Advertisement

Treatment of Autoimmune Hemolytic Anemia

  • Omar Niss
  • Russell E. WareEmail author
Chapter
First Online:

Abstract

Autoimmune hemolytic anemia (AIHA) is a relatively uncommon disorder, characterized by autoreactive antibodies directed against endogenous red blood cell antigens. AIHA caused by warm-reacting antibodies is the most common form, and half of these are idiopathic. Excluding secondary causes of AIHA is the first step in treatment decision-making. Treatment of AIHA is also dictated by the type of causative antibody, patient’s age, and comorbidities. Warm AIHA responds well to corticosteroids initially, but a second-line, steroid-sparing treatment is commonly needed. Rituximab, splenectomy, and immunosuppressive medications are used as second-line treatment options in warm AIHA; however, the optimal order of these therapies is not yet known. Cold AIHA is usually part of an underlying illness or disease, and does not respond well to steroids or splenectomy; and rituximab is the first-line treatment in adult forms of monoclonal cold agglutinin disease. In this chapter, we discuss the treatment approaches to different forms of AIHA and emphasize differences between adult and pediatric AIHA. We also discuss novel treatment approaches, especially for specific forms of secondary AIHA, highlighting how unraveling the genetic mechanisms of AIHA can lead to more precise and effective therapies that avoid toxicities.

Keywords

Autoreactive antibodies Idiopathic Primary Evans syndrome Common variable immune deficiency 
This is a preview of subscription content, log in to check access.

