SpringerLink
Log in

Cold-antibody Autoimmune Hemolytic Anemia: its Association with Neoplastic Disease and Impact on Therapy

  • REVIEW
  • Published:
Current Oncology Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Cold-antibody mediated autoimmune hemolytic anemia (cAIHA) is subclassified as cold agglutinin disease (CAD), secondary cold agglutinin syndrome (CAS), and paroxysmal cold hemoglobinuria (PCH). This review aims to address the occurrence of neoplastic disorders with these three entities and analyze the impact of such neoplasias on treatment for cAIHA.

Recent Findings

“Primary” CAD is a distinct clonal B-cell lymphoproliferative disorder in probably all cases, although not classified as a malignant lymphoma. CAS is secondary to malignant lymphoma in a minority of cases. Recent findings allow a further clarification of these differential diagnoses and the therapeutic consequences of specific neoplastic entities.

Summary

Appropriate diagnostic workup is critical for therapy in cAIHA. Patients with CAD should be treated if they have symptomatic anemia, significant fatigue, or bothersome circulatory symptoms. The distinction between CAD and CAS and the presence of any underlying malignancy in CAS have essential therapeutic implications.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Copyright: Ferrata Storti Foundation

Fig. 3
Fig. 4

Copyright: The American Society of Hematology

Similar content being viewed by others

References

  1. • Jäger U, Barcellini W, Broome CM, Gertz MA, Hill A, Hill QA, et al. Diagnosis and treatment of autoimmune hemolytic anemia in adults: Recommendations from the First International Consensus Meeting. Blood Rev. 2020;41:100648. Comprehensive review on AIHA, first international consensus on diagnosis and treatment.

  2. Berentsen S, Barcellini W. Autoimmune Hemolytic Anemias. N Engl J Med. 2021;385:1407–19.

    Article  CAS  PubMed  Google Scholar 

  3. 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;124:2930–6.

    Article  CAS  PubMed  Google Scholar 

  4. Dacie J. The auto-immune haemolytic anaemias: introduction. In: Dacie J, editor. The Haemolytic Anaemias, vol. 3. London: Churchill Livingstone; 1992. p. 1–5.

    Google Scholar 

  5. Sokol RJ, Hewitt S, Stamps BK. Autoimmune haemolysis: an 18-year study of 865 cases referred to a regional transfusion centre. Br Med J (Clin Res Ed). 1981;282:2023–7.

    Article  CAS  PubMed  Google Scholar 

  6. Schubothe H. The cold hemagglutinin disease. Semin Hematol. 1966;3:27–47.

    CAS  PubMed  Google Scholar 

  7. Berentsen S, Tjønnfjord GE. Diagnosis and treatment of cold agglutinin mediated autoimmune hemolytic anemia. Blood Rev. 2012;26:107–15.

    Article  CAS  PubMed  Google Scholar 

  8. Hill QA, Hill A, Berentsen S. Defining autoimmune hemolytic anemia: a systematic review of the terminology used for diagnosis and treatment. Blood Adv. 2019;3:1897–906.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Shanbhag S, Spivak J. Paroxysmal cold hemoglobinuria. Hematol Oncol Clin North Am. 2015;29:473–8.

    Article  PubMed  Google Scholar 

  10. • Jacobs JW, Figueroa Villalba CA, Booth GS, Woo JS, Stephens LD, Adkins BD. Clinical and epidemiological features of paroxysmal cold hemoglobinuria: a systematic review. Blood Adv. 2023;7:2520-7. Recent review of all published cases of PCH, providing new data on an ultra-rare disease.

  11. Berentsen S, Fattizzo B, Barcellini W. The choice of new treatments in autoimmune hemolytic anemia: How to pick from the basket? Front Immunol. 2023;14:1180509.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Liesveld JL, Rowe JM, Lichtman MA. Variability of the erythropoietic response in autoimmune hemolytic anemia: analysis of 109 cases. Blood. 1987;69:820–6.

    Article  CAS  PubMed  Google Scholar 

  13. Coombs RR, Mourant AE, Race RR. A new test for the detection of weak and incomplete Rh agglutinins. Br J Exp Pathol. 1945;26:255–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Meulenbroek EM, de Haas M, Brouwer C, Folman C, Zeerleder SS, Wouters D. Complement deposition in autoimmune hemolytic anemia is a footprint for difficult-to-detect IgM autoantibodies. Haematologica. 2015;100:1407–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Berentsen S. Complement activation and inhibition in autoimmune hemolytic anemia: Focus on cold agglutinin disease. Semin Hematol. 2018;55:141–9.

