HIF-1α induced by hypoxic condition regulates Treg/Th17 axis polarization in chronic immune thrombocytopenia.

Immune thrombocytopenia (ITP) is an acquired immune disorder characterized by increased platelet destruction and reduced platelet (Plt) production. Hypoxia-inducible factor-1α (HIF-1α) have regulatory effects on Treg/Th17 axis balance and may represent relevant factors in the pathogenesis of ITP. Treg/Th17 ratio, serum levels and gene expression were investigated in new diagnosed ITP (NITP) and chronic ITP (CITP). The Treg/Th17 ratio obviously decreased in CITP (P = 0.001). The ratio of Treg/Th17 was correlated with the level of HIF-1α level both in mRNA (r = 0.49, P < 0.0001) and serum level (r = 0.50, P < 0.0001). However, none statistical upregulation of HIF-1α was observed in CITP. In vitro, There was significant polarization difference of Treg/Th17 axis (P = 0.042) and Foxp3-MFI/IL17-MFI (P = 0.0003) in hypoxic condition between NITP and CITP. These findings suggest that HIF-1α induced by hypoxia plays a crucial role in the chronicity of ITP by mediating the imbalance of the Treg/Th17 axis.

Spotlight on eltrombopag concentration in pediatric immune thrombocytopenia: A single-center observational study in China.

Importance: Eltrombopag has been recommended for pediatric immune thrombocytopenia (ITP). Response and adverse drug reactions (ADRs) varied widely between individuals, even at the same dose of eltrombopag. The appropriate eltrombopag concentration in ITP has not been reported. Objective: This study aims to explore the appropriate eltrombopag concentration in pediatric ITP. Methods: This was a single-center, prospective cohort study. Children diagnosed with refractory persistent/chronic ITP and platelet count < 30×109/L were treated with eltrombopag and followed up for at least 2 months. Concentration was detected by high-performance liquid chromatography-mass spectrometry at least 2 weeks after eltrombopag. The clinical characteristics-concentration, concentration-response, and concentration-ADRs were analyzed. Results: A total of 30 patients were enrolled, comprising 13 males and 17 females, with a median age of 72 (45‒94) months. The median dose and concentration were 1.39 (1.09‒1.56) mg/kg and 2.70 (2.25‒4.13) mg/L, respectively. Of the enrolled patients, 14 responded to treatment, whereas 16 did not. Additionally, five experienced adverse drug reactions. No linear correlation was observed between eltrombopag concentration and clinical characteristics. The concentration was lower in the response group than in the nonresponse group, but there was no significant difference (t = 0.755, P = 0.457). Patients who experienced ADRs had a higher concentration than those without ADRs (t = 2.538, P = 0.017). The area under the receiver operating characteristic curve of ADRs was 0.78 (95% confidence interval: 0.56‒1.00). Youden's index identified the cutoff point as 4.33 mg/L, with a sensitivity of 88% and a specificity of 60%. Logistic regression analysis demonstrated that a higher platelet count before eltrombopag predicted a favorable response. Interpretation: Eltrombopag proves efficacious and well-tolerated for treating pediatric ITP. However, prolonged and high-dose administration may increase the likelihood of ADRs. Thus, examining the appropriate eltrombopag concentration assists in directing individualized management of pediatric ITP.

Efficacy and safety of avatrombopag in Chinese children with persistent and chronic primary immune thrombocytopenia: A multicentre observational retrospective study in China.

