Paroxysmal Nocturnal Hemoglobinuria in Patients with Aplastic Anemia: Challenges, Characteristics, and Analysis of Clinical Experience

RARE HEMATOLOGICAL TUMORS AND SYNDROMES , , , , ,

ER Shilova1, TV Glazanova1, ZhV Chubukina1, OE Rozanova1, MN Zenina1, AV Seltser1, VI Rugal1, VA Balashova1, VA Kobilyanskaya1, II Krobinets1, VYu Udal’eva1, II Zotova1, LV Stelmashenko1, NA Romanenko1, TB Zamotina1, IV Khorsheva1, SV Voloshin1,2,3

1 Russian Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024

2 SM Kirov Military Medical Academy, 6 Akademika Lebedeva str., Saint Petersburg, Russian Federation, 194044

3 II Mechnikov North-Western State Medical University, 41 Kirochnaya str., Saint Petersburg, Russian Federation, 191015

For correspondence: Elena Romanovna Shilova, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024; Tel.: +7(981)129-09-77; e-mail: rniiht@mail.ru

For citation: Shilova ER, Glazanova TV, Chubukina ZhV, et al. Paroxysmal Nocturnal Hemoglobinuria in Patients with Aplastic Anemia: Challenges, Characteristics, and Analysis of Clinical Experience. Clinical oncohematology. 2019;12(3):319–28 (In Russ).

doi: 10.21320/2500-2139-2019-12-3-319-328

ABSTRACT

Background & Aims. Paroxysmal nocturnal hemoglobinuria (PNH) is a disease caused by an acquired clonal disorder of hematopoietic stem cells with clone cell membrane hypersensitivity to the complement. PNH can exist as an independent disease and can also be associated with other pathological conditions characterized by bone marrow deficiency, first of all with aplastic anemia (AA). In PNH-associated AA (AA/PNH) pathological clones may be initially of different size. In some patients a gradual growth of PNH clone is observed together with occurring signs of intravascular hemolysis and transformation into classical hemolytic PNH. In this case it is important to assess the clinical situation and determine eligibility for complement inhibitor therapy. During targeted therapy it is necessary to assess the efficacy of treatment based on monitoring of complement-mediated hemolysis and to identify probable reasons for insufficient effect.

Materials & Methods. The paper deals with 1 clinical case. A female patient born in 1964, with initial diagnosis of AA was followed-up from 1989 till present at the Russian Research Institute of Hematology and Transfusiology. Her treatment included blood-component therapy, the use of antilymphocyte immunoglobulin, cyclosporine, plasmapheresis, eculizumab, and symptom-relieving drugs.

Results. The study deals with the case of transformation of non-severe AA with remission after immune-suppressive therapy into classical hemolytic PNH. The case report describes the characteristic features, AA/PNH diagnosis and treatment issues at different stages of the disease, and the reasons for incomplete effect of targeted therapy.

Conclusion. The case under discussion confirms the relevance of current methods of detecting PNH clone at early stages of AA diagnosis and dynamic follow-up with respect to a probable growth of clone with PNH phenotype, especially at the stage of hematopoietic recovery. Determination of PNH clone size and lactate dehydrogenase serum level is required for timely amendment of treatment strategy with a switch to long-term targeted monitoring of hemolysis which allows to prevent irreversible visceral changes and severe complications. In case of insufficient effect of targeted therapy with ongoing anemia Coombs test is recommended because of probability of C3-mediated extravascular hemolysis.

Keywords: aplastic anemia, paroxysmal nocturnal hemoglobinuria, PNH phenotype, PNH clone, targeted therapy, C3-mediated hemolysis.

Received: December 24, 2018

Accepted: May 29, 2019

Read in PDF 

REFERENCES

  1. Borowitz MJ, Craig FE, Digiuseppe JA, et al. Guidelines for the diagnosis and monitoring of paroxysmal nocturnal hemoglobinuria and related disorders by flow cytometry. Cytometry B Clin Cytom. 2010;78(4):211–30. doi: 10.1002/cyto.b.20525.

  2. Sutherland DR, Keeney M, Illingworth A. Practical guidelines for the high-sensitivity detection and monitoring of paroxysmal nocturnal hemoglobinuria clones by flow cytometry. Cytometry B Clin. Cytom. 2012;82(4):195–208. doi: 10.1002/cyto.b.21023.