References

  1. 1.
    Miano M. How I manage Evans syndrome and AIHA cases in children. Br J Haematol. 2016;172(4):524–34.CrossRefPubMedGoogle Scholar
  2. 2.
    Zanella A, Barcellini W. Treatment of autoimmune hemolytic anemias. Haematologica. 2014;99(10):1547–54.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Aladjidi N, Leverger G, Leblanc T, Picat MQ, Michel G, Bertrand Y, et al. New insights into childhood autoimmune hemolytic anemia: a French national observational study of 265 children. Haematologica. 2011;96(5):655–63.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Barcellini W, Fattizzo B, Zaninoni A, Radice T, Nichele I, Di Bona E, et al. Clinical heterogeneity and predictors of outcome in primary autoimmune hemolytic anemia: a GIMEMA study of 308 patients. Blood. 2014;124(19):2930–6.CrossRefPubMedGoogle Scholar
  5. 5.
    Segel GB, Lichtman MA. Direct antiglobulin (“Coombs”) test-negative autoimmune hemolytic anemia: a review. Blood Cells Mol Dis. 2014;52(4):152–60.CrossRefPubMedGoogle Scholar
  6. 6.
    McGann PT, McDade J, Mortier NA, Combs MR, Ware RE. IgA-mediated autoimmune hemolytic anemia in an infant. Pediatr Blood Cancer. 2011;56(5):837–9.CrossRefPubMedGoogle Scholar
  7. 7.
    Go RS, Winters JL, Kay NE. How I treat autoimmune hemolytic anemia. Blood. 2017;129(22):2971–9.CrossRefPubMedGoogle Scholar
  8. 8.
    Lechner K, Jager U. How I treat autoimmune hemolytic anemias in adults. Blood. 2010;116(11):1831–8.CrossRefPubMedGoogle Scholar
  9. 9.
    Garratty G. Drug-induced immune hemolytic anemia. Hematol Am Soc Hematol Educ Prog. 2009:73–9.CrossRefGoogle Scholar
  10. 10.
    Borthakur G, O’Brien S, Wierda WG, Thomas DA, Cortes JE, Giles FJ, et al. Immune anaemias in patients with chronic lymphocytic leukaemia treated with fludarabine, cyclophosphamide and rituximab—incidence and predictors. Br J Haematol. 2007;136(6):800–5.CrossRefPubMedGoogle Scholar
  11. 11.
    Barcellini W. New insights in the pathogenesis of autoimmune hemolytic anemia. Transfus Med Hemother. 2015;42(5):287–93.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Fattizzo B, Zaninoni A, Nesa F, Sciumbata VM, Zanella A, Cortelezzi A, et al. Lessons from very severe, refractory, and fatal primary autoimmune hemolytic anemias. Am J Hematol. 2015;90(8):E149–51.CrossRefPubMedGoogle Scholar
  13. 13.
    Branch DR, Petz LD. Detecting alloantibodies in patients with autoantibodies. Transfusion. 1999;39(1):6–10.CrossRefPubMedGoogle Scholar
  14. 14.
    Petz LD. A physician’s guide to transfusion in autoimmune haemolytic anaemia. Br J Haematol. 2004;124(6):712–6.CrossRefPubMedGoogle Scholar
  15. 15.
    Kalfa TA. Warm antibody autoimmune hemolytic anemia. Hematol Am Soc Hematol Educ Prog. 2016;2016(1):690–7.Google Scholar
  16. 16.
    Birgens H, Frederiksen H, Hasselbalch HC, Rasmussen IH, Nielsen OJ, Kjeldsen L, et al. A phase III randomized trial comparing glucocorticoid monotherapy versus glucocorticoid and rituximab in patients with autoimmune haemolytic anaemia. Br J Haematol. 2013;163(3):393–9.CrossRefPubMedGoogle Scholar
  17. 17.
    Dussadee K, Taka O, Thedsawad A, Wanachiwanawin W. Incidence and risk factors of relapses in idiopathic autoimmune hemolytic anemia. J Med Assoc Thail. 2010;93(Suppl 1):S165–70.Google Scholar
  18. 18.
    Reynaud Q, Durieu I, Dutertre M, Ledochowski S, Durupt S, Michallet AS, et al. Efficacy and safety of rituximab in auto-immune hemolytic anemia: a meta-analysis of 21 studies. Autoimmun Rev. 2015;14(4):304–13.CrossRefPubMedGoogle Scholar
  19. 19.
    Dierickx D, Kentos A, Delannoy A. The role of rituximab in adults with warm antibody autoimmune hemolytic anemia. Blood. 2015;125(21):3223–9.CrossRefPubMedGoogle Scholar
  20. 20.
