Published Ahead of Print on November 10, 2009, as doi:10.3324/haematol.2009.017749. Copyright 2009 Ferrata Storti Foundation.
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Successful eradication of acquired factor-VIII-inhibitor using single low-dose rituximab by Martin Wermke, Malte von Bonin, Siegmund Gehrisch, Gabriele Siegert, Gerhard Ehninger, and Uwe Platzbecker Haematologica 2009 [Epub ahead of print] doi:10.3324/haematol.2009.017749 Publisher's Disclaimer. E-publishing ahead of print is increasingly important for the rapid dissemination of science. Haematologica is, therefore, E-publishing PDF files of an early version of manuscripts that have completed a regular peer review and have been accepted for publication. E-publishing of this PDF file has been approved by the authors. This paper will now undergo editing, proof correction and final approval by the authors. Please note that during this production process changes may be made, and errors may be identified and corrected. The final version of the manuscript will appear both in the print and the online journal. All legal disclaimers that apply to the journal also pertain to this production process. Haematologica (pISSN: 0390-6078, eISSN: 1592-8721, NLM ID: 0417435, www.haematologica.org) publishes peer-reviewed papers across all areas of experimental and clinical hematology. The journal is owned by the Ferrata Storti Foundation, a non-profit organization, and serves the scientific community with strict adherence to the principles of open access publishing (www.doaj.org). In addition, the journal makes every paper published immediately available in PubMed Central (PMC), the US National Institutes of Health (NIH) free digital archive of biomedical and life sciences journal literature. Haematologica is the official organ of the European Hematology Association (www.ehaweb.org).
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LETTERS TO THE EDITOR Successful eradication of acquired factor-VIII inhibitor using single low-dose rituximab With great interest we read the recent recommendations regarding the treatment of acquired hemophilia A published in Haematologica1 and followed the subsequent discussion.2,3 The described treatment algorithm for this disease, which occurs at an incidence of 1.5/million/year,4 stresses the importance of early eradication of the acquired fVIII-inhibitor. Using prednisolone alone or in combination with cyclophosphamide, this approach will be successful in 30-50% of affected individuals.5 As Huth-Kühne pointed out, the CD20-antibody rituximab may be an attractive alternative in nonresponders or patients with contraindications to steroids.6 However, concerns have been raised because of rituximab side-effects including associations with progressive multifocal leukencephalopathy (PML).7 Furthermore, as Mannucci et al.2 emphasized, the use of this drug is hampered by its substantial costs. Restricting the administered dose to the lowest effective level, seems to be a reasonable strategy to minimize potential risks and costs of rituximab treatment. We report a 66-year old male AHA-patient successfully treated with single low-dose rituximab. The patient presented with multiple hematomas and severe anemia after recovering from a respiratory infection. Prolonged activated partial-thromboplastin-time (aPTT) in combination with undetectable fVIII-activity due to a fVIIIinhibitor was observed. History did neither reveal any prior hemorrhages nor a family history of bleeding. Clinical and imaging examinations could not reveal any pathological findings suggesting an idiopathic cause of AHA. Prednisolone (1 mg/kg) was started immediately and 2 units of packed red blood cells had to be administered. Afterwards, bleeding ceased correlating with an increase of fVIII-activity to 28%. Steroids were completely tapered over the next weeks and the patient was lost to follow-up. However, during the following year the patient experienced recurrent episodes of minor bleeding. Seventeen months after the first onset of AHA, he again presented at our institution for follow-up reporting of no spontaneous bleeding episodes, however with a fVIII-activity of 15% translating into a fVIII-inhibitor of 133 BU (Bethesda units). Another two months later, severe limb-bleeding requiring surgical treatment occurred after a minor accident. FVIII-inhibitor could still be detected at high levels (79 BU). Because of impaired wound-healing, steroids were deemed contraindicated. Therefore, inhibitor-eradication treatment was started with a single flat dose of 100 mg rituximab given our experiences in patients with auto-immune diseases other than AHA.8 Treatment was well tolerated and three weeks later complete B-cell depletion could be demonstrated (Figure 1). Significant bleeding did not reoccur and even an accident was tolerated without complications. At last presentation, nearly 10 months after rituximab-treatment, the patient had only a low residual fVIII-inhibitor activity, in spite of a normal Bcells count. FVIII-levels stabilized at a level of 15 to 20 % and aPTT was never found to be prolonged again after rituximab treatment
Figure 1. Clinical course overview. Time since diagnosis is given on the x-axis in months. Left y-axis shows fVIII-inhibitor titer in Bethesda-Units (BU), while B-cell-proportion is depicted in percent on the right y-axis. R corresponds to the time of rituximab application.