    Article  PubMed  Google Scholar 

  16. Berentsen S. How I treat cold agglutinin disease. Blood. 2021;137:1295–303.

    Article  CAS  PubMed  Google Scholar 

  17. Rosse WF, Adams JP. The variability of hemolysis in the cold agglutinin syndrome. Blood. 1980;56:409–16.

    Article  CAS  PubMed  Google Scholar 

  18. Ulvestad E, Berentsen S, Bø K, Shammas FV. Clinical immunology of chronic cold agglutinin disease. Eur J Haematol. 1999;63:259–66.

    Article  CAS  PubMed  Google Scholar 

  19. Berentsen S, Röth A, Randen U, Jilma B, Tjønnfjord GE. Cold agglutinin disease: current challenges and further prospects. J Blood Med. 2019;10:93–103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Guenther A, Tierens A, Malecka A, Delabie J. The histopathology of cold agglutinin disease-associated B-Cell lymphoproliferative disease. Am J Clin Pathol. 2023;160:229–37.

    Article  CAS  PubMed  Google Scholar 

  21. •• Berentsen S, Barcellini W, D'Sa S, Randen U, Tvedt THA, Fattizzo B, et al. Cold agglutinin disease revisited: a multinational, observational study of 232 patients. Blood. 2020;136:480-8. The largest observational study of patients with confirmed CAD. Pivotal data on interpretation of biopsy findings. Long-term follow-up data from 2 prosepctive trials.

  22. Hansen DL, Berentsen S, Fattizzo B, Hansen PL, Barcellini W, Frederiksen H. Seasonal variation in the incidence of cold agglutinin disease in Norway, Denmark, and Italy. Am J Hematol. 2021;96:E262–5.

    Article  CAS  PubMed  Google Scholar 

  23. •• Randen U, Trøen G, Tierens A, Steen C, Warsame A, Beiske K, et al. Primary cold agglutinin-associated lymphoproliferative disease: a B-cell lymphoma of the bone marrow distinct from lymphoplasmacytic lymphoma. Haematologica. 2014;99:497-504. First description of CAD-associated lymphoproliferative disorder.

  24. Naresh KN, Rossi D, Chen X, Berentsen S, Randen U. Cold agglutinin disease. WHO Classification of Haematolymphoid Tumours, 5th Edition. Lyon: International Agency for Research on Cancer; 2022. p. 349. Online version available at https://tumourclassification.iarc.who.int/chaptercontent/63/.

  25. Harboe M, van Furth R, Schubothe H, Lind K, Evans RS. Exclusive occurrence of K chains in isolated cold haemagglutinins. Scand J Haematol. 1965;2:259–66.

    Article  CAS  PubMed  Google Scholar 

  26. 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;91:460–6.

    PubMed  Google Scholar 

  27. Jaffe CJ, Atkinson JP, Frank MM. The role of complement in the clearance of cold agglutinin-sensitized erythrocytes in man. J Clin Invest. 1976;58:942–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Shi J, Rose EL, Singh A, Hussain S, Stagliano NE, Parry GC, et al. TNT003, an inhibitor of the serine protease C1s, prevents complement activation induced by cold agglutinins. Blood. 2014;123:4015–22.

    Article  CAS  PubMed  Google Scholar 

  29. Berentsen S. Sutimlimab for the treatment of cold agglutinin disease. Hemasphere. 2023;7:e879.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Röth A, Bommer M, Hüttmann A, Herich-Terhurne D, Kuklik N, Rekowski J, et al. Eculizumab in cold agglutinin disease (DECADE): an open-label, prospective, bicentric, nonrandomized phase 2 trial. Blood Adv. 2018;2:2543–9.

    Article  PubMed  PubMed Central  Google Scholar 

  31. •• Röth A, Barcellini W, D'Sa S, Miyakawa Y, Broome CM, Michel M, et al. Sutimlimab in Cold Agglutinin Disease. N Engl J Med. 2021;384:1323-34. Pivotal paper on complement inhibition with sutimlimab in cold agglutinin disease.

