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Background: The traditional weight‐based dosing regimen can lead to under‐ or overdosage due to the interindividual variability of pharmacokinetic (PK) parameters. PK‐guided prophylaxis can be an optimized therapy choice. Aim: This study aimed to investigate the clinical outcomes of PK‐guided prophylaxis in 46 boys with severe haemophilia A. Methods: Forty‐six boys with severe haemophilia A were enrolled in Beijing Children's Hospital. The PK tests were performed using a five‐point assay. PK parameters were calculated using WinNonlin software. The dosing regimen and bleeding rates recorded during the observation period. The adjustment was based on PK evaluation, bleeding details, doctor's advice and patients' choice. Results: The half‐life time, in vivo recovery and clearance of Kovaltry were 14.34 ± 2.68 h, 1.78 ± 0.29 kg/dl and 3.38 ± 0.94 ml/kg/h, respectively. In 18 patients without any change in the dosing regimen, the trough level was 4.0 ± 2.41 IU/dl and the bleeding rates were similar after PK tests. For patients with a higher trough level after adjustment, higher dose and frequency were observed, as well as a higher trough level. Also, reduced annual bleeding rate (ABR), annual joint bleeding rate and annual spontaneous bleeding rate (ASBR) were found. In five patients with a reduced trough level, lower infusion frequency and weekly coagulation factor VIII (FVIII) consumption were observed, with no statistically significant difference in ABR and ASBR. Conclusion: PK‐guided prophylaxis can help haemophiliac patients improve quality of life by decreasing bleeds with appropriate FVIII consumption and reducing infusion frequency without increments in bleeds, thus optimizing haemophilia treatment. [ABSTRACT FROM AUTHOR]

Background: Kovaltry (BAY81‐8973) is an unmodified full‐length factor VIII (FVIII) concentrate that enhances the pharmacokinetic (PK) profiles as compared to some other standard half‐life time FVIII concentrates. However, the PK of Kovaltry in haemophiliac patients aged <12 years has not been reported previously. Aim: To investigate the pharmacokinetics and clinical outcomes of Kovaltry in 35 paediatric patients aged <12 years. Methods: A total of 35 boys with severe haemophilia A were enrolled from August 2019 to May 2020 in Beijing Children's Hospital. After 72‐hour washout, PK tests were performed post‐infusion of 50 IU/kg Kovaltry in a five‐timepoint assay. WinNonlin software was used to generate individual PK parameters. The dose, frequency and bleeding details were collected within the first 6 months after switching to Kovaltry from other FVIII concentrates. Results: Compared to the blood group O, patients with blood group non‐O showed longer mean half‐life (t1/2) (p <.01), lower mean clearance (CL) (p =.01) and similar in vivo recovery (IVR) (p =.51). Higher von Willebrand factor antigen (VWF:Ag) level was correlated to longer t1/2 (p <.0001) and lower CL (p <.01). IVR was correlated to body mass index (BMI) (p <.0001). Patients with trough level >3 IU/dL demonstrated lower annual bleeding rate (ABR) (p <.01), annual joint bleeding rate (AJBR) (p <.01) and annual spontaneous bleeding rate (ASBR) (p <.01). Conclusion: This study firstly reported the PK profiles of Kovaltry in 35 paediatric patients <12 years old. The great inter‐individual variability of PK parameters was also confirmed in these patients. VWF:Ag and blood group were major influencing factors of t1/2 and CL of Kovaltry, while BMI was a vital predictor for IVR. Patients with high trough FVIII level in routine prophylaxis had reduced bleeding rates. [ABSTRACT FROM AUTHOR]

