Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2017 Jul 7;7(7):CD010810.
doi: 10.1002/14651858.CD010810.pub3.

Rituximab for treating inhibitors in people with inherited severe hemophilia

Lucan Jiang  1 , Yi Liu, Lingli Zhang, Cristina Santoro, Armando Rodriguez
Affiliations

Rituximab for treating inhibitors in people with inherited severe hemophilia

Lucan Jiang et al. Cochrane Database Syst Rev. .

Update in

Abstract

Background: Hemophilia A and B are inherited coagulation disorders characterized by a reduced or absent level of factor VIII or factor IX respectively. The severe form is characterized by a factor level less than 0.01 international units (IU) per milliliter. The development of inhibitors in hemophilia is the main complication of treatment, because the presence of these antibodies, reduces or even nullifies the efficacy of replacement therapy, making it very difficult to control the bleeding. People with inhibitors continue to have significantly higher risks of morbidity and mortality, with considerable treatment costs. Given the wide 'off-label' use of rituximab for treating people with hemophilia and inhibitors, its efficacy and safety need to be evaluated. This is an update of a previously published Cochrane Review.

Objectives: To assess the efficacy and safety of rituximab for treating inhibitors in people with inherited severe hemophilia A or B.

Search methods: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, complied from electronic database searches and handsearching of journals and conference abstract books. We searched the reference lists of relevant articles and reviews and also searched for ongoing or unpublished studies. We also undertook further searches of other bibliographic databases and trial registries.Date of last search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register: 16 February 2017.

Selection criteria: Randomized controlled trials and controlled clinical trials investigating the efficacy and safety of rituximab for treating inhibitors in people with hemophilia.

Data collection and analysis: No randomized controlled trials matching the selection criteria were eligible for inclusion.

Main results: No randomized controlled trials on rituximab for treating inhibitors in people with hemophilia were identified.

Authors' conclusions: We were unable to identify any relevant trials on the efficacy and safety of rituximab for treating inhibitors in people with hemophilia. The research evidence available is from case reports and case series. Randomized controlled trials are needed to evaluate the efficacy and safety of rituximab for this condition. However, prior to the publication of any possible future randomized controlled trials, meta-analysis of case reports and case series may provide some evidence.

PubMed Disclaimer

Conflict of interest statement

All authors: none known.