  32. Berentsen S. New insights in the pathogenesis and therapy of cold agglutinin-mediated autoimmune hemolytic anemia. Front Immunol. 2020;11:590. https://doi.org/10.3389/fimmu.2020.00590.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Joly F, Schmitt LA, Watson PAM, Pain E, Testa D. The burden of cold agglutinin disease on patients’ daily life: Web-based cross-sectional survey of 50 American patients. JMIR Form Res. 2022;6:e34248.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Broome CM, Cunningham JM, Mullins M, Jiang X, Bylsma LC, Fryzek JP, et al. Increased risk of thrombotic events in cold agglutinin disease: A 10-year retrospective analysis. Res Pract Thromb Haemost. 2020;. https://doi.org/10.1002/rth2.12333:928.

  35. Kamesaki T, Nishimura JI, Wada H, Yu E, Tsao E, Morales J, et al. Demographic characteristics, thromboembolism risk, and treatment patterns for patients with cold agglutinin disease in Japan. Int J Hematol. 2020;112:307–15.

    Article  CAS  PubMed  Google Scholar 

  36. Dacie J. Auto-immune haemolytic anaemia (AIHA): cold-antibody syndromes I: idiopathic types: clinical presentation and haematological and serological findings. In: Dacie J, editor. The Haemolytic Anaemias, vol. 3. London: Churchill Livingstone; 1992. p. 210–39.

    Google Scholar 

  37. Khwaja J, D’Sa S, Minnema MC, Kersten MJ, Wechalekar A, Vos JM. IgM monoclonal gammopathies of clinical significance: diagnosis and management. Haematologica. 2022;107:2037–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Crisp D, Pruzanski W. B-cell neoplasms with homogeneous cold-reacting antibodies (cold agglutinins). Am J Med. 1982;72:915–22.

    Article  CAS  PubMed  Google Scholar 

  39. Linz DH, Tolle SW, Elliot DL. Mycoplasma pneumoniae pneumonia. Experience at a referral center. West J Med. 1984;140:895–900.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Dacie J. Auto-immune haemolytic anaemia (AIHA): cold-antibody syndromes III: haemolytic anaemia following mycoplasma pneumonia. In: Dacie J, editor. The Haemolytic Anaemias, vol. 3. London: Churchill Livingstone; 1992. p. 296–312.

    Google Scholar 

  41. Quinn R, Murakhovskaya I. SARS-CoV-2 and Autoimmune Cytopenia. Hemato. 2021;2:463–76.

    Article  Google Scholar 

  42. Zagorski E, Pawar T, Rahimian S, Forman D. Cold agglutinin autoimmune haemolytic anaemia associated with novel coronavirus (COVID-19). Br J Haematol. 2020;190:e183–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Fattizzo B, Giannotta JA, Cecchi N, Barcellini W. SARS-CoV-2 vaccination in patients with autoimmune cytopenias: The experience of a reference center. Am J Hematol. 2021;96:E413–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Perez-Lamas L, Moreno-Jimenez G, Tenorio-Nunez MC, Velazquez-Kennedy K, Jimenez-Chillon C, Astibia-Mahillo B, et al. Hemolytic crisis due to Covid-19 vaccination in a woman with cold agglutinin disease. Am J Hematol. 2021;96:E288–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Dacie J. Auto-immune haemolytic anaemia (AIHA): cold-antibody syndromes IV: haemolytic anemia following infectious mononucleosis annd other viral infections. In: Dacie J, editor. The Haemolytic Anaemias, vol. 3. London: Churchill Livingstone; 1992. p. 313–28.

    Google Scholar 

  46. Niainle F, Hamnvik OP, Gulmann C, Bermingham C, Kelly J, Mc Evoy P, et al. Diffuse large B-cell lymphoma with isolated bone marrow involvement presenting with secondary cold agglutinin disease. Int J Lab Hematol. 2008;30:444–5.

    Article  CAS  PubMed  Google Scholar 

  47. Wongsaengsak S, Czader M, Suvannasankha A. Cold agglutinin-mediated autoimmune haemolytic anaemia associated with diffuse large B cell lymphoma. BMJ Case Rep. 2018;2018.

  48. Chen M, Abedi M. Atypical lymphocytosis, cold agglutinin hemolytic anemia, and monoclonal gammopathy in an HIV patient with marrow involvement by diffuse large B-cell lymphoma. Blood. 2013;122:3711.

