A (HA) patients (FVIII level < 1%) with peak historical inhibitor ≥ 5 and < 200 Bethesda Unite (BU/ml). In the first year of recruitment (Part A), patients with age ≤ 8 years at time of randomized will be included. In the second year of recruitment (Part B), patients with age ≤ 12 years at time of randomized will be included. Patients have received ITI therapy before randomization will be excluded. Subjects were randomized 1:1 to LD or MD ITI with the first domestic recombinant factor VIII (rFVIII) (Omfiloctocog alfa, SCT800) approved in China. Factor III (FVIII) inhibitor screening, ITI monitoring and dose tapering will be based on the consensus from United Kingdom Hemophilia Center Doctors' Organization (UKHCDO)4. If (a) there is an upward trend in titer over 3-6 months period; or (b) fall in chromogenic Bethesda titer of less than 20% in 6 months period after initial peak inhibitor titer; or (c) titer ≥ 200BU/ml during ITI therapy; or (d) spontaneous bleeding > 1 monthly over 3-6 months period, modify the regimen as below: In the LD arm, increase to 100IU/kg daily;In the MD arm, rituximab 375 mg/m2 weekly × 4 weeks (maximum 600 mg) and prednisone 2 mg/kg daily × 1 month (maximum 60 mg, tapering over 3 months) would be added. Once the patient had achieved Success, taper dose as below: In the LD arm, the FVIII dose would be reduced slowly to 25IU/kg three times a week for continuing prophylaxis;In the MD arm, the FVIII dose would be reduced slowly to LD ITI, then same as LD arm. The primary endpoints are ITI outcomes (Success: negative inhibitor titer and FVIII recovery ≥ 66% of expected) and the time taken to ITI Success, in PwHI with LD ITI compared to those with MD ITI. Key secondary endpoints include annualized bleeding rate (ABR), annualized joint bleeding rate (AJBR) for any bleeds and treated bleeds; joint and bone health assessed by Hemophilia Joint Health Score 2.0 (HJHS 2.0) and ultrasound; quality of life measured by the Canadian Hemophilia Outcomes-Kids Life Assessment Tool 2.0 (CHO-KLAT 2.0) and numbers of days out of school; average consumption cost (per kg body weight) was calculated based on the intermediate number of treatment doses consumed to achieve Success. This included the cost of rFVIII and rituximab for ITI, prothrombin complex concentrate (PCC) or recombinant activated factor VII (rFVIIa) for treatment of breakthrough bleed, and intravenous immunoglobulin (IVIG) for infection prevention in patients receiving immunosuppressants. Safety was also a secondary endpoint. Results: Ten subjects were randomized into the study with median follow-up time of 1.64 [range (minimum, maximum), 0.23, 3.91] months in LD arm, and 2.66 (0.26,3.91) months in MD arm. Baseline includes age at time of randomized, age of inhibitor detection, exposure days before inhibitor detection, initial inhibitor titer, inhibitor titer at start of ITI and so on, between two arms are summarized in Table 1. Twenty percent (1/5) in MD arm achieved Success after 7 weeks of treatment and still maintained until the latest follow-up. No one achieved Success in LD arm. The bleeds between the treatment arms are summarized in Table 2. Nearly 2-fold difference in mean ABR and AJBR for treated bleeds, between treatment arms, and 3- to 4-fold in ABR and AJBR for any bleeds. Conclusions: It is planned to enroll 40 patients in Part A and 60 patients in Part B, who will be followed for up to 2 years. The study is ongoing and, currently, 10/40 (25%, in Part A) PwHI from 4 HTCs have been included. LOME study is the first, multicenter, prospective, randomized trial of LD vs MD ITI with domestic rFVIII (Omfiloctocog alfa, SCT800) in Chinese PwHI. This study is likely to contribute with the choice of optimal ITI regimen. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Shorter Time Interval from Inhibitor Detection to Starting Low-Dose Immune Tolerance Induction Therapy Is Associated with Better Inhibitor Eradication Outcomes in Severe Hemophilia a Children with High-Titer Inhibitors in China