Figures

1
1
Study flow diagram.
See this image and copyright information in PMC

Update of

References

Additional references

Borker 2011
    1. Borker A, Choudhary N. Rituximab. Indian Pediatrics 2011;48(8):627‐32. - PubMed
Carcao 2006
    1. Carcao M, Louis J, Poon MC, Grunebaum E, Lacroix S, Stain AM, et al. on behalf of the Inhibitor Subcommittee of the Association of Hemophilia Clinic Directors of Canada. Rituximab for congenital hemophiliacs with inhibitors: a Canadian experience. Haemophilia 2006;12(1):7‐8. - PubMed
Collins 2009
    1. Collins PW, Mathias M, Hanley J, Keeling D, Keenan R, Laffan M, et al. Rituximab and immune tolerance in severe hemophilia A: a consecutive national cohort. Journal of Thrombosis and Haemostasis 2009;7(5):787‐94. - PubMed
Cooper 2006
    1. Cooper N, Khair K, Mathias M, Leisner RI. Rituximab is effective and well tolerated in children with hemophilia and factor VIII inhibitors. Blood 2006;108:Abstract no: 1031.
Coppola 2012
    1. Coppola A, Tagliaferri A, Capua M, Franchini M. Prophylaxis in children with hemophilia: evidence‐based achievements, old and new challenges. Seminars in Thrombosis and Hemostasis 2012;38(1):79‐94. - PubMed
DiMichele 2007
    1. DiMichele DM, Hoots WK, Pipe SW, Rivard GE, Santagostino E. International workshop on immune tolerance induction: consensus recommendations. Haemophilia 2007;13 Suppl 1:1‐22. - PubMed
Egger 1997
    1. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta‐analysis detected by a simple, graphical test. BMJ 1997;315(7109):629‐34. - PMC - PubMed
FDA 2013
    1. Food, Drug Administration. Highlights of Prescribing Information (Rituxan). www.accessdata.fda.gov/drugsatfda_docs/label/2013/103705s5409lbl.pdf (accessed 21 Augest 2013).
Fox 2006
    1. Fox RA, Neufeld EJ, Bennett CM. Rituximab for adolescents with haemophilia and high titre inhibitors. Haemophilia 2006;12(3):218‐22. - PubMed
Franchini 2008
    1. Franchini M, Mengoli C, Lippi G, Targher G, Montagnana M, Salvagno GL, et al. Immune tolerance with rituximab in congenital haemophilia with inhibitors: a systematic literature review based on individual patients analysis. Haemophilia 2008;14(5):903‐12. - PubMed
Giulino 2007
    1. Giulino LB, Bussel JB, Neufeld EJ, Pediatric and Platelet Immunology Committees of the TMH Clinical Trial Network. Treatment with rituximab in benign and malignant hematologic disorders in children. Journal of Pediatrics 2007;150(4):338‐44, 344. e1. - PMC - PubMed
Gouw 2007a
    1. Gouw SC, van der Bom JG, Marijke van den Berg H. Treatment‐related risk factors of inhibitor development in previously untreated patients with hemophilia A: the CANAL cohort study. Blood 2007;109(11):4648‐54. - PubMed
Gouw 2007b
    1. Gouw SC, van der Bom JG, Auerswald G, Ettinghausen CE, Tedgård U, van den Berg HM. Recombinant versus plasma‐derived factor VIII products and the development of inhibitors in previously untreated patients with severe hemophilia A: the CANAL cohort study. Blood 2007;109(11):4693‐7. - PubMed
Gouw 2013a
    1. Gouw SC, van den Berg HM, Fischer K, Auerswald G, Carcao M, Chalmers E, et al. Intensity of factor VIII treatment and inhibitor development in children with severe hemophilia A: the RODIN study. Blood 2013;121(20):4046‐55. - PubMed
Gouw 2013b
    1. Gouw SC, Bom JG, Ljung R, Escuriola C, Cid AR, Claeyssens‐Donadel S, et al. Factor VIII products and inhibitor development in severe hemophilia A. New England Journal of Medicine 2013;368(3):231‐39. - PubMed
Grace 2012
    1. Grace RF, Bennett CM, Ritchey AK, Jeng M, Thornburg CD, Lambert MP, et al. Response to steroids predicts response to rituximab in pediatric chronic immune thrombocytopenia. Pediatric Blood & Cancer 2012;58(2):221‐5. - PMC - PubMed
Hay 2012
    1. Hay CR, DiMichele DM, on behalf of the International Immune Tolerance Study. The principal results of the International Immune Tolerance Study: a randomized dose comparison. Blood 2012;119(6):1335‐44. - PubMed
Higgins 2011a
    1. Higgins JPT, Altman DG, Sterne JAC, editor(s). Chapter 8: Assessing risk of bias in included studies. In: Higgins JPT, Green S, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from www.cochrane‐handbook.org.
Higgins 2011b
    1. Higgins JPT, Deeks JJ, Altman DG, editor(s). Chapter 16: Special topics in statistics. In: Higgins JPT, Green S, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from www.cochrane‐handbook.org.
Iorio 2010a
    1. Iorio A, Halimeh S, Holzhauer S, Goldenberg N, Marchesini E, Marcucci M, et al. Rate of inhibitor development in previously untreated hemophilia A patients treated with plasma‐derived or recombinant factor VIII concentrates: a systematic review. Journal of Thrombosis and Haemostasis 2010;8(6):1256‐65. - PubMed
Iorio 2010b