    Article  PubMed  Google Scholar 

  49. Eskazan AE, Akmurad H, Ongoren S, Ozer O, Ferhanoglu B. Primary gastrointestinal diffuse large B cell lymphoma presenting with cold agglutinin disease. Case Rep Gastroenterol. 2011;5:262–6.

    Article  PubMed  PubMed Central  Google Scholar 

  50. • Jalink M, Berentsen S, Castillo JJ, Treon SP, Cruijsen M, Fattizzo B, et al. Effect of ibrutinib treatment on hemolytic anemia and acrocyanosis in cold agglutinin disease/cold agglutinin syndrome. Blood. 2021;138:2002-5. First systematic study on Bruton tyrosine kinase inhibitor therapy for CAD and CAS.

  51. Tanaka H, Hashimoto S, Sugita Y, Sakai S, Takeda Y, Abe D, et al. Occurrence of lymphoplasmacytic lymphoma 6 years after amelioration of primary cold agglutinin disease by rituximab therapy. Int J Hematol. 2012;96:501–5.

    Article  PubMed  Google Scholar 

  52. Diebold J, Reynes M, Tricot G, Zafrani E, Weill B, Dao C, et al. Splenic lympho-plasmocytic sarcomas discovered by exploratory laparotomy in 2 cases of cold agglutinin disease. Sem Hop. 1978;54:1325–30.

    CAS  PubMed  Google Scholar 

  53. Al Matham K, Alabed I, Zaidi SZ, Qushmaq KA. Cold agglutinin disease in fibrolamellar hepatocellular carcinoma: a rare association with a rare cancer variant. Ann Saudi Med. 2011;31:197–200.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Carlsson J, Batge R, Rahlf G, Tebbe U. Cold agglutinin disease and metastatic melanoma. Med Klin (Munich). 1994;89:343–5.

    CAS  PubMed  Google Scholar 

  55. Dacie J. Haemolytic anaemias associated with malignant lymphomas other than Hodgkin’s disease and chronic lymphocytic leukaemia (CLL). In: Dacie J, editor. The Haemolytic Anaemias, vol. 4. London: Churchill Livingstone; 1995. p. 27–40.

    Google Scholar 

  56. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al. WHO classification of tumours of haematopoietic and lymphoid tissues, 4th Ed. Lyon: International Agency for Research on Cancer; 2017.

  57. Swiecicki PL, Hegerova LT, Gertz MA. Cold agglutinin disease. Blood. 2013;122:1114–21.

    Article  CAS  PubMed  Google Scholar 

  58. Treon SP, Xu L, Yang G, Zhou Y, Liu X, Cao Y, et al. MYD88 L265P somatic mutation in Waldenstrom’s macroglobulinemia. N Engl J Med. 2012;367:826–33.

    Article  CAS  PubMed  Google Scholar 

  59. Owen RG, Rawstron A, de Tute RM. Waldenström Macroglobulinaemia: Pathological Features and Diagnostic Assessment. In: Leblond V, Treon S, Dimopoulos M, editors. Waldenström’s Macroglobulinemia. Switzerland: Springer International Publishing; 2017. p. 3–19.

    Chapter  Google Scholar 

  60. Malecka A, Troen G, Tierens A, Ostlie I, Malecki J, Randen U, et al. Frequent somatic mutations of KMT2D (MLL2) and CARD11 genes in primary cold agglutinin disease. Br J Haematol. 2018;183:838–42.

    Article  CAS  PubMed  Google Scholar 

  61. Donath J, Landsteiner K. Ueber Paroxysmale Hämoglobinurie. Münchener medizinische Wochenschrift. 1904;36:1590–3.

    Google Scholar 

  62. Lau-Braunhut SA, Stone H, Collins G, Berentsen S, Braun BS, Zinter MS. Paroxysmal cold hemoglobinuria successfully treated with complement inhibition. Blood Adv. 2019;3:3575–8.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Barcellini W, Broome CM, Berentsen S. Fast facts: Cold Agglutinin Disease. Abingdon, UK: S. Karger Publishers Ltd; 2023.