Background Shorter time from inhibitor detection to immune tolerance induction (ITI) start (interval-time) might play a critical role in ITI outcomes for severe Hemophilia A (SHA) children with high-titer inhibitors. However, the acceptable interval-time hasn't well been confirmed yet, especially for treatment-delay patients undergoing low-dose ITI therapy in China. Aim To explore the interval-time in Chinese SHA children with high-titer inhibitors, undergoing low-dose ITI strategy with outcomes. Methods A retrospective study in single center, 47 Chinese SHA children with high-titer inhibitors [> 10 Bethesda Unite (BU)/ml] undergoing low-dose ITI strategy with more than 24 months follow-up period. ITI outcomes were evaluated at the 24th month of treatment. The association between interval-time and outcomes was analyzed. Success was defined as negative inhibitor titer and FVIII recovery ≥ 66% of expected. The predictive ability of interval-time to identify ITI success was determined using receiver operating characteristic (ROC) curve. Results Forty-seven cases enrolled in this study, the median age of inhibitor detection was 2.4 (range, 0.6, 10.4) years and the interval-time was 5.8 (0, 61.1) months with the peak inhibitor titer of 55.8 (10.1, 512.0) BU/ml, 42.6% (20/47) using ITI-alone and 57.4% using ITI combined with Rituximab based immunosuppression (IS). Over a follow-up time of 31.3 (24.0, 69.5) months, 34 patients (72.3%) achieved success with the time to success of 11.0 (3.1, 23.0) months. (Table 1) The interval-time in ITI success group was shorter than in non-success group significantly [2.8 (0. 59.1) vs 28.1 (0, 61.1) months, p = 0.04]. Multivariate logistic regression model demonstrated the peak inhibitor titer and the interval-time were two independent predictors of ITI success (P < 0.05). The area under ROC curve (AUC) was 0.701 (95%CI: 0.507 - 0.896, p = 0.034) and reliable cut-off value of 22.3 months could be calculated in the prediction of ITI outcomes with the sensitivity of 0.853 and the specificity of 0.615. (Figure 1) Univariable linear regression demonstrated the relationship between the time to success and the interval-time, the equation y=0.1552*x+9.285 (R2 = 0.2252, p = 0.005). ROC curve describing the accuracy of the predictor of early-success (ITI time < 12 months); the AUC was 0.704 (95%CI: 0.521 - 0.887, p = 0.049); the cut-off value was 9.4 months with the sensitivity of 0.824 and the specificity of 0.533. (Figure 1) Conclusions Our study shows that shorter interval-time was associated with better inhibitor eradication outcomes in terms of ITI success rate and time to success in our SHA children with high-titer inhibitors (> 10BU/ml) undergoing low-dose ITI strategy. We showed that an interval-time of ≤ 22.3 months was associated with higher ITI success rate. And an interval-time of ≤ 9.4 months was related to shorter time to success. Our study on low-dose ITI in a developing country setting support the findings using higher dose ITI in developed countries setting that ITI should be started as soon as possible after inhibitor development. However, stronger evidence is needed from further clinical studies with better study design. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Is there any place for replacement therapy of hemophilia A in children in present and future?

In recent years, we have seen a revolution in the treatment of patients with hemophilia A. The emergence of new methods of non-factor and the development of gene therapy raise a natural question for doctors: what are the prospects for the classical treatment of hemophilia A using factor concentrates? This is especially true for patients with hemophilia A and inhibitors (HAI), for whom, until now, the only option to reduce the frequency of hemorrhagic manifestations has been the use of bypassing agents that do not allow complete control of bleeding. Improving the results of treatment of patients with HAI was possible only with complete eradication of inhibitors. The most effective and safe method to get rid of inhibitors is immune tolerance induction therapy (ITI). With the advent of emicizumab and the truly fantastic results of its use in patients with HAI, doctors are increasingly faced with the question of the need for ITI. This issue is especially acute in children with HAI.This review provides basic information about modern advances in the treatment of hemophilia A, and also determines the place of substitution therapy drugs in the present and future.