    Maung SW, Leahy M, O’Leary HM, Khan I, Cahill MR, Gilligan O, et al. A multi-centre retrospective study of rituximab use in the treatment of relapsed or resistant warm autoimmune haemolytic anaemia. Br J Haematol. 2013;163(1):118–22.CrossRefPubMedGoogle Scholar
  21. 21.
    Zecca M, Nobili B, Ramenghi U, Perrotta S, Amendola G, Rosito P, et al. Rituximab for the treatment of refractory autoimmune hemolytic anemia in children. Blood. 2003;101(10):3857–61.CrossRefPubMedGoogle Scholar
  22. 22.
    Barcellini W, Zaja F, Zaninoni A, Imperiali FG, Battista ML, Di Bona E, et al. Low-dose rituximab in adult patients with idiopathic autoimmune hemolytic anemia: clinical efficacy and biologic studies. Blood. 2012;119(16):3691–7.CrossRefPubMedGoogle Scholar
  23. 23.
    Jaime-Perez JC, Rodriguez-Martinez M, Gomez-de-Leon A, Tarin-Arzaga L, Gomez-Almaguer D. Current approaches for the treatment of autoimmune hemolytic anemia. Arch Immunol Ther Exp. 2013;61(5):385–95.CrossRefGoogle Scholar
  24. 24.
    Akpek G, McAneny D, Weintraub L. Comparative response to splenectomy in coombs-positive autoimmune hemolytic anemia with or without associated disease. Am J Hematol. 1999;61(2):98–102.CrossRefPubMedGoogle Scholar
  25. 25.
    Centers for Disease Control and Prevention. Epidemiology and prevention of vaccine-preventable diseases. In: Hamborsky J, Kroger A, Wolfe S, editors, 13th ed. Washington, DC: Public Health Foundation; 2015.Google Scholar
  26. 26.
    Neven B, Bruneau J, Stolzenberg MC, Meyts I, Magerus-Chatinet A, Moens L, et al. Defective anti-polysaccharide response and splenic marginal zone disorganization in ALPS patients. Blood. 2014;124(10):1597–609.CrossRefPubMedGoogle Scholar
  27. 27.
    Rao VK, Dugan F, Dale JK, Davis J, Tretler J, Hurley JK, et al. Use of mycophenolate mofetil for chronic, refractory immune cytopenias in children with autoimmune lymphoproliferative syndrome. Br J Haematol. 2005;129(4):534–8.CrossRefPubMedGoogle Scholar
  28. 28.
    Howard J, Hoffbrand AV, Prentice HG, Mehta A. Mycophenolate mofetil for the treatment of refractory auto-immune haemolytic anaemia and auto-immune thrombocytopenia purpura. Br J Haematol. 2002;117(3):712–5.CrossRefPubMedGoogle Scholar
  29. 29.
    Kotb R, Pinganaud C, Trichet C, Lambotte O, Dreyfus M, Delfraissy JF, et al. Efficacy of mycophenolate mofetil in adult refractory auto-immune cytopenias: a single center preliminary study. Eur J Haematol. 2005;75(1):60–4.CrossRefPubMedGoogle Scholar
  30. 30.
    Miano M, Scalzone M, Perri K, Palmisani E, Caviglia I, Micalizzi C, et al. Mycophenolate mofetil and Sirolimus as second or further line treatment in children with chronic refractory primitive or secondary autoimmune cytopenias: a single centre experience. Br J Haematol. 2015.Google Scholar
  31. 31.
    Acquazzino MA, Fischer RT, Langnas A, Coulter DW. Refractory autoimmune hemolytic anemia after intestinal transplant responding to conversion from a calcineurin to mTOR inhibitor. Pediatr Transplant. 2013;17(5):466–71.CrossRefPubMedGoogle Scholar
  32. 32.
    Valentini RP, Imam A, Warrier I, Ellis D, Ritchey AK, Ravindranath Y, et al. Sirolimus rescue for tacrolimus-associated post-transplant autoimmune hemolytic anemia. Pediatr Transplant. 2006;10(3):358–61.CrossRefPubMedGoogle Scholar
  33. 33.
    Miano M, Calvillo M, Palmisani E, Fioredda F, Micalizzi C, Svahn J, et al. Sirolimus for the treatment of multi-resistant autoimmune haemolytic anaemia in children. Br J Haematol. 2014;167(4):571–4.CrossRefPubMedGoogle Scholar
  34. 34.