    1. Iorio A, Matino D, D'Amico R, Makris M. Recombinant Factor VIIa concentrate versus plasma derived concentrates for the treatment of acute bleeding episodes in people with haemophilia and inhibitors. Cochrane Database of Systematic Reviews 2010, Issue 8. [DOI: 10.1002/14651858.CD004449.pub3] - DOI - PubMed
Iorio 2011
    1. Iorio A, Marchesini E, Marcucci M, Stobart K, Chan AK. Clotting factor concentrates given to prevent bleeding and bleeding‐related complications in people with hemophilia A or B. Cochrane Database of Systematic Reviews 2011, Issue 9. [DOI: 10.1002/14651858.CD003429.pub4] - DOI - PubMed
Kavcic 2013
    1. Kavcic M, Fisher BT, Seif AE, Li Y, Huang YS, Walker D, et al. Leveraging administrative data to monitor rituximab use in 2875 patients at 42 freestanding children's hospitals across the United States. Journal of Pediatrics 2013;162(6):1252‐8. - PMC - PubMed
Kobayashi 2015
    1. Kobayashi R, Sano H, Suzuki D, Kishimoto K, Yasuda K, et al. Successful treatment of immune tolerance induction with rituximab in a patient with severe hemophilia B and inhibitor. Blood Coagulation and Fibrinolysis 2015;26(5):580‐2. - PubMed
Kuzmanovic 2012
    1. Kuzmanovic M, Jurisic V. Rituximab for treatment of autoimmune hemolytic anemia. Indian Pediatrics 2012;49(8):672‐4. - PubMed
Leissinger 2011
    1. Leissinger C, Gringeri A, Antmen B, Berntorp E, Biasoli C, Carpenter S, et al. Anti‐inhibitor coagulant complex prophylaxis in hemophilia with inhibitors. New England Journal of Medicine 2011;365(18):1684‐92. - PubMed
Mateo 2006
    1. Mateo J, Badell I, Forner R, Borrell M, Tizzano E, Fontcuberta J. Successful suppression using Rituximab of a factor VIII inhibitor in a boy with severe congenital haemophilia: an example of a significant decrease of treatment costs. Thrombosis and Haemostasis 2006;95(2):386‐7. - PubMed
Moschovi 2006
    1. Moschovi M, Aronis S, Trimis G, Platokouki H, Salavoura K, et al. Rituximab in the treatment of high responding inhibitors in severe haemophilia A. Haemophilia 2006;12(1):95‐9. - PubMed
NCT01064284
    1. NCT01064284. Survey of inhibitors in plasma‐product exposed toddlers (SIPPET). https://clinicaltrials.gov/ct2/show/NCT01064284 (accessed 27 January 2015).
NHLBI 2011
    1. U.S. National Heart Lung and Blood Institute. What is hemophilia?. http://www.nhlbi.nih.gov/health/health‐topics/topics/hemophilia/ (accessed 18 November 2012).
Nwobi 2008
    1. Nwobi O, Abitbol CL, Chandar J, Seeherunvong W, Zilleruelo G. Rituximab therapy for juvenile‐onset systemic lupus erythematosus. Pediatric Nephrology 2008;23(3):413‐9. - PMC - PubMed
Pescovitz 2006
    1. Pescovitz MD. Rituximab, an anti‐cd20 monoclonal antibody: history and mechanism of action. American Journal of Transplantation 2006;6(5 Pt 1):859‐66. - PubMed
RevMan 2014 [Computer program]
    1. The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.
Selewski 2010
    1. Selewski DT, Shah GV, Mody RJ, Rajdev PA, Mukherji SK. Rituximab (Rituxan). American Journal of Neuroradiology 2010;31(7):1178‐80. - PMC - PubMed
Stedman 2011
    1. Stedman MR, Curtin F, Elbourne DR, Kesselheim AS, Brookhart MA. Meta‐analyses involving cross‐over trials: methodological issues. International Journal of Epidemiology 2011;40(6):1732‐4. - PubMed
Verbruggen 1995
    1. Verbruggen B, Novakova I, Wessels H, Boezeman J, van den Berg M, Mauser‐Bunschoten E, et al. The Nijmegen modification of the Bethesda assay for factor VIII:C inhibitors: improved specificity and reliability. Thrombosis and Haemostasis 1995;73(2):247‐51. - PubMed
WFH 2012a
    1. World Federation of Hemophilia. About bleeding disorders‐How are inhibitors diagnosed?. www.wfh.org/en/page.aspx?pid=648 (accessed 18 November 2012).
WFH 2012b
    1. World Federation of Hemophilia. About bleeding disorders‐Who is at risk of developing inhibitors?. www.wfh.org/en/page.aspx?pid=653 (accessed in 19 Augest 2013).
WFH 2013
    1. World Federation of Hemophilia. About bleeding disorders ‐ What are inhibitors?. www.wfh.org/en/page.aspx?pid=651 (accessed 19 August 2013).
Yadav 2012
    1. Yadav SP, Chinnabhandar C. Rituximab usage in children: a double edged sword. Indian Pediatrics 2012;49(4):335‐6. - PubMed

References to other published versions of this review

Liu 2013
    1. Liu Y, Zhang L, Santoro C, Song J, Rodriguez A, Wang L. Rituximab for treating inhibitors in children with hemophilia. Cochrane Database of Systematic Reviews 2013, Issue 10. [DOI: 10.1002/14651858.CD010810] - DOI
Liu 2015
    1. Liu Y, Zhang L, Santoro C, Song J, Rodriguez A, Wang L. Rituximab for treating inhibitors in people with inherited severe hemophilia. Cochrane Database of Systematic Reviews 2015, Issue 4. [DOI: 10.1002/14651858.CD010810.pub2] - DOI - PubMed

Publication types

LinkOut - more resources