Low-dose Immune Tolerance Induction in Children with Severe Hemophilia A with High-titer Inhibitors: Type of Factor 8 Mutation and Outcomes

Overview

Journal Res Pract Thromb Haemost

Publisher Elsevier

Date 2022 Oct 31

PMID 36313984

Authors

Jie Sun

Zekun Li

Gang Li

Kun Huang

Di Ai

Guoqing Liu

Wanru Yao

Xingjuan Xie

Hao Gu

Yingzi Zhen

Zhenping Chen

Runhui Wu

Affiliations

Soon will be listed here.

Abstract

Background: No studies evaluated the role of mutations in outcomes for low-dose immune tolerance induction (ITI) in people with severe hemophilia A (SHA) with high-titer inhibitors.

Objectives: To explore the association between mutation types and low-dose ITI outcomes in children with SHA with high-titer inhibitors.

Methods: Children SHA with high-titer inhibitors who received low-dose ITI therapy at least for 1 year were included in this study. Based on the risk of inhibitor development, 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.

Results: Of 104 children included, 101 had 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%; = 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%; = 0.001) and a shorter time to success (mean time, 9.3 months vs. 13.2 months; = 0.04) compared to those in the high-risk group. In multivariable logistic regression, 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.

Conclusions: Types of 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.

Citing Articles

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

Sun J, Li Z, Li G, Huang K, Ai D, Liu G Res Pract Thromb Haemost. 2022; 6(7):e12824.

PMID: 36313984 PMC: 9606347. DOI: 10.1002/rth2.12824.

References

Sun J, Li Z, Li G, Huang K, Ai D, Liu G . Low-dose immune tolerance induction in children with severe hemophilia A with high-titer inhibitors: Type of factor 8 mutation and outcomes. Res Pract Thromb Haemost. 2022; 6(7):e12824. PMC: 9606347. DOI: 10.1002/rth2.12824. View

Hay C, DiMichele D . The principal results of the International Immune Tolerance Study: a randomized dose comparison. Blood. 2011; 119(6):1335-44. DOI: 10.1182/blood-2011-08-369132. View

DiMichele D . The North American Immune Tolerance Registry: contributions to the thirty-year experience with immune tolerance therapy. Haemophilia. 2008; 15(1):320-8. DOI: 10.1111/j.1365-2516.2008.01880.x. View

Rocino A, Santagostino E, Mancuso M, Mannucci P . Immune tolerance induction with recombinant factor VIII in hemophilia A patients with high responding inhibitors. Haematologica. 2006; 91(4):558-61. View

Coppola A, Margaglione M, Santagostino E, Rocino A, Grandone E, Mannucci P . Factor VIII gene (F8) mutations as predictors of outcome in immune tolerance induction of hemophilia A patients with high-responding inhibitors. J Thromb Haemost. 2009; 7(11):1809-15. DOI: 10.1111/j.1538-7836.2009.03615.x. View

Ter Avest P, Fischer K, Mancuso M, Santagostino E, Yuste V, van den Berg H . Risk stratification for inhibitor development at first treatment for severe hemophilia A: a tool for clinical practice. J Thromb Haemost. 2008; 6(12):2048-54. DOI: 10.1111/j.1538-7836.2008.03187.x. View

Garagiola I, Palla R, Peyvandi F . Risk factors for inhibitor development in severe hemophilia a. Thromb Res. 2018; 168:20-27. DOI: 10.1016/j.thromres.2018.05.027. View

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J . Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015; 17(5):405-24. PMC: 4544753. DOI: 10.1038/gim.2015.30. View

van den Berg H, Fischer K, Carcao M, Chambost H, Kenet G, Kurnik K . Timing of inhibitor development in more than 1000 previously untreated patients with severe hemophilia A. Blood. 2019; 134(3):317-320. DOI: 10.1182/blood.2019000658. View

10.

Peyvandi F, Jayandharan G, Chandy M, Srivastava A, Nakaya S, Johnson M . Genetic diagnosis of haemophilia and other inherited bleeding disorders. Haemophilia. 2006; 12 Suppl 3:82-9. DOI: 10.1111/j.1365-2516.2006.01263.x. View

11.

Li Z, Chen Z, Cheng X, Liu G, Wu X, Li G . 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. Haemophilia. 2020; 27(4):e469-e472. DOI: 10.1111/hae.14157. View

12.

Nogami K, Taki M, Matsushita T, Ohga S, Oka T, Horikoshi Y . The Japanese Immune Tolerance Induction (J-ITI) study in haemophilia patients with inhibitor: Outcomes and successful predictors of ITI treatment. Haemophilia. 2018; 24(5):e328-e337. DOI: 10.1111/hae.13531. View

13.

Salviato R, Belvini D, Radossi P, Sartori R, Pierobon F, Zanotto D . F8 gene mutation profile and ITT response in a cohort of Italian haemophilia A patients with inhibitors. Haemophilia. 2007; 13(4):361-72. DOI: 10.1111/j.1365-2516.2007.01437.x. View

14.

Nakar C, Shapiro A . Hemophilia A with inhibitor: Immune tolerance induction (ITI) in the mirror of time. Transfus Apher Sci. 2019; 58(5):578-589. DOI: 10.1016/j.transci.2019.08.008. View

15.

Nakar C, Manco-Johnson M, Lail A, Donfield S, Maahs J, Chong Y . Prompt immune tolerance induction at inhibitor diagnosis regardless of titre may increase overall success in haemophilia A complicated by inhibitors: experience of two U.S. centres. Haemophilia. 2015; 21(3):365-373. DOI: 10.1111/hae.12608. View

16.

Srivastava A, Brewer A, Mauser-Bunschoten E, Key N, Kitchen S, Llinas A . Guidelines for the management of hemophilia. Haemophilia. 2012; 19(1):e1-47. DOI: 10.1111/j.1365-2516.2012.02909.x. View

17.

Haya S, Lopez M, Aznar J, Batlle J . Immune tolerance treatment in haemophilia patients with inhibitors: the Spanish Registry. Haemophilia. 2001; 7(2):154-9. DOI: 10.1046/j.1365-2516.2001.00469.x. View

18.

Di Minno G, Coppola A, Margaglione M, Rocino A, Mancuso M, Tagliaferri A . Predictors of inhibitor eradication by primary immune tolerance induction in severe haemophilia A with high responding inhibitors. Haemophilia. 2021; 28(1):55-64. DOI: 10.1111/hae.14431. View

19.

Li Z, Chen Z, Liu G, Cheng X, Yao W, Huang K . Low-dose immune tolerance induction alone or with immunosuppressants according to prognostic risk factors in Chinese children with hemophilia A inhibitors. Res Pract Thromb Haemost. 2021; 5(5):e12562. PMC: 8279128. DOI: 10.1002/rth2.12562. View

20.

Peyvandi F, Mannucci P, Garagiola I, El-Beshlawy A, Elalfy M, Ramanan V . A Randomized Trial of Factor VIII and Neutralizing Antibodies in Hemophilia A. N Engl J Med. 2016; 374(21):2054-64. DOI: 10.1056/NEJMoa1516437. View