Avatrombopag (AVA) is a novel thrombopoietin receptor agonist (TPO-RA) that has been recently approved as a second-line therapy for immune thrombocytopenia (ITP) in adults; however, its safety and efficacy data in children are lacking. Here, we demonstrated the efficacy and safety of AVA as second-line therapy in children with ITP. A multicentre, retrospective, observational study was conducted in children with persistent or chronic ITP who did not respond to or relapsed from previous treatment and were treated with AVA for at least 12 weeks between August 2020 and December 2022. The outcomes were the responses (defined as achieving a platelet count ≥30 × 109 /L, twofold increase in platelet count from baseline and absence of bleeding), including rapid response within 4 weeks, sustained response at weeks 12 and 24, bleeding control and adverse events (AEs). Thirty-four (18 males) patients with a mean age of 6.3 (range: 1.9-15.3) years were enrolled. The median number of previous treatment types was four (range: 1-6), and 41.2% patients switched from other TPO-RAs. Within 4 weeks, overall response (OR) was achieved in 79.4% patients and complete response (CR, defined as a platelet count ≥100 × 109 /L and the absence of bleeding) in 67.7% patients with a median response time of 7 (range: 1-27) days. At 12 weeks, OR was achieved in 88.2%, CR in 76.5% and sustained response in 44% of patients. At 24 weeks, 22/34 (64.7%) patients who achieved a response and were followed up for 24 weeks were evaluated; 12/22 (54.55%) achieved a sustained response. During AVA therapy, median platelet counts increased by week 1 and were maintained throughout the treatment period. The proportion of patients with grade 1-3 bleeding decreased from 52.95% at baseline to 2.94% at 12 weeks, while concomitant ITP medications decreased from 36.47% at baseline to 8.82% at 12 weeks, with only 9 (26.47%) patients receiving rescue therapy 23 times within 12 weeks. There were 61.8% patients with 59 AEs: 29.8% with Common Terminology Criteria for Adverse Events grade 1 and the rest with grade 2. These findings show that AVA could achieve a rapid and sustained response in children with persistent or chronic ITP as a second-line treatment, with good clinical bleeding control and reduction of concomitant ITP therapy, without significant AEs.

The influence of dead space in blood sampling needle on FVIII level and pharmacokinetic profiles in children with hemophilia.

OBJECTIVE: To investigate the influence of the dead space in disposable blood sampling needle on activated partial thromboplastin time (APTT), FVIII level and pharmacokinetic (PK) profiles in children with hemophilia. METHODS: Children (<18 years) with severe hemophilia A were enrolled. After three days' washout-period, blood samples were collected at pre-dose, 1 h, 3 h, 9 h, 24 h and 48 h post-infusion. At each timepoint, two 2 mL vacuum tubes with 3.2% trisodium citrate were used. The first tube was signed as 'non-standard' (NS) and the second tube was signed as 'standard' (S). FVIII activities were evaluated by one-stage assay. WAPPS-Hemo was used to generate PK profiles like half-life time (t1/2), clearance (CL), trough level and time to 1, 2 and 5IU/dL after a dose of 50 ± 10IU/dL. The FVIII activities at 9 h and 24 h post-infusion were put into WAPPS and thus brought four combinations by true or biased FVIII level that used. RESULT: Compared with standard-collected blood samples, prolonged APTT results (P-values < 0.01) and decreased FVIII activity (P-values < 0.05) were revealed in those non-standard blood samples. The corresponding bias was in positive relation to both APTT-S (r = 0.44, P < 0.0001) and FVIII-S level(r = 0.68, P < 0.001). The FVIII bias percentage got larger as FVIII-S level reduced (r = -0.24, P < 0.01). During the four combinations of FVIII activity at 9 h and 24 h, statistically longer t1/2, lower CL and longer time to 1, 2 or 5IU/dL were observed in 9H-S&24H-S group and 9H-NS&24H-S group. CONCLUSION: While using vacuum tubes for clotting indicators and PK profiles, the dead space of blood sampling needle should be eliminated in advance.

Oral health status and oral habits of children and adolescents with hemophilia: a report from the children's hemophilia comprehensive care center of China.

