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Rituximab for treatment of inhibitors in haemophilia A

Journal: Thrombosis and Haemostasis
ISSN: 0340-6245
DOI: http://dx.doi.org/10.1160/TH14-01-0078
Issue: 2014: 112/3 (Sep) pp. 427–626
Pages: 445-458
Ahead of Print: 2014-06-12

Rituximab for treatment of inhibitors in haemophilia A

A Phase II Study

Online Supplementary Material

C. Leissinger (1), C. D. Josephson (2, 3), S. Granger (4), B. A. Konkle (5), R. Kruse-Jarres (1), M. V. Ragni (6), J. M. Journeycake (7), L. Valentino (8), N. S. Key (9), J. C. Gill (10), K. R. McCrae (11), E. J. Neufeld (12), C. Manno (13), L. Raffini (14), K. Saxena (15), M. Torres (16), V. Marder (17), C. M. Bennett (3), S. F. Assmann (4)

(1) Tulane University, New Orleans, Louisianna, USA; (2) Center for Transfusion and Cellular Therapies, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA; (3) Aflac Cancer and Blood Disorder Center, Children’s Healthcare of Atlanta, Emory University, Atlanta, Georgia, USA; (4) Center for Statistical Analysis and Research, New England Research Institutes, Watertown, Massachusetts, USA; (5) Puget Sound Blood Center, Seattle, Washington, USA; (6) University of Pittsburgh and Hemophilia Center of Western Pennsylvania, Pittsburgh, Pennsylvania, USA; (7) University of Texas Southwestern Medical Center, Dallas, Texas, USA; (8) RUSH University Medical Center, Chicago, Illinois, USA; (9) University of North Carolina, Chapel Hill, North Carolina, USA; (10) Blood Center of Wisconsin and Medical College of Wisconsin, Milwaukee, Wisconsin, USA; (11) Cleveland Clinic, Cleveland, Ohio, USA; (12) Boston Children’s Hospital, Harvard University, Boston, Massachusetts, USA; (13) NYU Langone Medical Center, New York, New York, USA; (14) The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA; (15) University of Oklahoma, Oklahoma City, Oklahoma, USA; (16) Cook’s Children’s Medical Center, Fort Worth, Texas, USA; (17) Orthopaedic Hospital Special Coagulation Laboratory, Los Angeles, California, USA

Keywords

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

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.

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