    Book  Google Scholar 

  64. Berentsen S. How I manage patients with cold agglutinin disease. Br J Haematol. 2018;181:320–30.

    Article  PubMed  Google Scholar 

  65. Dacie J. Treatment and prognosis of cold-antibody AIHA. In: Dacie J, editor. The Haemolytic Anaemias, vol. 3. London: Churchill Livingstone; 1992. p. 502–20.

    Google Scholar 

  66. Murakhovskaya I. Rituximab Use in Warm and Cold Autoimmune Hemolytic Anemia. J Clin Med. 2020;9. https://doi.org/10.3390/jcm9124034.

  67. 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;103:2925–8.

    Article  CAS  PubMed  Google Scholar 

  68. Schöllkopf C, Kjeldsen L, Bjerrum OW, Mourits-Andersen HT, Nielsen JL, Christensen BE, et al. Rituximab in chronic cold agglutinin disease: a prospective study of 20 patients. Leuk Lymphoma. 2006;47:253–60.

    Article  PubMed  Google Scholar 

  69. Berentsen S, Randen U, Vågan 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;116:3180–4.

    Article  CAS  PubMed  Google Scholar 

  70. •• 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;130:537-41. Prosepctive trial of rituximab plus bendamustine combination therapy in CAD.

  71. Rossi G, Gramegna D, Paoloni F, Fattizzo B, Binda F, D’Adda M, et al. Short course of bortezomib in anemic patients with relapsed cold agglutinin disease: a phase 2 prospective GIMEMA study. Blood. 2018;132:547–50.

    Article  CAS  PubMed  Google Scholar 

  72. Yao M, Zhang J, Li Y, Lv L, Jia L, Yang C, et al. Combination of low-dose rituximab, bortezomib and dexamethasone for the treatment of autoimmune hemolytic anemia. Medicine (Baltimore). 2022;101:e28679.

    Article  CAS  PubMed  Google Scholar 

  73. Fadlallah J, Michel M, Crickx E, Limal N, Costedoat N, Malphettes M, et al. Bortezomib and dexamethasone, an original approach for treating multi-refractory warm autoimmune haemolytic anaemia. Br J Haematol. 2019;187:124–8.

    Article  CAS  PubMed  Google Scholar 

  74. Winter O, Dame C, Jundt F, Hiepe F. Pathogenic long-lived plasma cells and their survival niches in autoimmunity, malignancy, and allergy. J Immunol. 2012;189:5105–11.

    Article  CAS  PubMed  Google Scholar 

  75. El-Ayoubi A, Wang JQ, Hein N, Talaulikar D. Role of plasma cells in Waldenstrom macroglobulinaemia. Pathology. 2017;49:337–45.

    Article  CAS  PubMed  Google Scholar 

  76. Berentsen S, Barcellini W, D’Sa S, Jilma B. Sutimlimab for treatment of cold agglutinin disease: why, how and for whom? Immunotherapy. 2022;14:1191–204.

    Article  CAS  PubMed  Google Scholar 

  77. Jäger U, D’Sa S, Schörgenhofer C, Bartko J, Derhaschnig U, Sillaber C, et al. Inhibition of complement C1s improves severe hemolytic anemia in cold agglutinin disease: a first-in-human trial. Blood. 2019;133:893–901.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Bartko J, Schörgenhofer C, Schwameis M, Firbas C, Beliveau M, Chang C, et al. A randomized, first-in-human, healthy volunteer trial of sutimlimab, a humanized antibody for the specific inhibition of the classical complement pathway. Clin Pharmacol Ther. 2018;104:655–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Röth A, Berentsen S, Barcellini W, D’Sa S, Jilma B, Michel M, et al. Sutimlimab in patients with cold agglutinin disease: Results of the randomized placebo-controlled phase 3 CADENZA trial. Blood. 2022;140:980–91.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Mackness BC, Jaworski JA, Boudanova E, Park A, Valente D, Mauriac C, et al. Antibody Fc engineering for enhanced neonatal Fc receptor binding and prolonged circulation half-life. MAbs. 2019;11:1276–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Simmons KT, Chan J, Hussain S, Rose EL, Markham K, Byun TS, et al. Anti-C1s humanized monoclonal antibody SAR445088: A classical pathway complement inhibitor specific for the active form of C1s. Clin Immunol. 2023;251:109629.

