International Journal of Hematology

, Volume 93, Issue 6, pp 704–714 | Cite as

Chronic treatment of paroxysmal nocturnal hemoglobinuria patients with eculizumab: safety, efficacy, and unexpected laboratory phenomena

  • Alexander RöthEmail author
  • Christina Hock
  • Anna Konik
  • Sandra Christoph
  • Ulrich Dührsen
Original Article


The terminal complement inhibitor eculizumab has become the standard of treatment in patients with symptomatic paroxysmal nocturnal hemoglobinuria (PNH). In this retrospective study, 19 PNH patients received chronic therapy with eculizumab with a median duration of 16 months (range 6–46 months). Parameters of hemolysis, transfusion requirements, and serum iron parameters were analyzed. Lactate dehydrogenase levels were significantly decreased by 85% from a median of 1897 U/l (range 293–3360) to 283 U/l (range 143–667), with an 86% reduction of transfusion requirements, whereas other parameters of hemolysis remained abnormal. Six patients (31.6%) became completely transfusion independent. A significant increase in ferritin levels from a median of 104 μg/l before to a median of 528 μg/l (p = 0.011) during treatment with eculizumab was observed. This was more pronounced in patients with low reticulocyte production index and/or requiring blood transfusions. Monospecific direct Coombs test was positive in most PNH patients, indicating a shift to extravascular hemolysis. Positive immunofixation for IgG kappa was observed, due to the presence of eculizumab in the serum. Eculizumab was safe and well tolerated long term in our study population. Iron should not be routinely supplemented in PNH patients treated with eculizumab without close monitoring of iron parameters, and iron depletion therapy should be considered in the case of overload.


PNH Eculizumab Terminal complement inhibitor Iron homeostasis Immunofixation 



We thank Margret Gottlieb, Barbara Friedman, and Ute Schmücker for their expert technical assistance.

Conflict of interest

Lecture fees was given from Alexion Pharmaceuticals to A.R. and U.D. A.R. served on advisory boards for Alexion Pharmaceuticals. The authors have no other relevant conflicts of interest.