In recent years, the diagnosis and treatment of hemophilic children in China has significantly improved. However, oral health conditions, which affect quality of life, haven't received attention in this population. To explore the oral health status and oral hygiene of children and adolescents with hemophilia in the Children's Hemophilia Comprehensive Care Center of China. Dental and oral hygiene examinations were performed in children and adolescents with hemophilia who visited Beijing Children's Hospital. DMFT/dmft (decayed, missing, filled teeth in permanent and primary teeth) was assessed according to World Health Organization (WHO) criteria. The simplified oral hygiene index (OHI-S) was used to evaluate the oral hygiene condition of the subjects. Questionnaires were completed by their parents. SPSS 21.0 was used for statistical analysis. A total of 114 children and adolescents were enrolled. The caries prevalence was 57.4%, 72.2% and 41.2% in primary, mixed and permanent dentitions respectively. The filling rates were 14.4%, 13.9%, and 11.4%, respectively, and the OHI-S scores of the three dentition groups were 1.49 ± 0.46, 1.57 ± 0.43, and 1.76 ± 0.46, respectively. A total of 103 valid questionnaires were collected. Sixty-nine children (67%) didn't brushed their teeth 2 times a day. Nearly half of the parents knew little about fluoride toothpaste. Multiple linear regression analysis revealed that brushing teeth with the help of parents had a significant positive impact on OHI-S.  Conclusion: Dental health was unsatisfactory among hemophilic children and adolescents. The caries filling rates were low. Patients and their parents did not give much attention to oral health. What is Known: • Caries and gingivitis are the two main oral diseases that affect children with hemophilia. • However, the oral health conditions of children and adolescents with hemophilia have not received much attention in China. What is New: • This is the first study concentrating on the dental health of children with hemophilia in China. • Dental health was unsatisfactory among children and adolescents with hemophilia in China.

Machine learning models developed and internally validated for predicting chronicity in pediatric immune thrombocytopenia.

BACKGROUND: Primary immune thrombocytopenia (ITP) in children is typically self-limiting; however, 20% to 30% of patients may experience prolonged thrombocytopenia lasting over a year. The challenge is predicting chronicity to ensure personalized treatment approaches. OBJECTIVES: To address this issue, we developed and internally validated 4 machine learning (ML) models using demographic and immunologic characteristics to predict the likelihood of chronicity. METHODS: The present study was conducted at Beijing Children's Hospital from June 2018 to December 2021, aiming to develop predictive models for determining the chronicity of pediatric ITP. Four ML models, based on a logistic regression classifier, random forest classifier, eXtreme Gradient Boosting (XGBoost), and support vector machine, were employed. These models used a set of 16 variables, including 14 immunologic and 2 demographic predictors. The performance evaluation criteria included prediction accuracy, precision, recall, F1 score, and area under the receiver operating characteristic curve (AUROC). RESULTS: Data were collected from 662 patients who were randomly assigned to either a training dataset or a testing dataset using a random number generator. Among them, 26.5% had chronic disease. All models performed well, with AUROC values ranging from 0.81 to 0.84, and XGBoost was selected for its highest AUROC score and interpretability in constructing the predictive model. Age, T helper 17, T helper 17-to-regulatory T cell ratio, T helper 1, and double-negative T cells were identified as significant predictors by the XGBoost algorithm. CONCLUSION: We developed a precise predictive model for chronicity in pediatric ITP using ML during the initial phase. The XGBoost model achieved high predictive accuracy by using individual patient clinical parameters and demonstrated commendable interpretability.

Long-term eltrombopag in children with chronic immune thrombocytopenia: A single-centre extended real-life observational study in China.

We have previously confirmed the efficacy and safety of eltrombopag (ELT) in children with chronic immune thrombocytopenia (cITP). However, data on both long-term exposure and early use of TPO-RAs are lacking, so further 'field-practice' evidence on treatment is required. Here, we report the long-term follow-up results (between September 2018 and June 2023) of our previous study. The main objective of this study was to retrospectively review our large institutional experience with ITP patients previously enrolled in our paediatric cITP study. We had more than 3 years of follow-up by June 2023 for treatment patterns and outcomes. A total of 65 patients (28 males) were enrolled, with a median age at ELT initiation of 6.34 (range 1.65, 14.13) years and a follow-up of 47.07 (36.00, 57.00) months, with 40.36 (10.53, 56.83) months of ELT therapy at the time of analysis. In total, 29.23% (19/65) of patients discontinued ELT due to stable response, and 18.46% (12/65) of patients switched to other ITP therapies due to loss of response (LOR) after 19.13 (14.53, 26.37) months. Of the 19 patients who discontinued ELT due to a stable response, 24.62% (16/65) achieved a 12 m sustained response off-treatment (SRoT); the last recorded platelet count ranged from 56 to 166 × 109 /L (median 107 × 109/L); and 4.62% (3/65) patients relapsed at 5, 6 and 9 months after discontinuation. Of the 12 patients who LOR to ELT after 19.13 (14.53, 26.37) months of therapy, four switched to avatrombopag, three switched to hetrombopag, two switched to traditional Chinese medicine (TCM), one underwent splenectomy and two received additional prednisolone under ELT treatment. Thirty-four patients who tapered and maintained a durable response. The patients with LOR and the patients with tapering were compared; the platelet count at the start of ELT is lower, and the time to response is longer in the patients with LOR. The platelet count at the start of ELT and the time to response may be the predictive factors for LOR during ELT treatment. We report more than 3 years of long-term clinical data on children with cITP using ELT. These data do not raise any new safety concerns regarding the long-term use of ELT in children with cITP.