    Article  CAS  PubMed  Google Scholar 

  82. D’Sa S, Vos JMI, Barcellini W, Wardecki M, Perrin L, Barker G, et al. Safety, tolerability, and activity of the active C1s antibody riliprubart in cold agglutinin disease: a phase 1b study. Blood. 2024;143:713–20.

    Article  CAS  PubMed  Google Scholar 

  83. 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.

    Article  PubMed  Google Scholar 

  84. Gertz M, Roman E, Fattizzo B, Shum M, Hanna W, Ortega G, et al. Inhibition of C3 with APL-2 Controls Haemolysis and Increases Haemoglobin Levels in Subjects with Autoimmune Haemolytic Anaemia (AIHA). HemaSphere. 2019;3:405.

    Article  Google Scholar 

  85. Alashkar F, Vance C, Herich-Terhurne D, Turki AT, Schmitz C, Bommer M, et al. Serologic response to meningococcal vaccination in patients with cold agglutinin disease (CAD) in the novel era of complement inhibition. Vaccine. 2019;37:6682–7.

    Article  CAS  PubMed  Google Scholar 

  86. Arthold C, Skrabs C, Mitterbauer-Hohendanner G, Thalhammer R, Simonitsch-Klupp I, Panzer S, et al. Cold antibody autoimmune hemolytic anemia and lymphoproliferative disorders: a retrospective study of 20 patients including clinical, hematological, and molecular findings. Wien Klin Wochenschr. 2014;126:376–82.

    Article  CAS  PubMed  Google Scholar 

  87. Berentsen S, D’Sa S, Randen U, Malecka A, Vos JMI. Cold agglutinin disease: Improved understanding of pathogenesis helps define targets for therapy. Hemato. 2022;3:574–94.

    Article  Google Scholar 

  88. Berentsen S, Bø K, Shammas FV, Myking AO, Ulvestad E. Chronic cold agglutinin disease of the “idiopathic” type is a premalignant or low-grade malignant lymphoproliferative disease. APMIS. 1997;105:354–62.

    Article  CAS  PubMed  Google Scholar 

  89. Malecka A, Delabie J, Østlie I, Tierens A, Randen U, Berentsen S, et al. Cold agglutinin–associated B-cell lymphoproliferative disease shows highly recurrent gains of chromosome 3 and 12 or 18. Blood Adv. 2020;4:993–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Malecka A, Østlie I, Troen G, Malecki J, Delabie J, Tierens A, et al. Gene expression analysis revealed downregulation of complement receptor 1 in clonal B cells in cold agglutinin disease. Clin Exp Immunol. 2023.

  91. Malecka A, Trøen G, Delabie J, Malecki J, Ostlie I, Tierens A, et al. The mutational landscape of cold agglutinin disease: CARD11 and CXCR4 mutations are correlated with lower hemoglobin levels. Am J Hematol. 2021;96:E279–83.

    Article  CAS  PubMed  Google Scholar 

  92. Rummel M, Kaiser U, Balser C, Stauch M, Brugger W, Welslau M, et al. Bendamustine plus rituximab versus fludarabine plus rituximab for patients with relapsed indolent and mantle-cell lymphomas: a multicentre, randomised, open-label, non-inferiority phase 3 trial. Lancet Oncol. 2016;17:57–66.

    Article  CAS  PubMed  Google Scholar 

  93. Buske C, Castillo JJ, Abeykoon JP, Advani R, Arulogun SO, Branagan AR, et al. Report of consensus panel 1 from the 11(th) International Workshop on Waldenstrom’s Macroglobulinemia on management of symptomatic, treatment-naive patients. Semin Hematol. 2023;60:73–9.

    Article  PubMed  Google Scholar 

  94. Dimopoulos MA, Trotman J, Tedeschi A, Matous JV, Macdonald D, Tam C, et al. Ibrutinib for patients with rituximab-refractory Waldenstrom’s macroglobulinaemia (iNNOVATE): an open-label substudy of an international, multicentre, phase 3 trial. Lancet Oncol. 2017;18:241–50.

    Article  CAS  PubMed  Google Scholar 

  95. Dimopoulos MA, Opat S, D’Sa S, Jurczak W, Lee HP, Cull G, et al. Zanubrutinib versus Ibrutinib in symptomatic Waldenstrom Macroglobulinemia: Final analysis from the randomized phase III ASPEN study. J Clin Oncol. 2023;41:5099–106.