    Bride KL, Vincent T, Smith-Whitley K, Lambert MP, Bleesing JJ, Seif AE, et al. Sirolimus is effective in relapsed/refractory autoimmune cytopenias: results of a prospective multi-institutional trial. Blood. 2016;127(1):17–28.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Teachey DT, Greiner R, Seif A, Attiyeh E, Bleesing J, Choi J, et al. Treatment with sirolimus results in complete responses in patients with autoimmune lymphoproliferative syndrome. Br J Haematol. 2009;145(1):101–6.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Flores G, Cunningham-Rundles C, Newland AC, Bussel JB. Efficacy of intravenous immunoglobulin in the treatment of autoimmune hemolytic anemia: results in 73 patients. Am J Hematol. 1993;44(4):237–42.CrossRefPubMedGoogle Scholar
  37. 37.
    Pignon JM, Poirson E, Rochant H. Danazol in autoimmune haemolytic anaemia. Br J Haematol. 1993;83(2):343–5.CrossRefPubMedGoogle Scholar
  38. 38.
    Moyo VM, Smith D, Brodsky I, Crilley P, Jones RJ, Brodsky RA. High-dose cyclophosphamide for refractory autoimmune hemolytic anemia. Blood. 2002;100(2):704–6.CrossRefPubMedGoogle Scholar
  39. 39.
    Passweg JR, Rabusin M. Hematopoetic stem cell transplantation for immune thrombocytopenia and other refractory autoimmune cytopenias. Autoimmunity. 2008;41(8):660–5.CrossRefPubMedGoogle Scholar
  40. 40.
    Snowden JA, Saccardi R, Allez M, Ardizzone S, Arnold R, Cervera R, et al. Haematopoietic SCT in severe autoimmune diseases: updated guidelines of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant. 2012;47(6):770–90.CrossRefPubMedGoogle Scholar
  41. 41.
    Khandelwal P, Davies SM, Grimley MS, Jordan MB, Curtis BR, Jodele S, et al. Bortezomib for refractory autoimmunity in pediatrics. Biol Blood Marrow Transplant. 2014;20(10):1654–9.CrossRefPubMedGoogle Scholar
  42. 42.
    Nader K, Patel M, Ferber A. Ofatumumab in rituximab-refractory autoimmune hemolytic anemia associated with chronic lymphocytic leukemia: a case report and review of literature. Clin Lymphoma Myeloma Leuk. 2013;13(4):511–3.CrossRefPubMedGoogle Scholar
  43. 43.
    Karageorgas T, Zomas A, Kazakou P, Katsimbri P, Mantzourani M, Boumpas D. Successful treatment of life-threatening autoimmune haemolytic anaemia with ofatumumab in a patient with systemic lupus erythematosus. Rheumatology (Oxford). 2016;55(11):2085–7.CrossRefGoogle Scholar
  44. 44.
    Ma K, Caplan S. Refractory IgG warm autoimmune hemolytic anemia treated with Eculizumab: a novel application of anticomplement therapy. Case Rep Hematol. 2016;2016:9181698.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Evans RS, Takahashi K, Duane RT, Payne R, Liu C. Primary thrombocytopenic purpura and acquired hemolytic anemia; evidence for a common etiology. AMA Arch Intern Med. 1951;87(1):48–65.CrossRefPubMedGoogle Scholar
  46. 46.
    Teachey DT, Manno CS, Axsom KM, Andrews T, Choi JK, Greenbaum BH, et al. Unmasking Evans syndrome: T-cell phenotype and apoptotic response reveal autoimmune lymphoproliferative syndrome (ALPS). Blood. 2005;105(6):2443–8.CrossRefPubMedGoogle Scholar
  47. 47.
    Norton A, Roberts I. Management of Evans syndrome. Br J Haematol. 2006;132(2):125–37.CrossRefPubMedGoogle Scholar
  48. 48.
    Michel M, Chanet V, Dechartres A, Morin AS, Piette JC, Cirasino L, et al. The spectrum of Evans syndrome in adults: new insight into the disease based on the analysis of 68 cases. Blood. 2009;114(15):3167–72.CrossRefPubMedGoogle Scholar
  49. 49.
    Bader-Meunier B, Aladjidi N, Bellmann F, Monpoux F, Nelken B, Robert A, et al. Rituximab therapy for childhood Evans syndrome. Haematologica. 2007;92(12):1691–4.CrossRefPubMedGoogle Scholar
  50. 50.
    Miano M, Ramenghi U, Russo G, Rubert L, Barone A, Tucci F, et al. Mycophenolate mofetil for the treatment of children with immune thrombocytopenia and Evans syndrome. A retrospective data review from the Italian association of paediatric haematology/oncology. Br J Haematol. 2016;175(3):490–5.CrossRefPubMedGoogle Scholar