  3. Kulagin A, Lisukov I, Ivanova M, et al. Prognostic value of paroxysmal nocturnal haemoglobinuria clone presence in aplastic anaemia patients treated with combined immunosuppression: results of two-centre prospective study. Br J Haematol. 2014;164(4):546–54. doi: 10.1111/bjh.12661.

  4. Shilova ER, Glazanova TV, Chubukina ZV, et al. Aplastic anemia associated with PNH-clone – a single centre experience. Blood. 2016;128(22):5080.

  5. De Latour RP, Mary JY, Salanoubat C, et al. Paroxysmal nocturnal hemoglobinuria: natural history of disease subcategories. Blood. 2008;112(8):3099–106. doi: 10.1182/blood-2008-01-133918.

  6. Hill A, Kelly RJ, Hillmen P. Thrombosis in paroxysmal nocturnal hemoglobinuria. 2013;121(25):4985–96. doi: 10.1182/blood-2012-09-311381.

  7. Shresenmeier H, Hertenstein B, Wagner B, et al. A patogenetic link between aplastic anemia and paroxysmal nocturnal haemoglobinuria is suggested by a high frequency of aplastic anaemia patients with a deficiency of phosphatidylinositol glycan anchored proteins. Exp Haematol. 1995;23(2):181.

  8. Wanachiwanawin W, Siripanyaphinyo U, Piyawattanasakul N, et al. A cohort study of the nature of paroxysmal nocturnal hemoglobinuria clones and PIG-A mutations in patients with aplastic anemia. Eur J Haematol. 2006;76(6):502–9. doi: 10.1111/j.0902-4441.2005.t01-1-EJH2467.x.

  9. Glazanova TV, Chubukina ZV, Rozanova OE, et al. Detection of PNH-clone in patients with depression of hemopoiesis. Haematologica. 2013;98(Suppl 1):579.

  10. Young NS, Calado RT, Scheinberg P. Current concepts in the pathophysiology and treatment of aplastic anemia. Blood. 2006;108(8):2509–19. doi: 10.1182/blood-2006-03-010777.

  11. Mortazavi Y, Merk B, McIntosh J, et al. The spectrum of PIG-A gene mutations in aplastic anaemia/paroxysmal nocturnal hemoglobinuria (AA/PNH): a high incidence of multiple mutation and evidence of mutational hot spot. Blood. 2003;101(7):2833–41. doi: 10.1182/blood-2002-07-2095.

  12. Кулагин А.Д., Лисуков И.А., Птушкин В.В. и др. Национальные клинические рекомендации по диагностике и лечению пароксизмальной ночной гемоглобинурии. Онкогематология. 2014;9(2):20–8. doi: 10.17650/1818-8346-2014-9-2-20-28.

    [Kulagin AD, Lisukov IA, Ptushkin VV, et al. National clinical guidelines for the diagnosis and treatment of paroxysmal nocturnal hemoglobinuria. 2014;9(2):20–8. doi: 10.17650/1818-8346-2014-9-2-20-28. (In Russ)]

  13. Kulagin A, Golubovskaya I, Ivanova M, et al. Incidence and risk factors for hemolytic paroxysmal nocturnal hemoglobinuria (PNH) in aplastic anemia (AA) patients. Bone Marrow Transplant. 2014;49(Suppl 1):S42–43.

  14. Lee JW, Jang JH, Kim JS, et al. Clinical signs and symptoms associated with increased risk for thrombosis in patients with paroxysmal nocturnal hemoglobinuria from a Korean Registry. Int J Hematol. 2013;97(6):749–57. doi: 10.1007/s12185-013-1346-4.

  15. Loshi M, Porcher R, Barraco F, et al. Impact of eculizumab treatment on paroxysmal nocturnal hemoglobinuria: a treatment versus no-treatment study. Am J Hematol. 2016;91(4):366–70. doi: 10.1002/ajh.24278.

  16. Kelly R, Hill A, Hillmen P, et al. Long-term treatment with eculizumab in paroxysmal nocturnal hemoglobinuria: sustained efficacy and improved survival. Blood. 2011;117(25):6786–92. doi: 10.1182/blood-2011-02-333997.

  17. Nishimura J, Yamamoto M, Hayashi S, et al. Genetic variants in C5 and poor response to eculizumab. N Engl J Med. 2014;370(7):632–9. doi: 10.1056/NEJMoa1311084.