As the most commonly used FVIII concentrate in China, the individualized pharmacokinetics (PK) and clinical outcomes of Kovaltry (BAY81-8973) are not fully investigated in this population. Pediatric patients with severe hemophilia A were enrolled in Beijing Children's Hospital. After a three-day washout, they received PK tests after a single-dose infusion of 50 IU/kg. The blood samples were collected with a six-point assay. One-stage-based activated partial thromboplastin time was used for FVIII activity. The PK parameters were generated by WinNonlin software. The bleeding rates were calculated by their routine therapy record. The ultrasound was used to evaluate their both sides of knees, elbows and ankles. Sixty-one boys with severe hemophilia A were enrolled and their median age was 5.73 years. Twenty-nine of them were blood group-O. Compared with blood group-O patients, those non-O patients showed longer t 1/2 (15.26 vs. 13.03 h, P < 0.001) and reduced CL (3.04 vs. 3.66 mL/kg/h, P < 0.05). Patients with higher VWF:Ag level had longer half-life time (t 1/2) (r = 0.60, P < 0.0001) and lower clearance (CL) (r = −0.45, P < 0.001). Patients with higher trough level showed decreased bleeding rates compared with those owning a trough level below 1 IU/dL (P < 0.05). In general, the zero bleeding rates raised with elevation of trough level. However, 20–30% of patients with low trough level (<1 IU/dL) also showed no bleeds and 10–20% of patients with high trough level (>5 IU/dL) still suffer bleeds. An inconsistency of 28% between joint bleeds and ultrasound evaluation was showed. This study revealed the great inter-individual variability in PK parameters, clinical bleeding phenotype and joint vulnerability, which all should be considered in treating hemophilia A. [ABSTRACT FROM AUTHOR]

Comparative pharmacokinetics of Kogenate FS and Kovaltry in 14 Chinese paediatric patients with haemophilia A: A single-centre study Although the CL of Kogenate FS and Kovaltry showed no statistical difference in our study, the CL of Kovaltry showed a decreasing trend when compared with Kogenate (3.35 vs 3.78 mL/kg/h). Keywords: factor VIII; haemophilia A; haemorrhage; paediatric patients; pharmacokinetics EN factor VIII haemophilia A haemorrhage paediatric patients pharmacokinetics e287 e290 4 03/23/21 20210301 NES 210301 Dear Editor, Haemophilia A is an X-linked inherited bleeding disease caused by a deficiency in the activity of coagulation factor VIII (FVIII). According to the World Federation of Hemophilia (WFH), the management of haemophilia A involves prophylaxis as standard of care, especially for patients with severe haemophilia A.1 However, significant interindividual variability is observed within the patients of haemophilia A in response to treatment. [Extracted from the article]

Physical activity is a crucial part of an active lifestyle for haemophiliac children. However, the fear of bleeds has been identified as barriers to participating physical activity for haemophiliac children even with prophylaxis. Lack of evidence and metrics driven by data is key problem. We aim to develop machine learning models based on clinical data with multiple potential factors considered to predict risk of physical activity bleeding for haemophilia children with prophylaxis. From this cohort study, we collected information on 98 haemophiliac children with adequate prophylaxis (trough FVIII:C level > 1 %). The involved potential predictor variables include demographic information, treatment information, physical activity, joint evaluation, and pharmacokinetic parameters, etc. We applied CoxPH, Random Survival Forests (RSF) and DeepSurv to construct prediction models for the risk of bleeding during physical activities. All three survival analysis models were internally and externally validated. A total of 98 patients were enrolled in this study. Their median age was 7.9 (5.5, 10.2) years. The CoxPH, RSF and DeepSurv models' discriminative and calibration abilities were all high, and the RSF model had the best performance (Internal validation: C-index, 0.7648 ± 0.0139; Brier Score, 0.1098 ± 0.0015; External validation: C-index, 0.7260 ± 0.0154; Brier Score, 0.0930 ± 0.0018). The prediction curves demonstrated that the developed RSF model can distinguish the risks well between bleeding and non-bleeding patients, as well as patients with different levels of physical activity. Meanwhile, the feature importance analysis confirmed that physical activity bleeding was deduced by comprehensive effects of various factors, and the importance of different factors on bleeding outcome is discrepant. This study revealed from the mechanism that it is necessary to incorporate multiple factors to accurately predict physical activity related bleeding risk. In clinical practice, the designed machine learning models can provide guidance for children with haemophilia A to positively participate in physical activity. • Predicting the risk of bleeding during physical activity in children withhaemophilia A • Three machine learning methods used to construct prediction models • The RSF model had the best discriminative and calibration • The models can guide children with haemophilia regarding participation in physical activities [ABSTRACT FROM AUTHOR]