  51. 51.
    Jasinski S, Weinblatt ME, Glasser CL. Sirolimus as an effective agent in the treatment of immune thrombocytopenia (ITP) and Evans syndrome (ES): a single Institution’s experience. J Pediatr Hematol Oncol. 2017;39(6):420–4.CrossRefPubMedGoogle Scholar
  52. 52.
    Mathew P, Chen G, Wang W. Evans syndrome: results of a national survey. J Pediatr Hematol Oncol. 1997;19(5):433–7.CrossRefPubMedGoogle Scholar
  53. 53.
    Oliveira JB, Bleesing JJ, Dianzani U, Fleisher TA, Jaffe ES, Lenardo MJ, et al. Revised diagnostic criteria and classification for the autoimmune lymphoproliferative syndrome (ALPS): report from the 2009 NIH International Workshop. Blood. 2010;116(14):e35–40.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Price S, Shaw PA, Seitz A, Joshi G, Davis J, Niemela JE, et al. Natural history of autoimmune lymphoproliferative syndrome associated with FAS gene mutations. Blood. 2014;123(13):1989–99.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Rao VK, Oliveira JB. How I treat autoimmune lymphoproliferative syndrome. Blood. 2011;118(22):5741–51.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Rao VK, Price S, Perkins K, Aldridge P, Tretler J, Davis J, et al. Use of rituximab for refractory cytopenias associated with autoimmune lymphoproliferative syndrome (ALPS). Pediatr Blood Cancer. 2009;52(7):847–52.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Walter JE, Farmer JR, Foldvari Z, Torgerson TR, Cooper MA. Mechanism-based strategies for the management of autoimmunity and immune dysregulation in primary immunodeficiencies. J Allergy Clin Immunol Pract. 2016;4(6):1089–100.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Gathmann B, Mahlaoui N, Ceredih, Gérard L, Oksenhendler E, Warnatz K, et al. Clinical picture and treatment of 2212 patients with common variable immunodeficiency. J Allergy Clin Immunol. 2014;134(1):116–26.CrossRefPubMedGoogle Scholar
  59. 59.
    Heeney MM, Zimmerman SA, Ware RE. Childhood autoimmune cytopenia secondary to unsuspected common variable immunodeficiency. J Pediatr. 2003;143(5):662–5.CrossRefPubMedGoogle Scholar
  60. 60.
    Gobert D, Bussel JB, Cunningham-Rundles C, Galicier L, Dechartres A, Berezne A, et al. Efficacy and safety of rituximab in common variable immunodeficiency-associated immune cytopenias: a retrospective multicentre study on 33 patients. Br J Haematol. 2011;155(4):498–508.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Gamez-Diaz L, August D, Stepensky P, Revel-Vilk S, Seidel MG, Noriko M, et al. The extended phenotype of LPS-responsive beige-like anchor protein (LRBA) deficiency. J Allergy Clin Immunol. 2016;137(1):223–30.CrossRefPubMedGoogle Scholar
  62. 62.
    Schubert D, Bode C, Kenefeck R, Hou TZ, Wing JB, Kennedy A, et al. Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nat Med. 2014;20(12):1410–6.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Lee S, Moon JS, Lee CR, Kim HE, Baek SM, Hwang S, et al. Abatacept alleviates severe autoimmune symptoms in a patient carrying a de novo variant in CTLA-4. J Allergy Clin Immunol. 2016;137(1):327–30.CrossRefPubMedGoogle Scholar
  64. 64.
    Lo B, Zhang K, Lu W, Zheng L, Zhang Q, Kanellopoulou C, et al. AUTOIMMUNE DISEASE. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy. Science. 2015;349(6246):436–40.CrossRefPubMedGoogle Scholar
  65. 65.
    Weinacht KG, Charbonnier LM, Alroqi F, Plant A, Qiao Q, Wu H, et al. Ruxolitinib reverses dysregulated T helper cell responses and controls autoimmunity caused by a novel signal transducer and activator of transcription 1 (STAT1) gain-of-function mutation. J Allergy Clin Immunol. 2017;139(5):1629–40.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Bader-Meunier B, Armengaud JB, Haddad E, Salomon R, Deschênes G, Koné-Paut I, et al. Initial presentation of childhood-onset systemic lupus erythematosus: a French multicenter study. J Pediatr. 2005;146(5):648–53.CrossRefPubMedGoogle Scholar