Machine learning model for predicting physical activity related bleeding risk in Chinese boys with haemophilia A.

BACKGROUND: 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. OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Complete F9 Gene Deletion, Duplication, and Triplication Rearrangements: Implications for Factor IX Expression and Clinical Phenotypes.

BACKGROUND: Factor IX (FIX) plays a critical role in blood coagulation. Complete deletion of F9 results in severe hemophilia B, whereas the clinical implications of complete F9 duplication and triplication remain understudied. OBJECTIVE: To investigate the rearrangement mechanisms underlying complete F9 deletion (cases 1 and 2), duplication (cases 3 and 4), and triplication (case 5), and to explore their association with FIX expression levels and clinical impacts. METHODS: Plasma FIX levels were detected using antigen and activity assays. CNVplex technology, optical genome mapping, and long-distance polymerase chain reaction were employed to characterize the breakpoints of the chromosomal rearrangements. RESULTS: Cases 1 and 2 exhibited FIX activities below 1%. Case 3 displayed FIX activities within the reference range. However, cases 4 and 5 showed a significant increase in FIX activities. Alu-mediated nonallelic homologous recombination was identified as the cause of F9 deletion in case 1; FoSTeS/MMBIR (Fork Stalling and Template Switching/microhomology-mediated break-induced replication) contributed to both F9 deletion and tandem duplication observed in cases 2 and 3; BIR/MMBIR (break-induced replication/microhomology-mediated break-induced replication) mediated by the same pair of low-copy repeats results in similar duplication-triplication/inversion-duplication (DUP-TRP/INV-DUP) rearrangements in cases 4 and 5, leading to complete F9 duplication and triplication, respectively. CONCLUSION: Large deletions involving the F9 gene exhibit no apparent pattern, and the extra-hematologic clinical phenotypes require careful analysis of other genes within the deletion. The impact of complete F9 duplication and triplication on FIX expression might depend on the integrity of the F9 upstream sequence and the specific rearrangement mechanisms. Notably, DUP-TRP/INV-DUP rearrangements significantly elevate FIX activity and are closely associated with thrombotic phenotypes.

Application of peripherally inserted central catheter in immune tolerance induction treatment of children with hemophilia A and accompanying inhibitors in China.

OBJECTIVE: 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. METHOD: 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. RESULTS: 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. CONCLUSION: 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.

Treatment-related outcome from patient report outcome (PRO) of children with severe and moderate hemophilia A in China: An analysis report of registration data from patient organization "hemophilia home care center".