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

BackgroundNo studies evaluated the role of F8 mutations in outcomes for low‐dose immune tolerance induction (ITI) in people with severe hemophilia A (SHA) with high‐titer inhibitors. ObjectivesTo explore the association between F8 mutation types and low‐dose ITI outcomes in children with SHA with high‐titer inhibitors. MethodsChildren SHA with high‐titer inhibitors who received low‐dose ITI therapy at least for 1 year were included instudy. Based on the risk of inhibitor development, F8 mutations were classified into a high‐risk group and a non–high‐risk group. Rapid tolerance and the final ITI outcomes were assessed at the 12th and 24th month of treatment, respectively, and the predictor of outcomes was analyzed. ResultsOf 104 children included, 101 had F8 mutations identified. The children with non–high‐risk mutations presented a higher rate of rapid tolerance than those with high‐risk mutations (61.0% vs. 29.2%; p = 0.006). Among 72 children beyond 24 months of ITI, 55 children (76.4%) achieved success, 3 (4.2%) achieved partial success, and 14 (19.4%) failed. The children in the non–high‐risk group showed a higher success rate (86.8% vs. 43.8%; p = 0.001) and a shorter time to success (mean time, 9.3 months vs. 13.2 months; p = 0.04) compared to those in the high‐risk group. In multivariable logistic regression, F8 mutations were an independent predictor of ITI success (non–high‐risk group vs. high‐risk group, adjusted odds ratio [OR], 20.3; 95% confidence interval [CI], 3.5–117.8), as was the interval from inhibitor diagnosis to ITI start (adjusted OR, 0.95; 95% CI, 0.90–0.99). They remained the significant predictors when success time was taken into account in a Cox model. ConclusionsTypes of F8 mutation were a key predictor of outcomes for low‐dose ITI in children with SHA with high‐titer inhibitors. It can help to stratify the prognosis and guide clinical decisions.

Factor IX inhibitors in haemophilia B: A report of National Haemophilia Registry in China.

The development of inhibitors against factor FIX (FIX) is the most serious complication of FIX replacement therapy in haemophilia B (HB) patients. Currently, only few cohorts of HB inhibitor patients have been reported worldwide. This Chinese nationwide study of HB inhibitor patients explored their risk factors for FIX inhibitor development and experience on their management. We retrospectively analysed patient characteristics, F9 genotypes, treatment strategies and outcomes of HB inhibitor patients registered to the Chinese National Registry and Patient Organization Registry. Forty-four unique HB inhibitor patients were identified in 4485 unique HB patients registered by year 2021 to the two Registries. Inhibitor diagnosis were usually delayed and the low prevalence (.98%) may suggest some inhibitor patients were not identified. Their median age at inhibitor diagnosis was 7.5 (IQR, 3.0-14.8) years. Most patients (95.5%) had high-titre inhibitors. Allergic/Anaphylactic reactions occurred in 59.1% patients. Large deletions and nonsense mutations were the most common F9 mutation types in our FIX inhibitor patients. Patients with large F9 gene deletions were more likely to develop inhibitors (p =.0002), while those with missense mutations had a low risk (p <.0001). Thirteen (29.5%) patients received immune tolerance induction (ITI) therapy using low-dose prothrombin complex concentrate regimens. Twelve completed ITI with three (25.0%) achieving success. Nephrotic syndrome developed in two (16.7%) patients during ITI. This study reports the largest Chinese cohort of HB inhibitor patients. Large deletions were most significantly associated with inhibitor development. Low-dose ITI might be feasible for FIX inhibitor eradication.

Longitudinal profiling of anti-factor VIII antibodies in Japanese patients with congenital hemophilia A during factor VIII replacement and immune-tolerance induction therapy.