    Article  CAS  PubMed  Google Scholar 

  96. Garcia-Sanz R, Hunter ZR, Poulain S, Varettoni M, Owen RG. New developments in the diagnosis and characterization of Waldenstrom’s macroglobulinemia. Expert Rev Hematol. 2023;16:835–47.

    Article  CAS  PubMed  Google Scholar 

  97. Tesfaye A, Broome C. A Novel Approach for Treatment of Cold Agglutinin Syndrome-Related Severe Hemolysis. J Hematol. 2016;5:30–3.

    Article  Google Scholar 

  98. Koppel A, Lim S, Osby M, Garratty G, Goldfinger D. Rituximab as successful therapy in a patient with refractory paroxysmal cold hemoglobinuria. Transfusion. 2007;47:1902–4.

    Article  CAS  PubMed  Google Scholar 

  99. Gregory GP, Opat S, Quach H, Shortt J, Tran H. Failure of eculizumab to correct paroxysmal cold hemoglobinuria. Ann Hematol. 2011;90:989–90.

    Article  PubMed  Google Scholar 

  100. Rossi G, Paolini F, Fattizzo B, Binda F, D’Adda M, Farina M, et al. Short course of Bortezomib in Anemic patients with refractory or relapsed cold agglutinin disease. a Phase II Prospective Study By the Gimema Group. 59th Annual Meeting of the Americal Society of Hematology, Atlanta, GA. Blood. 2017;130:2199.

    Google Scholar 

  101. Jalink M, Jacobs CF, Khwaja J, Evers D, Bruggeman C, Fattizzo B, et al. Daratumumab monotherapy in refractory warm autoimmune hemolytic anemia and cold agglutinin disease. Blood Adv. 2024;Online ahaed of print. https://doi.org/10.1182/bloodadvances.2024012585.

  102. Tomkins O, Berentsen S, Arulogun S, Sekhar M, D’Sa S. Daratumumab for disabling cold agglutinin disease refractory to B-cell directed therapy. Am J Hematol. 2020;95:E293–5.

    Article  CAS  PubMed  Google Scholar 

  103. Zaninoni A, Giannotta J, Galli A, Artuso R, Bianchi P, Malcovati L, et al. The immunomodulatory effect and clinical efficacy of daratumumab in a patient with cold agglutinin disease. Front Immunol. 2021;. https://doi.org/10.3389/fimmu.2021.649441.

  104. Dacie J. Haemolytic anaemias associated with malignant lymphoma other than Hodgkin’s disease and chronic lymphocytic leukaemia (CLL). In: Dacie J, editor. The Haemolytic Anaemias, vol. 4. London: Churchill Livingstone; 1995. p. 27–40.

    Google Scholar 

  105. Dacie J. Auto-immune haemolytic anaemia (AIHA): cold-antibody syndromes IV: haemolytic anaemia following infectious mononucleosis and other viral infections. In: Dacie J, editor. The Haemolytic Anaemias, vol. 3. London: Churchill Livingstone; 1992. p. 313–28.

    Google Scholar 

  106. Tenny S, Varacello M. Evidence Based Medicine. NIH: National Library of Medicine. 2022; Available at: https://www.ncbi.nlm.nih.gov/books/NBK470182/ . Accessed April 13, 2024.

Download references

Author information

Authors and Affiliations

  1. Department of Research and Innovation, Haugesund Hospital, Helse Fonna Hospital Trust, Haugesund, Norway

    Sigbjørn Berentsen

Authors
  1. Sigbjørn Berentsen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S. Berentsen collected the data, wrote the manuscript, and provided the tables and figures.

Corresponding author

Correspondence to Sigbjørn Berentsen.

Ethics declarations

No funding or writing assistance was received for this work. Outside this work, the author has received consultancy and advisory board honoraria from BeiGene, HillStar Bio, Hummingbird Bioscience, Sanofi, and Sobi, and lecture honoraria from BeiGene, Janssen-Cilag, Sanofi, and Sobi.

Conflict of Interest

The authors declare no competing interests.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Berentsen, S. Cold-antibody Autoimmune Hemolytic Anemia: its Association with Neoplastic Disease and Impact on Therapy. Curr Oncol Rep (2024). https://doi.org/10.1007/s11912-024-01569-8

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11912-024-01569-8

Keywords

Search

Navigation