OBJECTIVES: To assess current treatment-related outcomes for children with severe and moderate haemophilia A (cHA) in China. METHODS: This cross-section Patient Report Outcome (PRO) report collected PRO data of severe and moderate cHAs registered in the 'Hemophilia Home Care Center' database (http://web.bjxueyou.cn) between January 2021 and November 2022. Data included records of bleeding, activities, and concentrates consumption. All patients had a confirmed diagnosis of moderate or severe haemophilia A (FVIII: C ≤ 5%) and were < 18 years old. RESULTS: Among 1038 analysable cases, 9.6% of children with inhibitors had a higher rate of intracranial haemorrhage, dropout school rate, and higher FVIII consumption than children without inhibitors. Among 100 children with inhibitors, 36 patients were treated without immune tolerance induction (ITI), 14 patients with irregular treatment and 50 patients received ITI. Children with ITI had a lower ABR (2.4 (0,6.6) vs. 13.4 (9.5, 26.6), p<.001) and AJBR (0 (0, 3.1) vs. 8.9 (1.6, 19.3), p < .001) compared to those without ITI. Among 938 children without inhibitors, 28.5% received on-demand treatment and 71.5% received prophylaxis. Of 528 children with 1343.8 (1050.4, 2922.9)IU/kg/year median FVIII consumption, 43.0% received low-dose, 43.2% received intermediate-dose, and 13.8% received high-dose regimen; these children with prophylaxis had a lower ABR (3.1 (0, 10.7) vs. 12.8 (2.4, 45.5), p < .001), AJBR (0.5 (0, 3.9) vs. 3.0 (0, 12.0), p < .001) and disability rate (9.0% vs.18.5%, p = .032) compared to children who received on-demand treatment. CONCLUSION: The high rate of drop-out of school and disability still present a huge gap to meet the needs in China. It is necessary to improve the level of medical accessibility and medicine affordability and strengthen the patient/parent's education in China.

Transient increase in platelet counts associated with COVID-19 infection during TPO-RA as the second-line treatment in children with ITP.

The thrombopoietin receptor agonists (TPO-RA) were recommended for primary immune thrombocytopenia (ITP) during the pandemic of COVID-19. However, the incidence of thrombocytosis and thrombosis was sporadically reported in the chronic immune thrombocytopenia (CITP) patients receiving TPO-RA during the COVID-19 infection. With the local prevalence of COVID-19 in December 2022 in the Beijing area, we got more powerful evidence about the change in platelet (Plt) counts associated with COVID-19 infection. A single-centre observational cohort study was performed from the beginning of December 2022 to the end of February 2023 to enrol CITP children treated with TPO-RA alone as the second-line treatment and suffering from the COVID-19 infection in December 2022. The Plt counts before, during and after COVID-19 infection were collected. In total, 67 (34 males and 33 females) patients with 8.10 (2.15, 15.70) years of age were enrolled. Sixty-three patients who had responded to the TPO-RA showed a transient increase in Plt counts after the infection of COVID-19. The time of starting to increase was on Day 3 (2, 7), and to the peak level on Day 14 (7, 19) of infection with the peak Plt count was 289 (88, 1974) × 109 /L. With at least 2 months observation period from COVID-19 infection, the Plt counts of 100% (63/63) patients declined to the baseline on Day 25 (14, 41). The phenomenon of transient increase in Plt counts has been shown in the CITP children who responded to TPO-RA when suffering from COVID-19 infection.

Elevated TCR-αß+ double-negative T cells in pediatric patients with acquired aplastic anemia.

BACKGROUND AND AIMS: The pathophysiology of acquired aplastic anemia (aAA) is most associated with T cell mediated immune dysfunction, but the role of CD4- CD8- double negative T cells (DNTs) in pediatric patients with aAA is unclear. In this study, we aimed to investigate the proportion of TCR-αß+ DNTs in pediatric patients with aAA and correlation with the response to immunosuppressive therapy (IST). MATERIALS AND METHODS: Assessment of DNTs from peripheral blood was done by sensitive multi-color flow cytometry. The potential clinical value of TCR-αß+ DNTs was then assessed by the receiver operating characteristic (ROC) curves. RESULTS: The retrospective study evaluated 164 pediatric patients with aAA and 105 healthy donors (HD). Our data showed higher proportion of TCR-αß+ DNTs in total lymphocytes [1.04% (0.79%-1.40%) vs 0.69% (0.47%-0.87%), p < 0.001] and CD3+ T cells [1.52% (1.10%-1.96%) vs 1.10% (0.70%-1.40%), p < 0.001] in aAA compared to HD. Patients with SAA/VSAA achieving complete response (CR) after IST had a higher proportion of TCR-αß+ DNTs at initial diagnosis, than those not achieving CR for total (1.21%±0.39 vs 0.78%±0.38, p < 0.05) and CD3+ T cells (1.74%±0.53 vs 1.15%±0.59, p < 0.05). The ROC analysis showed areas under the curves (AUCs) for TCR-αß+ DNT proportion in lymphocytes and CD3+ T cells were 0.756 (cutoff value 1.33, p < 0.05) and 0.758 (cutoff value 1.38, p < 0.05), respectively. And the complete response rate was higher in TCR-αß+ DNT proportion high group than in TCR-αß+ DNT proportion low group at baseline (p < 0.001). CONCLUSION: Our observations suggest that elevated TCR-αß+ DNTs seems to play a role in the pathogenesis of aAA, and it was involve in immune response to IST.