  1. 1.
    Parker C, Omine M, Richards S, Nishimura J, Bessler M, Ware R, et al. Diagnosis and management of paroxysmal nocturnal hemoglobinuria. Blood. 2005;106:3699–709.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Hillmen P, Lewis SM, Bessler M, Luzzatto L, Dacie JV. Natural history of paroxysmal nocturnal hemoglobinuria. N Engl J Med. 1995;333:1253–8.CrossRefPubMedGoogle Scholar
  3. 3.
    de Latour RP, Mary JY, Salanoubat C, Terriou L, Etienne G, Mohty M, et al. Paroxysmal nocturnal hemoglobinuria: natural history of disease subcategories. Blood. 2008;112:3099–106.CrossRefPubMedGoogle Scholar
  4. 4.
    Parker CJ. Molecular basis of paroxysmal nocturnal hemoglobinuria. Stem Cells. 1996;14:396–411.CrossRefPubMedGoogle Scholar
  5. 5.
    Yamashina M, Ueda E, Kinoshita T, Takami T, Ojima A, Ono H, et al. Inherited complete deficiency of 20-kilodalton homologous restriction factor (CD59) as a cause of paroxysmal nocturnal hemoglobinuria. N Engl J Med. 1990;323:1184–9.CrossRefPubMedGoogle Scholar
  6. 6.
    Motoyama N, Okada N, Yamashina M, Okada H. Paroxysmal nocturnal hemoglobinuria due to hereditary nucleotide deletion in the HRF20 (CD59) gene. Eur J Immunol. 1992;22:2669–73.CrossRefPubMedGoogle Scholar
  7. 7.
    Takeda J, Miyata T, Kawagoe K, Iida Y, Endo Y, Fujita T, et al. Deficiency of the GPI anchor caused by a somatic mutation of the PIG-A gene in paroxysmal nocturnal hemoglobinuria. Cell. 1993;73:703–11.CrossRefPubMedGoogle Scholar
  8. 8.
    Bessler M, Mason PJ, Hillmen P, Miyata T, Yamada N, Takeda J, et al. Paroxysmal nocturnal haemoglobinuria (PNH) is caused by somatic mutations in the PIG-A gene. EMBO J. 1994;13:110–7.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Rother RP, Bell L, Hillmen P, Gladwin MT. The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease. JAMA. 2005;293:1653–62.CrossRefPubMedGoogle Scholar
  10. 10.
    Rosse WF, Nishimura J. Clinical manifestations of paroxysmal nocturnal hemoglobinuria: present state and future problems. Int J Hematol. 2003;77:113–20.CrossRefPubMedGoogle Scholar
  11. 11.
    Thomas TC, Rollins SA, Rother RP, Giannoni MA, Hartman SL, Elliott EA, et al. Inhibition of complement activity by humanized anti-C5 antibody and single-chain Fv. Mol Immunol. 1996;33:1389–401.CrossRefPubMedGoogle Scholar
  12. 12.
    Hillmen P, Young NS, Schubert J, Brodsky RA, Socie G, Muus P, et al. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2006;355:1233–43.CrossRefPubMedGoogle Scholar
  13. 13.
    Brodsky RA, Young NS, Antonioli E, Risitano AM, Schrezenmeier H, Schubert J, et al. Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Blood. 2008;111:1840–7.CrossRefPubMedGoogle Scholar
  14. 14.
    Schubert J, Hillmen P, Röth A, Young NS, Elebute MO, Szer J, et al. Eculizumab, a terminal complement inhibitor, improves anaemia in patients with paroxysmal nocturnal haemoglobinuria. Br J Haematol. 2008;142:263–72.CrossRefPubMedGoogle Scholar
  15. 15.
    Risitano AM, Notaro R, Marando L, Serio B, Ranaldi D, Seneca E, et al. Complement fraction 3 binding on erythrocytes as additional mechanism of disease in paroxysmal nocturnal hemoglobinuria patients treated by eculizumab. Blood. 2009;113:4094–100.CrossRefPubMedGoogle Scholar
  16. 16.
    Oelschlaegel U, Besson I, Arnoulet C, Sainty D, Nowak R, Naumann R, et al. A standardized flow cytometric method for screening paroxysmal nocturnal haemoglobinuria (PNH) measuring CD55 and CD59 expression on erythrocytes and granulocytes. Clin Lab Haematol. 2001;23:81–90.CrossRefPubMedGoogle Scholar
  17. 17.
    Sutherland DR, Kuek N, Davidson J, Barth D, Chang H, Yeo E, et al. Diagnosing PNH with FLAER and multiparameter flow cytometry. Cytom B Clin Cytom. 2007;72:167–77.CrossRefGoogle Scholar
  18. 18.
    Risitano AM, Marando L, Seneca E, Rotoli B. Hemoglobin normalization after splenectomy in a paroxysmal nocturnal hemoglobinuria patient treated by eculizumab. Blood. 2008;112:449–51.CrossRefPubMedGoogle Scholar
  19. 19.