  18. Camitta BM, Rozman C, Marin P, et al. Criteria for severe aplastic anaemia. Lancet 1988;331(8580):303–4. doi: 10.1016/s0140-6736(88)90388-1.

  19. van Kamp H, van Imhoff G, de Wolf J, et al. The effect of cyclosporine on hematological parameters in patients with paroxysmal nocturnal haemoglobinuria. Br J Haematol. 1995;89(1):79–82. doi: 10.1111/j.1365-2141.1995.tb08907.x.

  20. Лисуков И.А., Крючкова И.В., Кулагин А.Д. и др. Клинический случай пароксизмальной ночной гемоглобинурии с ответом на терапию циклоспорином А. Гематология и трансфузиология. 1998;43(5):45–6.

    [Lisukov IA, Kryuchkova IV, Kulagin AD, et al. Clinical case of paroxysmal nocturnal hemoglobinuria with response to cyclosporine A therapy. Gematologiya i transfuziologiya. 1998;43(5):45–6. (In Russ)]

  21. Подопригора Г.И., Андреев В.Н. Современные методы изучения фагоцитарной активности лейкоцитов in vitro. Журнал микробиологии, эпидемиологии и иммунологии. 1976;53(1):19–26.

    [Podoprigora GI, Andreev VN. Current methods of studying the phagocytic activity of leukocytes in vitro. Zhurnal mikrobiologii, epidemiologii i immunologii. 1976;53(1):19–26. (In Russ)]

  22. Hillmen P, Lewis SM, Bessler M, et al. Natural history of paroxysmal nocturnal hemoglobinuria. N Engl J Med. 1995;333(19):1253–8. doi: 10.1056/NEJM199511093331904.

  23. Hall SE, Rosse WF. The use of monoclonal antibodies and flow cytometry in the diagnosis of paroxysmal nocturnal hemoglobinuria. Blood. 1996;87(12):5332–40.

  24. Козлов Л.В. Исследование функциональной активности компонентов факторов системы комплемента человека. Вопросы медицинской химии. 2002;48(6):624–31.

    [Kozlov LV. Study of functional activity of components and factors of the human complement system. Voprosy meditsinskoi khimii. 2002;48(6):624–31. (In Russ)]

  25. Risitano A, Notaro R, Marando L, et al. Complement fraction 3 binding on erythrocytes as additional mechanism of disease in paroxysmal nocturnal hemoglobinuria patients treated by eculizumab. Blood. 2009;113(17):4094–5100. doi: 10.1182/blood-2008-11-189944.

  26. Hill A, Rother R, Arnold L, 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(4):567–73. doi: 10.3324/haematol.2009.007229.

  27. Sugimori C, Chuhjo T, Feng H, et al. Minor population of CD55-CD59- blood cells predict response to immunosuppressive therapy and prognosis in patients with aplastic anaemia. Blood. 2006;107(4):1308–14. doi: 10.1182/blood-2005-06-2485.

  28. Sosie G, Mary J-Y, de Gramont A, et al. Paroxysmal noctural haemoglobinuria: long-term follow-up and prognostic factors. Lancet. 1996;348(9027):573–7. doi: 10.1016/s0140-6736(95)12360-1.

  29. Araten D, Bessler M, McKenzie S, et al. Dynamics of hematopoiesis in paroxysmal nocturnal hemoglobinuria (PNH): no evidence for intrinsic growth advantage of PNH clones. Leukemia. 2002;16(11):2243–8. doi: 10.1038/sj.leu.2402694.

  30. Cacciapuoti C, Terrazzano G, Barone L, et al. Glycosyl-phosphatidyl-inositol-defective granulocytes from paroxysmal nocturnal haemoglobinuria patients show increased bacterial ingestion but reduced respiratory burst induction. Am J Hematol. 2007;82(2):98–107. doi: 10.1002/ajh.20779.

  31. Вуд М.Э., Банн П.А. Секреты гематологии и онкологии. Пер. с англ. М.: Бином, 2001.

    [Wood M, Bunn P. Hematology/Oncology Secrets. ( ed.: Wood ME, Bunn PA. Sekrety gematologii i onkologii. Moscow: Binom Publ.; 2001.)]

  32. Brodsky R. Paroxysmal nocturnal hemoglobinuria. Blood. 2014;124(18):2804–11. doi: 10.1182/blood-2014-02-522128.