Sustained response off treatment in eltrombopag for children with persistent/chronic primary immune thrombocytopenia: A multicentre observational retrospective study in China.

Eltrombopag (ELT) is effective and safe in adult persistent/chronic immune thrombocytopenia (p/cITP); a proportion could achieve a sustained response off treatment (SRoT); however, data on children are lacking. We attempted to analyse SRoT of ELT in children with p/cITP in this study. A multicentre retrospective observational study was performed in November 2022 for children with p/cITP who used ELT alone for >2 months between January 2017 and November 2021. Clinical data of pre-, during and post-ELT were collected. SRoT was defined as maintaining a platelet count of ≥30 × 109 /L without rescue therapy for at least 6 months off ELT. There were 143 patients enrolled; 69.2% (99/143) achieved an overall response of 43.3% and 25.9% achieved complete response (CR) and response (R). Among the 35 patients analysed from whom ELT was withdrawn, 71.4% (25/35) showed SRoT after discontinuing ELT without additional ITP therapy, with a median follow-up of 0.94 (range, 0.53-3.8) years, equal to 17.5% (25/143) in all patients treated with ELT. Compared with the patients with relapse (n = 10), the SRoT patients (n = 25) had a higher rate of CR (80% [20/25] vs. 40% [4/10]), shorter interval time from initiation to taper (6.4 months vs. 9.4 months), longer time from taper to withdrawal (1.1 years vs. 0.3 years) and a longer duration of ELT treatment (1.6 years vs. 0.5 years) with p < 0.05. Patients who achieved CR could attain SRoT more easily (p = 0.02). ELT had a response in 69.2% of children with p/cITP and 17.5% of them attained SRoT with good tolerance. The patients who achieved CR and began ELT treatment as early as possible, with a longer treatment duration and slower tapering, had a higher probability of SRoT.

Outcomes of switching to avatrombopag following treatment failure with eltrombopag in paediatric immune thrombocytopenia: A real-world study in China.

Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder characterized by isolated thrombocytopenia and a haemorrhagic risk. Thrombopoietin receptor agonists (TPO-RAs) are highly effective for ITP and are widely used to treat patients with steroid treatment failure or dependency. However, although treatment response to TPO-RAs may differ according to the type, the potential impact of switching from eltrombopag (ELT) to avatrombopag (AVA) with respect to efficacy or tolerance in children remains unknown. This study aimed to evaluate the outcomes of switching from ELT to AVA in paediatric patients with ITP. We retrospectively evaluated children with chronic immune thrombocytopenia (cITP) switched from ELT to AVA owing to treatment failure at the Hematology-Oncology Center of Beijing Children's Hospital between July 2021 and May 2022. Overall, 11 children (seven and four boys and girls respectively) with a median age of 8.3 (range: 3.8-15.3) years were included. The overall response and complete response (platelet [PLT] count ≥100 × 109 /L) rates during AVA treatment were 81.8% (9/11) and 54.6% (6/11) respectively. The median PLT count was significantly increased from ELT to AVA (7 [range: 2-33] × 109 /L vs. 74 [15-387] × 109 /L; p = 0.007). The median time to PLT count ≥30 × 109 /L was 18 (range: 3-120) days. Overall, 7/11 patients (63.6%) used concomitant medications, and concomitant medication use was gradually discontinued within 3-6 months after AVA initiation. In conclusion, AVA after ELT is effective in the heavily pretreated paediatric cITP population, with high response rates even in those with an inadequate response to a prior TPO-RA.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Efficacy and safety of fitusiran prophylaxis in people with haemophilia A or haemophilia B with inhibitors (ATLAS-INH): a multicentre, open-label, randomised phase 3 trial.

