Inhibitor eradication in refractory acquired hemophilia with lenalidomide

  • C. PfrepperEmail author
  • W. Poenisch
  • M. Pierer
  • M. Metze
  • T. Kaiser
  • S. Petros
Letter to the Editor

Dear Editor,

Acquired hemophilia A (AHA) is a very rare disease caused by antibodies against factor VIII (FVIII). Standard treatment consists of steroids, cyclophosphamide, and rituximab. However, only 42–70% of all patients achieve long-term remission after first-line treatment [1, 2]. The optimal treatment of refractory AHA is still controversial.

We report on a 66-year-old male patient diagnosed with AHA after spontaneous spinal bleeding resulting in paraplegia. Initial FVIII activity was < 1% and the inhibitor titer 700 Bethesda units (BU). Before the diagnosis of AHA, he was healthy and not taking any medication. Diagnostic workup showed 0.75% atypical B cells in the bone marrow but no cytologic abnormalities and a regular male karyotype. Immunofixation was weakly positive for IgG kappa but serum electrophoresis and free light chains were normal. CT scan did not reveal any sign of an underlying disease and there was no evidence for a rheumatologic disorder.

Inhibitor eradication...


Compliance with ethical standards

Conflict of interest

The authors declared that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants performed by any of the authors.

Informed consent

Informed consent was obtained from the patient for being included in the study.


