Hematological response in patients with paroxysmal nocturnal hemoglobinuria treated with C5-inhibitor

Background. Paroxysmal nocturnal hemoglobinuria is a rare clonal disease of the hematopoietic system, with the key manifestations of hemolytic anemia, a high thrombosis rate, and bone marrow failure. Despite the high efficacy of C5‑inhibitors in intravascular hemolysis cessation, a significant proportion of patients remain anemic. Causes of a sub‑optimal response may include C3‑mediated extravascular (intracellular) hemolysis, residual intravascular hemolysis, or bone marrow failure.

Aim. To analyze the results of pathogenetic therapy in patients with paroxysmal nocturnal hemoglobinuria.

Materials and methods. The study included 55 patients with paroxysmal nocturnal hemoglobinuria receiving complement C5 inhibitors for at least 6 months. Results. Suboptimal hematological response was observed in 31/55 (56 %) patients. The most common cause of anemia in the partial response group was C3‑mediated extravascular hemolysis in 8/10 (80 %), while bone marrow failure predominated (57 %) in the minor response group.

Conclusion. The study showed a high frequency of suboptimal response to pathogenetic therapy and necessity of ac‑
curate determination of leading cause of persistent anemia in order to modify therapy or switch to other drugs.

1. Brodsky R.A. How I treat paroxysmal nocturnal hemoglobinuria. Blood 2021;137(10):1304–9. DOI: 10.1182/blood.2019003812

2. Rother R.P., Rollins S.A., Mojcik C.F. et al. Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria. Nat Biotechnol 2007;25(11):1256–64. DOI: 10.1038/nbt1344

3. Savchenko V.G., Lukina E.A., Mikhaylova E.A. et al. Clinical guidelines for the management of patients with paroxysmal nocturnal hemoglobinuria. Gematologiya i transfuziologiya = Russian Journal of Hematology and Transfusiology 2022;67(3): 426–39. (In Russ.). DOI: 10.35754/0234-5730-2022-67-3-426-439

4. Hillmen P., Muus P., Röth A. et al. Long‐term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria. Br J Haematol 2013;162:62–73. DOI: 10.1111/bjh.12347

5. Risitano A.M., Marotta S., Ricci P. et al. Anti-complement treatment for paroxysmal nocturnal hemoglobinuria: time for proximal complement inhibition? A position paper from the SAAWP of the EBMT. Front Immunol 2019;10:1157. DOI: 10.3389/fimmu.2019.01157

6. Debureaux P.E., Kulasekararaj A.G., Cacace F. et al. Categorizing hematological response to eculizumab in paroxysmal nocturnal hemoglobinuria: a multicenter real-life study. Bone Marrow Transplant 2021;56:2600–2. DOI: 10.1038/s41409-021-01372-0

7. Hill A., Rother R.P., 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

8. Risitano A.M., 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;113:4094–100. DOI: 10.1182/blood-2008-11-189944

9. Risitano A.M., Notaro R., Luzzatto L. et al. Paroxysmal nocturnal hemoglobinuria – hemolysis before and after eculizumab. N Engl J Med 2010;363(23):2270–2. DOI: 10.1056/NEJMc1010351

10. Risitano A.M., Marando L., Seneca E., Rotoli B. Hemoglobin normalization after splenectomy in a paroxysmal nocturnal hemoglobinuria patient treated by eculizumab. Blood 2008;112:449–51. DOI: 10.1182/blood-2008-04-151613

11. Hillmen P., Szer J., Weitz I. et al. Pegcetacoplan versus eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med 2021;384:1028–37. DOI: 10.1056/NEJMoa2029073

12. Kulasekararaj A.G., Risitano A.M., Maciejewski J.P. et al. Phase 2 study of danicopan in patients with paroxysmal nocturnal hemoglobinuria with an inadequate response to eculizumab. Blood 2021;138:1928–38. DOI: 10.1182/blood.2021011388

13. Risitano A.M., Röth A., Soret J. et al. Addition of iptacopan, an oral factor B inhibitor, to eculizumab in patients with paroxysmal nocturnal haemoglobinuria and active haemolysis: an open-label, single-arm, phase 2, proof-of-concept trial. Lancet Haematol 2021;8:e344–54. DOI: 10.1016/S2352-3026(21)00028-4

14. Peffault de Latour R., Fremeaux-Bacchi V., Porcher R. et al. Assessing complement blockade in patients with paroxysmal nocturnal hemoglobinuria receiving eculizumab. Blood 2015;125:775–83. DOI: 10.1182/blood-2014-03-560540