BACKGROUND: Fitusiran, a subcutaneous investigational small interfering RNA therapeutic, targets antithrombin to rebalance haemostasis in people with haemophilia A or haemophilia B, irrespective of inhibitor status. We evaluated the efficacy and safety of fitusiran prophylaxis in people with haemophilia A or haemophilia B with inhibitors. METHODS: This multicentre, randomised, open-label phase 3 study was done at 26 sites (primarily secondary or tertiary centres) in 12 countries. Men, boys, and young adults aged 12 years or older with severe haemophilia A or haemophilia B with inhibitors previously treated with on-demand bypassing agents were randomly assigned (2:1) to receive once-a-month 80 mg subcutaneous fitusiran prophylaxis (fitusiran prophylaxis group) or to continue with bypassing agents on-demand (bypassing agents on-demand group) for 9 months. The primary endpoint was mean annualised bleeding rate during the efficacy period in the intention-to-treat population estimated by negative binomial model. Safety was assessed as a secondary endpoint in the safety population. This trial is complete and is registered with ClinicalTrials.gov, NCT03417102. FINDINGS: Between Feb 14, 2018, and June 23, 2021, 85 participants were screened for inclusion, of whom 57 (67%; 57 [100%] men; median age 27·0 years [IQR 19·5-33·5]) were randomly assigned: 19 (33%) participants to the bypassing agent on-demand group and 38 (67%) participants to the fitusiran prophylaxis. Negative binomial model-based mean annualised bleeding rate was significantly lower in the fitusiran prophylaxis group (1·7 [95% CI 1·0-2·7]) than in the bypassing agents on-demand group (18·1 [10·6-30·8]), corresponding to a 90·8% (95% CI 80·8-95·6) reduction in annualised bleeding rate in favour of fitusiran prophylaxis (p<0·0001). 25 (66%) participants had zero treated bleeds in the fitusiran prophylaxis group versus one (5%) in the bypassing agents on-demand group. The most frequent treatment-emergent adverse event in the fitusiran prophylaxis group was increased alanine aminotransferase in 13 (32%) of 41 participants in the safety population; there were no increased alanine aminotransferase treatment-emergent adverse events in the bypassing agents on-demand group. Suspected or confirmed thromboembolic events were reported in two (5%) participants in the fitusiran prophylaxis group. No deaths were reported. INTERPRETATION: Subcutaneous fitusiran prophylaxis resulted in statistically significant reductions in annualised bleeding rate in participants with haemophilia A or haemophilia B with inhibitors, with two-thirds of participants having zero bleeds. Fitusiran prophylaxis might show haemostatic efficacy in participants with haemophilia A or haemophilia B with inhibitors; therefore, the therapeutic might have the potential to improve the management of people with haemophilia. FUNDING: Sanofi.

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

BACKGROUND: 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. OBJECTIVES: To explore the relationship between interval-time and low-dose ITI outcomes in Chinese SHA children with high-risk-inhibitors. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Central venous access devices implantation in children with severe hemophilia a: data from the children comprehensive care center of China.

Objectives: To report the perioperative management experience of central venous access devices (CVAD) in Chinese children with severe hemophilia A (SHA) in China. Methods: This retrospective study included SHA children who underwent Port-A-Cath or peripherally inserted central catheter (PICC) implantation between 2020/01 and 2021/07. Collected data included baseline characteristics, factor replacement regimen and CVAD-related complications. Results: Nine patients had nine ports placed, and eight patients underwent 10 PICCs placement. Patients without or with low-titer inhibitor (<5 BU) received a port. The median preoperative and postoperative plasma-derived factor VIII (pd-FVIII) doses were 53.0 (44.4-61.1) and 315.9 (88.2-577.8) IU/kg. The median port duration was 189 (15-512) days, with infection incidence of 0.06 per 1000 CVAD days. Patients with high-titer inhibitors (>10 BU) received PICC. The median recombinant factor VIIa (rFVIIa) dose was 87.47 µg/kg before and for 5-7 doses after implantation over 2-3 days. The median PICC duration was 226.5 days, with infection incidence of 0.12 per 1000 catheter-days. Conclusions: CVADs can be safely implanted in China. PICC implantation is a practical and safe option for SHA children with high-titer inhibitors.