  67. 67.
    Roumier M, Loustau V, Guillaud C, Languille L, Mahevas M, Khellaf M, et al. Characteristics and outcome of warm autoimmune hemolytic anemia in adults: new insights based on a single-center experience with 60 patients. Am J Hematol. 2014;89(9):E150–5.CrossRefPubMedGoogle Scholar
  68. 68.
    Gomard-Mennesson E, Ruivard M, Koenig M, Woods A, Magy N, Ninet J, et al. Treatment of isolated severe immune hemolytic anaemia associated with systemic lupus erythematosus: 26 cases. Lupus. 2006;15(4):223–31.CrossRefPubMedGoogle Scholar
  69. 69.
    Kumar S, Benseler SM, Kirby-Allen M, Silverman ED. B-cell depletion for autoimmune thrombocytopenia and autoimmune hemolytic anemia in pediatric systemic lupus erythematosus. Pediatrics. 2009;123(1):e159–63.CrossRefPubMedGoogle Scholar
  70. 70.
    Olfat M, Silverman ED, Levy DM. Rituximab therapy has a rapid and durable response for refractory cytopenia in childhood-onset systemic lupus erythematosus. Lupus. 2015;24(9):966–72.CrossRefPubMedGoogle Scholar
  71. 71.
    Alba P, Karim MY, Hunt BJ. Mycophenolate mofetil as a treatment for autoimmune haemolytic anaemia in patients with systemic lupus erythematosus and antiphospholipid syndrome. Lupus. 2003;12(8):633–5.CrossRefPubMedGoogle Scholar
  72. 72.
    Mak A, Mok CC. Mycophenolate mofetil for refractory haemolytic anemia in systemic lupus erythematosus. Lupus. 2005;14(10):856–8.CrossRefPubMedGoogle Scholar
  73. 73.
    Swiecicki PL, Hegerova LT, Gertz MA. Cold agglutinin disease. Blood. 2013;122(7):1114–21.CrossRefPubMedGoogle Scholar
  74. 74.
    Berentsen S, Ulvestad E, Langholm R, Beiske K, Hjorth-Hansen H, Ghanima W, et al. Primary chronic cold agglutinin disease: a population based clinical study of 86 patients. Haematologica. 2006;91(4):460–6.PubMedGoogle Scholar
  75. 75.
    Berentsen S, Ulvestad E, Gjertsen BT, Hjorth-Hansen H, Langholm R, Knutsen H, et al. Rituximab for primary chronic cold agglutinin disease: a prospective study of 37 courses of therapy in 27 patients. Blood. 2004;103(8):2925–8.CrossRefPubMedGoogle Scholar
  76. 76.
    Berentsen S, Randen U, Vagan AM, Hjorth-Hansen H, Vik A, Dalgaard J, et al. High response rate and durable remissions following fludarabine and rituximab combination therapy for chronic cold agglutinin disease. Blood. 2010;116(17):3180–4.CrossRefPubMedGoogle Scholar
  77. 77.
    Berentsen S, Randen U, Oksman M, Birgens H, Tvedt THA, Dalgaard J, et al. Bendamustine plus rituximab for chronic cold agglutinin disease: results of a Nordic prospective multicenter trial. Blood. 2017;130(4):537–41.CrossRefPubMedGoogle Scholar
  78. 78.
    Carson KR, Beckwith LG, Mehta J. Successful treatment of IgM-mediated autoimmune hemolytic anemia with bortezomib. Blood. 2010;115(4):915.CrossRefPubMedGoogle Scholar
  79. 79.
    Roth A, Huttmann A, Rother RP, Duhrsen U, Philipp T. Long-term efficacy of the complement inhibitor eculizumab in cold agglutinin disease. Blood. 2009;113(16):3885–6.CrossRefPubMedGoogle Scholar
  80. 80.
    Wouters D, Stephan F, Strengers P, de Haas M, Brouwer C, Hagenbeeket A, et al. C1-esterase inhibitor concentrate rescues erythrocytes from complement-mediated destruction in autoimmune hemolytic anemia. Blood. 2013;121(7):1242–4.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division of Hematology, Department of PediatricsCincinnati Children’s Hospital Medical Center and University of Cincinnati College of MedicineCincinnatiUSA

Personalised recommendations

Cite chapter

Buy options