Low‐dose immune tolerance induction for children with hemophilia A with poor‐risk high‐titer inhibitors: A pilot study in China

Li, Zekun; Chen, Zhenping; Cheng, Xiaoling; Wu, Xinyi; Li, Gang; Zhen, Yi; Cai, Siyu; Poon, Man‐Chiu; Wu, Runhui

doi:10.1002/rth2.12248

Cited by 11 publications

(23 citation statements)

References 28 publications

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“…The cost of our low‐dose ITI regimen until phase 2 success was 74% to 90% lower than that for high‐dose ITI 6,25 and confirms the finding in our earlier pilot economic study 30 …”

Section: Discussionsupporting

confidence: 86%

“…The cost of our low‐dose ITI regimen until phase 2 success was 74% to 90% lower than that for high‐dose ITI 6 , 25 and confirms the finding in our earlier pilot economic study. 30 This low‐dose ITI alone or with IS strategy is affordable for children with HA with high‐titer inhibitor in China with economic constraint, and by extension also in other regions with developing economies.…”

Section: Discussionmentioning

confidence: 95%

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Low‐dose immune tolerance induction alone or with immunosuppressants according to prognostic risk factors in Chinese children with hemophilia A inhibitors

Chen

Liu

et al. 2021

Research and Practice in Thrombosis and Haemostasis

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Background In developing countries, children with hemophilia A (HA) with high‐titer inhibitor and poor immune tolerance induction (ITI) prognostic risk(s) cannot afford the recommended high‐ or intermediate‐dose ITI. Objectives To determine the efficacy of low‐dose ITI (plasma‐derived factor VIII [FVIII]/von Willebrand factor at 50 FVIII IU/kg every other day) by itself (ITI‐alone) or combined with immunosuppressants rituximab and prednisone (ITI‐IS) in children with HA with high‐titer inhibitor. Methods All enrolled patients had pre‐ITI inhibitor ≥10 BU. We used ITI‐alone if inhibitor titer was <40 BU pre‐ITI and during ITI, and ITI‐IS if titer was ≥100 BU (historic) or ≥40 BU (pre‐ or during ITI) or if the patient was nonresponsive on ITI‐alone. Results Fifty‐six children were analyzable, with median historic peak inhibitor titer 48.0 BU and followed for median 31.4 months. Overall, 35 (62.5%) achieved phase 2 success with negative inhibitor and normal FVIII recovery. The phase 2 success rate was 95% for the 20 patients receiving ITI‐alone. For the 36 patients receiving ITI‐IS, the phase 2 success rate was 44.4%, but would increase to 63.6% if the 14 patients with historic peak inhibitor titer ≥100 BU (and having phase 2 success rate of only 14.3%) were excluded. One patient developed repeated infection after IS treatment. Relapse occurred in 11.4% (4/35) patients with phase 2 success associated with rapid ITI dose reduction or irregular post‐ITI FVIII prophylaxis. Our strategy reduced the cost from high‐dose ITI by 74% to 90%. Conclusion The use of low‐dose ITI with or without immunosuppressants according to ITI prognostic risk(s) is a clinically and economically feasible strategy for eradicating inhibitors in children with HA, particularly for those with historic peak inhibitor titer <100 BU.

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“…The cost of our low‐dose ITI regimen until phase 2 success was 74% to 90% lower than that for high‐dose ITI 6,25 and confirms the finding in our earlier pilot economic study 30 …”

Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 95%

Low‐dose immune tolerance induction alone or with immunosuppressants according to prognostic risk factors in Chinese children with hemophilia A inhibitors

Chen

Liu

et al. 2021

Research and Practice in Thrombosis and Haemostasis

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“…The rate and accuracy of inhibitor detection have also been facilitated and improved by the establishment of three HTCCNC reference laboratories (Beijing, Tianjin and Shanghai), as well as the establishment of a national external quality assurance programme for haemophilia and inhibitor diagnosis. However, at this time, reports on patients with haemophilia with inhibitors only come from a limited number of provinces in China 14–16 . China started a national haemophilia registry in the 1990s.…”