15. Tarasova Yu.V., Klimova O.U., Andreeva L.A. et al. Kinetic parameters of complement activation in patients with paroxysmal nocturnal hemoglobinuria during eculizumab therapy. Gematologiya i transfuziologiya = Russian Journal of Hematology and Transfusiology 2020;65(2):126–37. (In Russ.). DOI: 10.35754/0234-5730-2020-65-2-126-137

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

17. Kelly R., Arnold L., Richards S. et al. Modification of the eculizumab dose to successfully manage intravascular breakthrough hemolysis in patients with paroxysmal nocturnal hemoglobinuria. Blood 2008;112:3441. DOI: 10.1182/blood.V112.11.3441.3441

18. Kulasekararaj A.G., Hill A., Rottinghaus S.T. et al. Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor–experienced adult patients with PNH: the 302 study. Blood 2019;133:540–9. DOI: 10.1182/blood-2018-09-876805

19. Fidarova Z.T., Mikhaylova E.A., Galtseva I.V. et al. The dynamics of paroxysmal nocturnal hemoglobinuria clone in patients with aplastic anemia in process of immune suppressive therapy. Klinichescheskaya laboratornaya diagnostika = Clinical Laboratory Diagnostics 2016;(8):490–4. (In Russ.). DOI: 10.18821/0869-2084-2016-61-8-490-494

20. Colden M.A., Kumar S., Munkhbileg B., Babushok D.V. Insights into the emergence of paroxysmal nocturnal hemoglobinuria. Front Immunol 2022;12:830172. DOI: 10.3389/fimmu.2021.830172

21. Luzzatto L., Notaro R. The “escape” model: a versatile mechanism for clonal expansion. Br J Haematol 2019;184:465–6. DOI: 10.1111/bjh.15111

22. Griffin M., Kulasekararaj A., Gandhi S. et al. Concurrent treatment of aplastic anemia/paroxysmal nocturnal hemoglobinuria syndrome with immunosuppressive therapy and eculizumab: a UK experience. Haematologica 2018;103:e345–7. DOI: 10.3324/haematol.2017.183046

23. Van Bijnen S.T.A., Ffrench M., Kruijt N. et al. Bone marrow histology in patients with a paroxysmal nocturnal hemoglobinuria clone correlated with clinical parameters. J Hematol 2013;6:71–82. DOI: 10.1007/s12308-013-0179-7

24. Sun L., Babushok D.V. Secondary myelodysplastic syndrome and leukemia in acquired aplastic anemia and paroxysmal nocturnal hemoglobinuria. Blood 2020;136:36–49. DOI: 10.1182/blood.2019000940 25. Pagliuca S., Risitano A.M., De Fontbrune F.S. et al. Combined intensive immunosuppression and eculizumab for aplastic anemia in the context of hemolytic paroxysmal nocturnal hemoglobinuria: a retrospective analysis. Bone Marrow Transplant 2018;53:105–7. DOI: 10.1038/bmt.2017.220

25. Alashkar F., Dührsen U., Röth A. Horse anti-thymocyte globulin and eculizumab as concomitant therapeutic approach in an aplastic paroxysmal nocturnal hemoglobinuria patient: go or no-go? Eur J Haematol 2016;97:403–5. DOI: 10.1111/ejh.12754

26. Hill A., de Latour R.P., Kulasekararaj A.G. et al. Concomitant immunosuppressive therapy and eculizumab use in patients with paroxysmal nocturnal hemoglobinuria: an international PNH registry analysis. Acta Haematol 2023;146(1):1–13. DOI: 10.1159/000526979

27. Markiewicz M., Drozd-Sokolowska J., Biecek P. et al. Allogeneic hematopoietic stem cell transplantation for paroxysmal nocturnal hemoglobinuria: multicenter analysis by the Polish Adult Leukemia Group. Biol Blood Marrow Transplant 2020;26(10):1833–9. DOI: 10.1016/j.bbmt.2020.05.024

28. Liu L., Wang S., Jiang E. et al. Haploidentical vs matched sibling donor transplant for paroxysmal nocturnal haemoglobinuria: a multicenter study. Blood Cancer J 2022;12:92. DOI: 10.1038/s41408-022-00682-w

29. Schaap C.C.M., Heubel-Moenen F.C.J.I., Nur E. et al. Nationwide study of eculizumab in paroxysmal nocturnal hemoglobinuria: evaluation of treatment indications and outcomes. Eur J Haematol 2023;110:648–58. DOI: 10.1111/ejh.13946

30. De Latour R.P., Mary J.Y., Salanoubat C. et al. Paroxysmal nocturnal hemoglobinuria: natural history of disease subcategories. Blood 2008;112:3099–106. DOI: 10.1182/blood-2008-01-133918