  1. 1.
    Tiede A, Klamroth R, Scharf RE, Trappe RU, Holstein K, Huth-Kuhne A, Gottstein S, Geisen U, Schenk J, Scholz U, Schilling K, Neumeister P, Miesbach W, Manner D, Greil R, von Auer C, Krause M, Leimkuhler K, Kalus U, Blumtritt JM, Werwitzke S, Budde E, Koch A, Knobl P (2015) Prognostic factors for remission of and survival in acquired hemophilia A (AHA). Results from the GTH-AH 01/2010 study. Blood 125(7):1091–1097. CrossRefGoogle Scholar
  2. 2.
    Collins P, Baudo F, Knoebl P, Levesque H, Nemes L, Pellegrini F, Marco P, Tengborn L, Huth-Kuhne A, on behalf of the EACH2 registry collaborators (2012) Immunosuppression for acquired hemophilia A. Results from the European Acquired Haemophilia Registry (EACH2). Blood 120(1):47–55. CrossRefGoogle Scholar
  3. 3.
    Brás GP, Pinto RJSM, Carvalho MMMC, Fernandes S, Andrade J, Guimarães J (2017) Bortezomib. Potential key role in the treatment of multiple myeloma-related acquired hemophilia a. Semin Thromb Hemost 43(1):109–112. Google Scholar
  4. 4.
    McFadyen JD, Tran H, Kaplan ZS (2017) Factor VIII inhibitor eradication with bortezomib in acquired haemophilia A. Br J Haematol 178(6):986–987. CrossRefGoogle Scholar
  5. 5.
    Pellom ST, Dudimah DF, Thounaojam MC et al (2015) Modulatory effects of bortezomib on host immune cell functions. Immunotherapy 7(9):1011–1022. CrossRefGoogle Scholar
  6. 6.
    Ratnasingam S, Walker PA, Tran H, Kaplan ZS, McFadyen JD, Tran H, Teh TC, Fleming S, Catalano JV, Chunilal SD, Johnston A, Opat SS, Shortt J (2016) Bortezomib-based antibody depletion for refractory autoimmune hematological diseases. Blood Adv 1(1):31–35. CrossRefGoogle Scholar
  7. 7.
    Alexander T, Sarfert R, Klotsche J, Kühl AA, Rubbert-Roth A, Lorenz HM, Rech J, Hoyer BF, Cheng Q, Waka A, Taddeo A, Wiesener M, Schett G, Burmester GR, Radbruch A, Hiepe F, Voll RE (2015) The proteasome inhibitior bortezomib depletes plasma cells and ameliorates clinical manifestations of refractory systemic lupus erythematosus. Ann Rheum Dis 74(7):1474–1478. CrossRefGoogle Scholar
  8. 8.
    Ichikawa HT, Conley T, Muchamuel T, Jiang J, Lee S, Owen T, Barnard J, Nevarez S, Goldman BI, Kirk CJ, Looney RJ, Anolik JH (2012) Beneficial effect of novel proteasome inhibitors in murine lupus via dual inhibition of type I interferon and autoantibody-secreting cells. Arthritis Rheum 64(2):493–503. CrossRefGoogle Scholar
  9. 9.
    Neuber B, Dai J, Waraich WA, Awwad MHS, Engelhardt M, Schmitt M, Medenhoff S, Witzens-Harig M, Ho AD, Goldschmidt H, Hundemer M (2017) Lenalidomide overcomes the immunosuppression of regulatory CD8+CD28- T-cells. Oncotarget 8(58):98200–98214. CrossRefGoogle Scholar
  10. 10.
    Zhang L, Bi E, Hong S, Qian J, Zheng C, Wang M, Yi Q (2015) CD4+ T cells play a crucial role for lenalidomide in vivo anti-tumor activity in murine multiple myeloma. Oncotarget 6(34):36032–36040. Google Scholar
  11. 11.
    Balaian E, Schuster C, Schönefeldt C, Germing U, Haase D, Tuve S, Ordemann R, Ehninger G, Bornhäuser M, Oelschlaegel U, Mohr B, von Bonin M, Platzbecker U, Wermke M (2016) Selective expansion of regulatory T cells during lenalidomide treatment of myelodysplastic syndrome with isolated deletion 5q. Ann Hematol 95(11):1805–1810. CrossRefGoogle Scholar
  12. 12.
    Lopez-Millan B, La Diaz de Guardia R, Roca-Ho H, García-Herrero CM, Lavoie JR, Rosu-Myles M, Gonzalez-Rey E, O'Valle F, Criado G, Delgado M, Menendez P (2017) Therapeutic effect of the immunomodulatory drug lenalidomide, but not pomalidomide, in experimental models of rheumatoid arthritis and inflammatory bowel disease. Exp Mol Med 49(2):e290. CrossRefGoogle Scholar
  13. 13.
    Wu EY, Schanberg LE, Wershba EC, Rabinovich CE (2017) Lenalidomide for refractory cutaneous manifestations of pediatric systemic lupus erythematosus. Lupus 26(6):646–649. CrossRefGoogle Scholar
  14. 14.
    Montefusco V, Galli M, Spina F, Stefanoni P, Mussetti A, Perrone G, de Philippis C, Dalto S, Maura F, Bonini C, Rezzonico F, Pennisi M, Roncari L, Soldarini M, Dodero A, Farina L, Cocito F, Caprioli C, Corradini P (2014) Autoimmune diseases during treatment with immunomodulatory drugs in multiple myeloma. Selective occurrence after lenalidomide. Leuk Lymphoma 55(9):2032–2037. CrossRefGoogle Scholar
  15. 15.
    Loree JM, Cai E, Sheffield BS, Dutz JP, Villa D, Shepherd LE, Connors JM, Sehn LH, Savage KJ (2017) Leukocytoclastic vasculitis following lenalidomide during the treatment of follicular lymphoma. Leuk Lymphoma 58(3):711–714. CrossRefGoogle Scholar
  16. 16.
    Saburi M, Ohtsuka E, Itani K, Nagamatsu K, Ikebe T, Miyazaki Y, Ogata M, Saburi Y (2015) Development of acquired hemophilia a during treatment of multiple myeloma with lenalidomide. Rinsho Ketsueki 56(5):496–500. Google Scholar
  17. 17.
    Braga WMT, da Silva BR, de Carvalho AC et al (2014) FOXP3 and CTLA4 overexpression in multiple myeloma bone marrow as a sign of accumulation of CD4(+) T regulatory cells. Cancer Immunol Immunother 63(11):1189–1197. CrossRefGoogle Scholar
  18. 18.
    Feyler S, von Lilienfeld-Toal M, Jarmin S, Marles L, Rawstron A, Ashcroft AJ, Owen RG, Selby PJ, Cook G (2009) CD4(+)CD25(+)FoxP3(+) regulatory T cells are increased whilst CD3(+)CD4(−)CD8(−)alphabetaTCR(+) double negative T cells are decreased in the peripheral blood of patients with multiple myeloma which correlates with disease burden. Br J Haematol 144(5):686–695. CrossRefGoogle Scholar
  19. 19.
    Saurwein-Teissl M, Lung TL, Marx F, Gschosser C, Asch E, Blasko I, Parson W, Bock G, Schonitzer D, Trannoy E, Grubeck-Loebenstein B (2002) Lack of antibody production following immunization in old age. Association with CD8+CD28- T cell clonal expansions and an imbalance in the production of Th1 and Th2 cytokines. J Immunol 168(11):5893–5899. CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Division of HemostaseologyUniversity Hospital LeipzigLeipzigGermany
  2. 2.Division of Hematology and Oncology LeipzigUniversity Hospital LeipzigLeipzigGermany
  3. 3.Division of RheumatologyUniversity Hospital LeipzigLeipzigGermany
  4. 4.Department of CardiologyUniversity Hospital LeipzigLeipzigGermany
  5. 5.Institute of Laboratory MedicineUniversity Hospital LeipzigLeipzigGermany

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