The clinical course of our patient demonstrates that complete B-cell depletion can be achieved with lowdose rituximab in AHA. We are aware that given the persistently low fVIII-level our patient does not meet the strict criteria for inhibitor eradication proposed by Huth-Kühne. On the other hand we have to acknowledge, that he experienced no further bleeding and had inhibitor-titers near the detection limit. We therefore believe that future clinical trials should incorporate this low-dose regimen rather than the classical lymphomadose (e.g. 375 mg/m2) in the treatment of both acquired hemophilia A. Martin Wermke,1 Malte von Bonin,1 Siegmund Gehrisch,2 Gabriele Siegert,2 Gerhard Ehninger,1 and Uwe Platzbecker1 1 Universitätsklinikum Carl-Gustav-Carus, Medizinische Klinik I, Fetscherstraße 74, 01307 Dresden, Germany; 2 Universitätsklinikum Carl-Gustav-Carus, Institut für Klinische Chemie und Laboratoriumsmedizin, Fetscherstraße 74, 01307 Dresden, Germany Key words: hemophilia A, partial-thromboplastin-time (aPTT), cyclophosphamide. Correspondence: Uwe Platzbecker, Universitätsklinikum Carl-Gustav-Carus, Medizinische Klinik I, Fetscherstraße 740 1307 Dresden, Germany. Phone: international +49.351.4582583. Fax: international +49.351.4584373. E-mail:
[email protected] Citation: Wermke M, von Bonin M, Gehrisch S, Siegert G, Ehninger G, and Platzbecker U. Successful eradication of acquired factor-VIII inhibitor using single low-dose rituximab. Haematologica 2009;94:XXX doi:10.3324/haematol.2009.017749 References 1. Huth-Kuhne A, Baudo F, Collins P, Ingerslev J, Kessler CM, Levesque H, et al. International recommendations on the diagnosis and treatment of patients with acquired hemophilia A. Haematologica. 2009;94(4):566-75. 2. Mannucci PM, Peyvandi F. Autoimmune hemophilia at rescue. Haematologica. 2009;94(4):459-61. 3. Huth-Kuhne A. Cautions and caveats to the treatment of acquired hemophilia A. Haematologica. 2009;94(8):11812. 4. Collins PW, Hirsch S, Baglin TP, Dolan G, Hanley J,
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Makris M, et al. Acquired hemophilia A in the United Kingdom: a 2-year national surveillance study by the United Kingdom Haemophilia Centre Doctors' Organisation. Blood. 2007;109(5):1870-7. 5. Green D, Rademaker AW, Briet E. A Prospective, Randomized Trial of Prednisone and Cyclophosphamide in the Treatment of Patients with Factor-Vii Autoantibodies. Thromb Haemost. 1993;70(5):753-7. 6. Franchini M. Rituximab in the treatment of adult acquired hemophilia A: A systematic review. Crit Rev Oncol Hematol. 2007;63(1):47-52.
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7. Carson KR, Evens AM, Richey EA, Habermann TM, Focosi D, Seymour JF, et al. Progressive multifocal leukoencephalopathy after rituximab therapy in HIVnegative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project. Blood. 2009;113(20):4834-40. 8. Von Bonin M, Oelschlagel U, Radke J, Stewart M, Ehninger G, Bornhauser M, et al. Treatment of chronic steroid-refractory graft-versus-host disease with lowdose rituximab. Transplantation. 2008;86(6):875-9.
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