To explore the feasibility, safety and cost effectiveness of the use of peripherally inserted central catheter (PICC) in children with hemophilia A and inhibitors who underwent ITI treatment. This retrospective cohort study evaluated the effect of PICC placement and ITI on bleeding rates, costs, and parents' satisfaction before and within 6 months after PICC placement in children with hemophilia A and inhibitors. A total of 20 children with hemophilia A and high-titer inhibitors were included, with a success rate for PICC placement of 100%, at a cost of ¥6730.50. Parents' satisfaction with PICC was 100%, and the total length of catheter indwelling was 6055 days. In terms of curative effect, the success rate of ITI treatment was 75%, and the annualized bleeding rate was decreased from 10.90 ± 12.16 times before placement to 2.10 ± 3.32 times (p < 0.05). The transportation expense for children and their parents to the clinic decreased from ¥20,920 ± 32,274.57 before catheter placement to ¥2915 ± 2195.99 (p < 0.05). Time of children missed school and their parents missed work decreased from 10.85 ± 22.36 days to 1.90 ± 3.58 (p < 0.05) days and 40.33 ± 46.11 days to 3.83 ± 7.11 days (p < 0.05), respectively. The use of PICC for ITI treatment in children with hemophilia A and accompanying inhibitors in developing countries (e.g. China) can ensure the effect of ITI, reducing expense and improving the quality of life without obvious side effects. [ABSTRACT FROM AUTHOR]

The 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. HA 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. Among 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). The 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. • Predictor of ITI outcomes in the same F8 gene background is unclear. • Inv22 children with high-responding inhibitors were included and analyzed. • Interval time from inhibitor diagnosis to ITI start (interval-time) was first identified as a unique predictor of ITI outcomes. • Interval-time of <25.8 months was associated with improved ITI outcomes. [ABSTRACT FROM AUTHOR]

Shorter 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. To explore the relationship between interval-time and low-dose ITI outcomes in Chinese SHA children with high-risk-inhibitors. This 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. Among 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. Interval-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. • The interval-time is the time from inhibitor detection to starting ITI. • Interval-time for predicting low-dose ITI outcomes remained unclear, for high-risk-inhibitors patients. • Interval-time had a strong predictive value for outcomes in our low-dose ITI strategy. • Interval-time cut-off values were 22.3 for success and 9.4 months for early-success. [ABSTRACT FROM AUTHOR]

• Refractoriness was inability to achieve negative inhibitor titer over at least 12 months period taking LD-ITI+Rituximab-IS. • There is therefore a need to explore rescue-regimen(s) for refractory patients. • MMF might exert T-cell immunosuppression not covered by Rituximab which focuses on B-cell suppression. • The sequential MMF-rescue-regimen had efficacy in the patients refractory to our initial LD-ITI+Rituximab-IS regimen. [ABSTRACT FROM AUTHOR]

Introduction: As standard care of severe haemophilia A (SHA), prophylaxis should be individualised. Aim: This study aimed to investigate the effectiveness of this new‐proposed individualised prophylaxis protocol. Methods: Boys with SHA were enrolled and followed a PK‐guided, trough‐level escalating protocol of prophylaxis after a six‐month observational period. In the next 2 years, clinical assessments including joint bleeds, ultrasound (US) scores and Haemophilia Joint Health Score (HJHS) in both sides of ankles, knees and elbows were conducted every 6 months as a scoring system, which determined whether the trough level's escalation. Adjustment of dosing regimen was based on WAPPS‐Hemo. Results: Fifty‐eight SHA boys were finally analysed. Their age and bodyweight were 5.3(2.8,6.9) years and 21.5(16,25) kg. During the study, 47 escalations were conducted. At study exit, the patient number and proportion of different trough level groups were: < 1 IU/dl, 17.2% (10/58); 1–3 IU/dl, 53.5% (31/58); 3–5 IU/dl, 15.5% (9/58); > 5 IU/dl, 13.8% (8/58). Significantly reduced annualised bleeding rate [4(0,8) to 0(0,2), p <.0001] and annualised joint bleeding rate [2(0,4) to 0(0,.25), p <.0001] was observed at study exit as well as the continuous trend of increased zero bleeding proportion (ZBP) (27.6%–69.0%) and zero joint bleeding proportion (46.5%–81.3%). Besides, 85% (6/7) of the target joints vanished. Statistical improvements of US scores (p =.04) and HJHS (p =.02) were also reported at study exit. Conclusion: Our results showed the effectiveness of our protocol based on individualised target trough level and emphasise the importance of personalised prophylaxis. [ABSTRACT FROM AUTHOR]

