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Thromb Haemost 2014; 112(03): 445-458
DOI: 10.1160/TH14-01-0078
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Rituximab for treatment of inhibitors in haemophilia A

A Phase II Study
Cindy Leissinger
1   Tulane University, New Orleans, Louisianna, USA
,
Cassandra D. Josephson
2   Center for Transfusion and Cellular Therapies, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA
17   Aflac Cancer and Blood Disorder Center, Children’s Healthcare of Atlanta, Emory University, Atlanta, Georgia, USA
,
Suzanne Granger
3   Center for Statistical Analysis and Research, New England Research Institutes, Watertown, Massachusetts, USA
,
Barbara A. Konkle
4   Puget Sound Blood Center, Seattle, Washington, USA
,
Rebecca Kruse-Jarres
1   Tulane University, New Orleans, Louisianna, USA
,
Margaret V. Ragni
5   University of Pittsburgh and Hemophilia Center of Western Pennsylvania, Pittsburgh, Pennsylvania, USA
,
Janna M. Journeycake
6   University of Texas Southwestern Medical Center, Dallas, Texas, USA
,
Leonard Valentino
7   RUSH University Medical Center, Chicago, Illinois, USA
,
Nigel S. Key
8   University of North Carolina, Chapel Hill, North Carolina, USA
,
Joan C. Gill
9   Blood Center of Wisconsin and Medical College of Wisconsin, Milwaukee, Wisconsin, USA
,
Keith R. McCrae
10   Cleveland Clinic, Cleveland, Ohio, USA
,
Ellis J. Neufeld
11   Boston Children’s Hospital, Harvard University, Boston, Massachusetts, USA
,
Catherine Manno
12   NYU Langone Medical Center, New York, New York, USA
,
Leslie Raffini
13   The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
,
Kapil Saxena
14   University of Oklahoma, Oklahoma City, Oklahoma, USA
,
Marcela Torres
15   Cook’s Children’s Medical Center, Fort Worth, Texas, USA
,
Victor Marder
16   Orthopaedic Hospital Special Coagulation Laboratory, Los Angeles, California, USA
,
Carolyn M. Bennett
17   Aflac Cancer and Blood Disorder Center, Children’s Healthcare of Atlanta, Emory University, Atlanta, Georgia, USA
,
Susan F. Assmann
3   Center for Statistical Analysis and Research, New England Research Institutes, Watertown, Massachusetts, USA
› Author Affiliations Financial support: This study was supported by grants from the National Heart, Lung, and Blood Institute of the National Institutes of Health to the Data Coordinating Center at New England Research Institutes (HL072268), Case Western Reserve University (HL072033), Children’s Hospital Boston (HL072291), Emory University (HL072248), Tulane (HL072274), University of North Carolina (HL072355), University of Oklahoma (HL072283), University of Pennsylvania (HL072346), University of Pittsburgh (HL072331), and the Blood Center of Wisconsin (HL072290).
Further Information

Publication History

Received: 24 January 2014

Accepted after major revision: 22 March 2014

Publication Date:
20 November 2017 (online)

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Summary

The development of antibodies against infused factor VIII (FVIII) in patients with haemophilia A is a serious complication leading to poorly controlled bleeding and increased morbidity. No treatment has been proven to reduce high titre antibodies in patients who fail immune tolerance induction or are not candidates for it. The Rituximab for the Treatment of Inhibitors in Congenital Hemophilia A (RICH) study was a phase II trial to assess whether rituximab can reduce anamnestic FVIII antibody (inhibitor) titres. Male subjects with severe congenital haemophilia A and an inhibitor titre ≥5 Bethesda Units/ml (BU) following a FVIII challenge infusion received rituximab 375 mg/m2 weekly for weeks 1 through 4. Post-rituximab inhibitor titres were measured monthly from week 6 through week 22 to assess treatment response. Of 16 subjects who received at least one dose of rituximab, three (18.8%) met the criteria for a major response, defined as a fall in inhibitor titre to <5 BU, persisting after FVIII re-challenge. One subject had a minor response, defined as a fall in inhibitor titre to <5 BU, increasing to 5–10 BU after FVIII re-challenge, but <50% of the original peak inhibitor titre. Rituximab is useful in lowering inhibitor levels in patients, but its effect as a solo treatment strategy is modest. Future studies are indicated to determine the role of rituximab as an adjunctive therapy in immune tolerisation strategies.

Trial: “Rituximab for the Treatment of Inhibitors in Congenital Hemophilia A: The RICH Study. Registered as Clinical Trials.gov identifier- NCT00331006.

Keywords

Anti-CD20 - antibodies - monoclonal - murine-derived - blood coagulation inhibitor - CD20 antibody - haemophilia A

 

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