Section: Introductionmentioning

confidence: 99%

Patients with haemophilia A with inhibitors in China: a national real‐world analysis and follow‐up

et al. 2021

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Summary The development of alloantibodies (inhibitors) against coagulation factor VIII (FVIII) is the most serious complication of FVIII replacement therapy in patients with haemophilia A (HA). We carried out a nationwide study focussing on patients with HA with inhibitors in China to evaluate the condition and management of this population. The study retrospectively analysed patient characteristics, clinical history, manifestation, treatment strategy as well as individual haemophilia care of 493 patients with inhibitors (466 with severe HA and 27 with non‐severe HA) registered all over China. The median (interquartile range) age at diagnosis of FVIII inhibitors was 13 (5–28) years in patients with severe HA and 24 (10·5–39·5) years in patients with non‐severe HA. Most patients (85%) had high‐titre inhibitors. Prothrombin complex concentrate and recombinant activated coagulation factor VII were used respectively in 76·2% and 29·2% of patients for acute bleeding. Only 22·3% of patients underwent immune tolerance induction (ITI) treatment, of whom 64·9% achieved negative inhibitor titre. In patients who did not undergo ITI, the inhibitors turned negative in 17·7%, and patients with low peak inhibitor titre were more likely to acquire negative titre spontaneously (odds ratio 11·524, 95% confidence interval 5·222–25·432; P = 0·000). We recorded that 3·2% of the patients died from haemophilia‐related life‐threatening bleeding.

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“…High inhibitor titers occurred in 18 out of the 20 patients who developed FVIII inhibitors, and only 2 had low titers. This finding calls for further exploration of immune tolerance induction treatment in the high inhibitor titer group since most of these patients have uncontrollable bleedings and do not respond to replacement therapy, in contrast to the low-inhibitor titer group ( 28 , 29 ). FVIII genotype is an important determinant of inhibitor development in patients with severe HA.…”

Section: Discussionmentioning

confidence: 99%

Prevalence of FVIII Inhibitors Among Children with Hemophilia A: Experience at the Jordanian Royal Medical Services

et al. 2020

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Introduction: Replacement therapy is constantly required by Hemophilia A (HA) patients lacking coagulation factor VIII (FVIII). The most serious complication of this treatment is the development of neutralizing antibodies (inhibitors). Aim: The aim of this study is to determine the frequency of FVIII inhibitors among children treated for HA at the Jordanian Royal Medical Services. Methods: A total of 165 diagnosed HA patients receiving on-demand treatment, were tested for FVIII inhibitors between 2003 and 2018. The age range was 6 months to 16 years. Coagulation and inhibitor screening assays were performed, followed by Bethesda assay for inhibitor-positive samples to quantify FVIII inhibitor titers. Results: Out of the 165 patients, 111 had severe hemophilia with FVIII level < 1%, 26 had moderate hemophilia with FVIII levels of 1–5% and 28 had mild hemophilia with FVIII levels of > 5%. Twenty patients had FVIII inhibitors, of whom 18 had high titers, 2 had low titers. The mean inhibitor level in low (titer) responders was 2.40 ± 0.85 BU, as opposed to 116.25 ±169.25 BU in high (titer) responders. In terms of disease severity, 18 of the 20 patients with FVIII inhibitors had severe HA, whereas two had moderate HA. No inhibitors were encountered in the mild HA group. Conclusion: Inhibitors only developed in moderate and severe cases of HA. The severity of the disease and age were the main contributing factors. The association between family history of inhibitors and the incidence of inhibitor formation warrants genetic evaluations to look for relevant mutations.

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Low‐dose immune tolerance induction for children with hemophilia A with poor‐risk high‐titer inhibitors: A pilot study in China

Cited by 11 publications

References 28 publications

Low‐dose immune tolerance induction alone or with immunosuppressants according to prognostic risk factors in Chinese children with hemophilia A inhibitors

Low‐dose immune tolerance induction alone or with immunosuppressants according to prognostic risk factors in Chinese children with hemophilia A inhibitors

Patients with haemophilia A with inhibitors in China: a national real‐world analysis and follow‐up

Prevalence of FVIII Inhibitors Among Children with Hemophilia A: Experience at the Jordanian Royal Medical Services

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