Introduction: Development of haemophilia B inhibitors (HBI) results in the ineffectiveness of FIX replacement therapy. Inhibitor eradication by immune tolerance induction (ITI) is therefore necessary. In HBI, ITI even at high FIX dose is less effective and has a higher risk of severe complications. Aim: To characterize clinical features and outcome of ITI on HBI. Methods: This retrospective study was conducted in Haemophilia Paediatric Comprehensive Care Centre of China. We used low‐dose ITI (25–50 FIX IU/kg/three‐times‐weekly to every‐other‐day) with domestic prothrombin complex concentrate (PCC), combined with two successive immunosuppressive (IS) regimens. Results: Sixteen HBI children, representing 5.7% of all and 14.4% of our severe registered HB patients, were enroled. Seven cases reported allergic reactions (ARs) proximal to inhibitor development. The historic peak inhibitor titre was median 54.2 (range 4.7–512) BU, and 15 (93.8%) had high‐titre inhibitors. Twelve patients adherent to ITI were analysable. Of the nine ITI patients who received rituximab/prednisone (IS Regimen‐1), four achieved tolerization in 1.4–43.3 months. Two subsequently relapsed but re‐tolerized after a second course of IS Regimen‐1. During ITI, the median treated bleed was.39/month (82.7% reduction from before ITI), and the incidence of AR and nephrotic syndrome (NS) complications was each at 22% (2/9). Three ITI patients received modified 'Beutel' protocol (IS Regimen‐2) using multiple‐IS‐drugs, and two had rapid tolerization (.8 and 1.8 months). Conclusions: Inhibitor eradication could be achieved by low‐dose ITI protocol using PCC combined with IS. Larger studies are needed to confirm if ITI with IS Regimen‐2 is more effective with less complications. [ABSTRACT FROM AUTHOR]

Allergic reactions to FIX have been associated with nephrotic syndrome and poor ITI outcome.3 Both our cases did, with case 2 having allergic reactions simultaneously with inhibitor development. This is consistent with previous observations that NS development was closely related to a significant decline in inhibitor titre.2 Interestingly, the NS in case 2 was preceded by a second allergic reactions to the ITI regimen and in case 1 by a fluctuation of inhibitor titres during ITI-rituximab. Patients with haemophilia B (HB) may develop factor IX (FIX) inhibitors with a cumulative incidence of 10.2% following FIX replacement therapy by 500 exposure days.1 In 50-60% cases, occurrence of severe allergic reactions may precede or occur simultaneously with the inhibitor development.2 The propensity for FIX to induce allergic reactions (compared to FVIII) may be related to the extravascular distribution of the smaller FIX molecules.3 Immune tolerance induction (ITI) therapy to eradicate FIX inhibitors has a poor success rate of only 13-31%.2,4 There is also a risk of developing nephrotic syndrome (NS) in 17-33% cases. Nephrotic syndrome in two haemophilia B children with inhibitor under low-dose immune tolerance induction combined with rituximab-based immunosuppressant protocol. [Extracted from the article]

A low-dose immune tolerance induction (ITI) protocol incorporating immunosuppressive agents in haemophilia A children with high-titre factor VIII inhibitor and poor-ITI prognostic risk These were all on good-ITI risk patients with inhibitor titre <10 BU at the initiation of ITI and historical peak inhibitor titre <200 BU. Nineteen haemophilia A inhibitor children with poor-ITI risk (historical peak inhibitor titre >=100 BU and/or inhibitor titre >=40 BU at ITI initiation) (Table 1) were enrolled from September 2016 through April 2019. Various ITI regimens achieved an overall success rates of 60%-80%.2,3 According to the UK guideline,4 low-dose ITI (50 IU/kg, every-other-day) was only suggested for using in patient with low-titre inhibitors (historical peak inhibitors <5 BU). [Extracted from the article]