When patients with hemophilia A develop factor VIII (FVIII) inhibitors, FVIII replacement therapy becomes ineffective. Although immune-tolerance induction (ITI) therapy has been used to eradicate inhibitors, treatment is unsuccessful in approximately 30% of cases. However, the mechanism behind treatment failure remains unclarified. We retrospectively examined the longitudinal profiles of immunoglobulin G (IgG) subclasses and/or the inhibitory activities of FVIII in plasma samples from 14 Japanese patients with congenital hemophilia A during hemostatic, FVIII replacement, and/or ITI therapies. In five patients, an increase in IgG4 was observed simultaneously with a decrease in IgG1 when the patient had a history of relatively high FVIII inhibitor titers, reflecting an apparent change in humoral immunity. In addition, we examined the reactivity and specificity of the patients' anti-FVIII IgG1 and IgG4 to FVIII domains by immunoblotting. Under our experimental conditions, plasma from three patients with historically higher inhibitor titers appeared to have high titers of antibodies against the A2-a2 domain, which did not necessarily correlate with ITI failure. These observations may improve scientific understanding of the immune response to infused FVIII in patients with hemophilia A.

Inhibitors: Diagnostic challenges, unknowns of inhibitor development, treatment of bleeding and surgery, and insights into diagnosis and treatment in China.

Factor (F) VIII inhibitors develop in around 30% of previously untreated patients (PUPs) with severe haemophilia, to a lesser extend in moderate and mild haemophilia A and in up to 10% in severe haemophilia B. Diagnostic challenges and questions remain including access to high quality testing, the role for functional inhibitor testing and binding antibody testing, and the adaptations needed in the presence of non-factor replacement therapy. Despite significant gains in knowledge there are still many unanswered questions underlying the immunologic mechanisms of inhibitor development and tolerance. Therapeutic options include eradication of inhibitors using immune tolerance induction therapy (ITI), prophylaxis with bypassing agents (i.e., recombinant activated factor VII /rFVIIa or activated prothrombin complex concentrate/aPCC) or non-factor replacement therapies (e.g., emicizumab) and treatment of bleeds or coverage of surgeries/invasive procedure. Recently a haemophilia centre capacity building program was launched in China to further develop the infrastructure and support needed to improve the diagnosis of haemophilia, detection of inhibitors, and continue to improve the care of patients with haemophilia and inhibitors.

Immune Tolerance Induction Experience from a Single Institute in the United Arab Emirates

Background: Immune tolerance induction (ITI) is the gold standard approach for eradicating inhibitors and increasing patient tolerance to factor VIII. The success rate of ITI may vary depending on patient variables and factors relating to the pattern of treatment for the induction of immune tolerance. Children with recently diagnosed inhibitors are the best candidates for ITI, and those with favourable expected results should be offered ITI as soon as inhibitors are identified. Recombinant factor VIII Fc fusion protein has proved a therapeutic advantage in patients with high factor VIII inhibitor titers AIMS AND OBJECTIVES: To evaluate the clinical characteristics and outcomes of ten hemophilic pediatric patients who underwent ITI therapies to eliminate FVIII inhibitors at Tawam Hospital, UAE MATERIALS AND METHODS: The data of ten hemophilia A children aged 2–7 years with high inhibitor titers who underwent ITI therapy at Tawam Hospital, UAE, were retrospectively collected for this case series. A comparison of bleeds before and after the ITI therapy was also made. Patients with either failed or partially successful primary ITI therapy underwent rescue ITI therapy. Data analysis was performed using SPSS version 26. RESULTS: Full success was achieved in 60% (6/10) of the patients, 10% (1/10) achieved partial success, whereas 30% (3/10) failed the primary ITI therapy. The rescue ITI therapy was successful in 50% (2/4) of the patients and the remaining 50% (2/4) achieved partial success [Table 2]. The rescue ITI was successful in 66% (2/3) of those patients who received Elocta and partially successful in 33% (1/3) CONCLUSION: ITI therapy is the gold standard for the eradication of antibodies against FVIII. The patients with good expected outcomes should be offered ITI as soon as the inhibitors are confirmed. The use of extended half life rFVIIIFc demonstrated therapeutic benefit, particularly in challenging ITI patients with high inhibitor titers

Pharmacokinetic analysis identifies a factor VIII immunogenicity threshold after AAV gene therapy in hemophilia A mice