    Röth A, Peine S, Dührsen U. Paroxysmal nocturnal hemoglobinuria turning Coombs-positive. Int J Hematol. 2010;91:159–60.CrossRefPubMedGoogle Scholar
  20. 20.
    Hill A, Rother RP, Arnold L, Kelly R, Cullen MJ, Richards SJ, et al. Eculizumab prevents intravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria and unmasks low-level extravascular hemolysis occurring through C3 opsonization. Haematologica. 2010;95:567–73.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Röth A, Dührsen U, Schrezenmeier H, Schubert J. Paroxysmal nocturnal hemoglobinuria (PNH). Dtsch Med Wochenschr. 2009;134:404–9.CrossRefPubMedGoogle Scholar
  22. 22.
    Hillmen P, Muus P, Dührsen U, Risitano AM, Schubert J, Luzzatto L, et al. Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria. Blood. 2007;110:4123–8.CrossRefPubMedGoogle Scholar
  23. 23.
    Pettigrew HD, Teuber SS, Gershwin ME. Clinical significance of complement deficiencies. Ann N Y Acad Sci. 2009;1173:108–23.CrossRefPubMedGoogle Scholar
  24. 24.
    Thompson MJ, Ninis N, Perera R, Mayon-White R, Phillips C, Bailey L, et al. Clinical recognition of meningococcal disease in children and adolescents. Lancet. 2006;367:397–403.CrossRefPubMedGoogle Scholar
  25. 25.
    Hillmen P, Elebute M, Kelly R, Urbano-Ispizua A, Hill A, Rother RP, et al. Long-term effect of the complement inhibitor eculizumab on kidney function in patients with paroxysmal nocturnal hemoglobinuria. Am J Hematol. 2010;85:553–9.CrossRefPubMedGoogle Scholar
  26. 26.
    Hill A, Rother RP, Wang X, Morris SM Jr, Quinn-Senger K, Kelly R, et al. Effect of eculizumab on haemolysis-associated nitric oxide depletion, dyspnoea, and measures of pulmonary hypertension in patients with paroxysmal nocturnal haemoglobinuria. Br J Haematol. 2010;149:414–25.CrossRefPubMedGoogle Scholar
  27. 27.
    Kelly RJ, Hill A, Mitchell LD, Richards SJ, Arnold LM, Valters GL, et al. Long term treatment with eculizumab in paroxysmal nocturnal hemoglobinuria (PNH): sustained efficacy and improved survival. ASH Annu Meet Abstr. 2010;116:639.Google Scholar
  28. 28.
    Dacie JV, Lewis SM. Paroxysmal nocturnal haemoglobinuria: clinical manifestations, haematology, and nature of the disease. Ser Haematol. 1972;5:3–23.PubMedGoogle Scholar
  29. 29.
    Rosse WF. Treatment of paroxysmal nocturnal hemoglobinuria. Blood. 1982;60:20–3.PubMedGoogle Scholar
  30. 30.
    Hartmann RC, Jenkins DE Jr, McKee LC, Heyssel RM. Paroxysmal nocturnal hemoglobinuria: clinical and laboratory studies relating to iron metabolism and therapy with androgen and iron. Medicine (Baltimore). 1966;45:331–63.CrossRefGoogle Scholar
  31. 31.
    Röth A, Hüttmann A, Rother RP, Dührsen U, Philipp T. Long-term efficacy of the complement inhibitor eculizumab in cold agglutinin disease. Blood. 2009;113:3885–6.CrossRefPubMedGoogle Scholar
  32. 32.
    Kelly R, Richards S, Arnold L, Valters G, Cullen M, Hill A, et al. A spontaneous reduction of clone size in paroxysmal nocturnal hemoglobinuria patients treated with eculizumab for greater than 12 months. ASH Annu Meet Abstr. 2009;114:1992.Google Scholar
  33. 33.
    Nürnberger J, Philipp T, Witzke O, Opazo SA, Vester U, Baba HA, et al. Eculizumab for atypical hemolytic-uremic syndrome. N Engl J Med. 2009;360:542–4.CrossRefPubMedGoogle Scholar
  34. 34.
    Gruppo RA, Rother RP. Eculizumab for congenital atypical hemolytic-uremic syndrome. N Engl J Med. 2009;360:544–6.CrossRefPubMedGoogle Scholar
  35. 35.
    Locke JE, Magro CM, Singer AL, Segev DL, Haas M, Hillel AT, et al. The use of antibody to complement protein C5 for salvage treatment of severe antibody-mediated rejection. Am J Transplant. 2009;9:231–5.CrossRefPubMedGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2011

Authors and Affiliations

  • Alexander Röth
    • 1
    Email author
  • Christina Hock
    • 1
  • Anna Konik
    • 1
  • Sandra Christoph
    • 1
  • Ulrich Dührsen
    • 1
  1. 1.Department of HematologyUniversity Hospital EssenEssenGermany

Personalised recommendations