AbstractAdvances in the development of novel treatment options for hemophilia A are prevalent. However, the anti–factor VIII (FVIII) neutralizing antibody (inhibitor) response to existing FVIII products remains a major treatment challenge. Although some novel products are designed to function in the presence of inhibitors, they do not specific address the immunogenicity risk or mechanistic causes of inhibitor development, which remain unclear. Furthermore, most preclinical studies supporting clinical gene therapy programs have reported immunogenicity signals in animal models, especially at higher vector doses and sometimes using multiple vector designs. In these settings, immunogenicity risk factor determination, comparative immunogenicity of competing vector designs, and the potential for obtaining meaningful prognostic data remain relatively unexplored. Additionally, there remains the opportunity to investigate clinical gene therapy as an alternative to standard immune tolerance induction therapy. The current study was designed to address these issues through longitudinal dose-response evaluation of 4 adeno-associated viral (AAV) vector candidates encoding 2 different FVIII transgenes in a murine model of hemophilia A. Plasma FVIII activity and anti-FVIII antibody data were used to generate a pharmacokinetic model that (1) identifies initial AAV-FVIII product expression kinetics as the dominant risk factor for inhibitor development, (2) predicts a therapeutic window where immune tolerance is achieved, and (3) demonstrates evidence of gene therapy–based immune tolerance induction. Although there are known limitations to the predictive value of preclinical immunogenicity testing, these studies can uncover or support the development of design principles that can guide the development of safe and effective genetic medicines.

AKATSUKI study: a prospective, multicentre, phase IV study evaluating the safety of emicizumab under and immediately after immune tolerance induction therapy in persons with congenital haemophilia A with factor VIII inhibitors

IntroductionFor persons with haemophilia A with factor (F) VIII inhibitors (PwHAwI), immune tolerance induction (ITI) therapy is indicated for inhibitor eradication; however, since PwHAwI on ITI were excluded from the...

Efficacy of rFVIIIFc for First-Time Immune Tolerance Induction (ITI) Therapy: Final Results from the Global, Prospective VerITI-8 Study

Efficacy of rFVIIIFc for First-Time Immune Tolerance Induction (ITI) Therapy: Final Results from the Global, Prospective VerITI-8 Study

Low-dose immune tolerance induction therapy in children of Arab descent with severe haemophilia A, high inhibitor titres and poor prognostic factors for immune tolerance induction treatment success.

IntroductionImmune Tolerance Induction (ITI) is the first‐choice therapy to eradicate Factor VIII (FVIII) neutralizing antibodies in patients with haemophilia A (HA). There is limited published data on ITI from East Mediterranean countries.AimTo assess the effectiveness of a low‐dose ITI regimen to eradicate FVIII neutralizing antibodies in children with severe HA and high‐titre inhibitors.MethodsA prospective, single‐arm study was conducted in children with HA (FVIII < 1 IU/dl), high‐titre inhibitors and poor prognostic factors for successful ITI. Patients were treated with ∼50 IU/kg plasma‐derived FVIII containing von Willebrand factor (pdFVIII/VWF) concentrate (Koate‐DVI, Grifols) three times a week. Time to achieve tolerance, total and partial success were analysed after ITI. Annual bleeding rate (ABR), number of target joints, FVIII recovery and school absence were compared before and after ITI.ResultsTwenty patients with median (range) age of 6.2 (3–12) years and pre‐ITI inhibitor titre of 36.5 (12–169) BU were enrolled. ITI lasted ≤12 months (early tolerization) in 45% of patients. Median follow‐up was 12 months (3–22) and total response rate was 80% (60% total success; 20% partial success). Patients with two and three poor prognosis factors achieved overall success rate of 60% and 50%, respectively. ABR, target joints and school absence were reduced after ITI by 60%, 50% and 44.1%, respectively. In successful ITI tolerized patients, FVIII recovery was 90 (60–100)%.ConclusionA low‐dose ITI therapy using a pdFVIII/VWF concentrate achieved at least partial tolerance in 80% of patients, and reduced annual bleeds in children with high inhibitor titres and at least one poor prognosis factor for ITI treatment success.