INTRODUCTION: Hemolysis in paroxysmal nocturnal hemoglobinuria (PNH) is complement-mediated due to the lack of complement inhibitors in the hemopoietic cell membranes, making complement inhibition the best approach to manage PNH. Three complement inhibitors are approved by the European Medicines Agency as targeted therapy for PNH: eculizumab and ravulizumab, two humanized monoclonal antibodies targeting the same complement 5 (C5) epitope, approved in 2007 and 2019, respectively, and the more recently approved cyclic peptide, the complement 3 (C3) inhibitor pegcetacoplan. Although national and international PNH treatment guidelines exist, they do not take into consideration the latest clinical trial evidence. Given the lack of evidence-based data for some clinical situations encountered in real life, we identified specific populations of patients who may benefit from switching to proximal C3 from terminal C5 inhibition. METHODS: The expert recommendations presented here were created using a Delphi-like process by a group of expert PNH specialists across Central Europe. Based on an initial advisory board meeting discussion, recommendations were prepared and reviewed as part of a Delphi survey to test agreement. RESULTS: Using a systematic approach, literature databases were searched for relevant studies, and 50 articles were reviewed by the experts and included as supporting evidence. CONCLUSION: Implementation of these recommendations uniformly across healthcare institutions will promote the best use of complement inhibition in managing PNH, and has the potential to positively impact patient outcomes in Central Europe and worldwide.

Bone Marrow Transplant Unit Department of Hematology Emergency University Hospital Carol Davila University of Medicine and Pharmacy Bucharest Romania

Department of Hematology and Transfusion Medicine Jessenius Medical Faculty in Martin Comenius University in Bratislava Martin Slovakia

Department of Hematology and Transplantology Medical University of Gdansk Gdansk Poland

Department of Hematology Tokuda Hospital Sofia Sofia Bulgaria

Department of Hematology University Medical Centre Ljubljana Faculty of Medicine University of Ljubljana Ljubljana Slovenia

Department of Hemostasis Disorders and Internal Medicine Institute of Hematology and Transfusion Medicine Warsaw Poland

Department of Internal Medicine and Hematology Semmelweis University 46 Szentkirályi u Budapest 1088 Hungary

Department of Orphan Diseases National Research Medical Center for Hematology Moscow Russia

Division of Haematology Department of Internal Medicine University Hospital Center Zagreb School of Medicine University of Zagreb Zagreb Croatia

Institute of Hematology and Blood Transfusion Prague Czech Republic

RM Gorbacheva Research Institute Pavlov University St Petersburg Russia

Zobrazit více v PubMed

Brodsky RA. Paroxysmal nocturnal hemoglobinuria. Blood. 2014;124(18):2804–2811. doi: 10.1182/blood-2014-02-522128. PubMed DOI PMC

Shah N, Bhatt H. Paroxysmal nocturnal hemoglobinuria. StatPearls [Internet]. Treasure Island: StatPearls Publishing; 2021. PubMed

Gulbis B, Eleftheriou A, Angastiniotis M, et al. Epidemiology of rare anaemias in Europe. Rare Dis Epidemiol. 2010;686:375–396. doi: 10.1007/978-90-481-9485-8_22. PubMed DOI

Kulagin AD, Klimova OU, Dobronravov AV, et al. Paroxysmal nocturnal hemoglobinuria in children and adults: comparative clinical profile and long-term prognosis. Ped Hematol/Oncol Immunopathol. 2018;17(3):11–21. doi: 10.24287/1726-1708-2018-17-3-11-21. DOI

Urbano-Ispizua A, Muus P, Schrezenmeier H, et al. Different clinical characteristics of paroxysmal nocturnal hemoglobinuria in pediatric and adult patients. Haematologica. 2016;102(3):e76–e79. doi: 10.3324/haematol.2016.151852. PubMed DOI PMC

Babushok DV. When does a PNH clone have clinical significance? Hematology. 2021;2021(1):143–152. doi: 10.1182/hematology.2021000245. PubMed DOI PMC

Fu R, Li L, Li L, et al. Analysis of clinical characteristics of 92 patients with paroxysmal nocturnal hemoglobinuria: a single institution experience in China. J Clin Lab Anal. 2020;34(1):e23008. doi: 10.1002/jcla.23008. PubMed DOI PMC

Hillmen P, Young NS, Schubert J, et al. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2006;355(12):1233–1243. doi: 10.1056/NEJMoa061648. PubMed DOI

Brodsky RA, Peffault de Latour R, Rottinghaus ST, et al. Characterization of breakthrough hemolysis events observed in the phase 3 randomized studies of ravulizumab versus eculizumab in adults with paroxysmal nocturnal hemoglobinuria. Haematologica. 2021;106(1):230–237. doi: 10.3324/haematol.2019.236877. PubMed DOI PMC

Al-Ani F, Chin-Yee I, Lazo-Langner A. Eculizumab in the management of paroxysmal nocturnal hemoglobinuria: patient selection and special considerations. Ther Clin Risk Manag. 2016;12(1):1161–1170. PubMed PMC

McKinley CE, Richards SJ, Munir T, et al. Extravascular hemolysis due to C3-loading in patients with PNH treated with eculizumab: defining the clinical syndrome. Blood. 2017;130(1):3471.

European Medicines Agency (EMA). 2021. https://www.ema.europa.eu/en. Accessed 17 Jan 2022.

Risitano AM, 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):1–24. PubMed PMC

Schubert J, Bettelheim P, Brümmendorf TH, et al. Deutsche Gesellschaft für Hämatologie und Medizinische Onkologie—PNH (2018). https://www.onkopedia-guidelines.info/de/hinweise/erstellung-von-leitlinien-1. Accessed 25 Jan 2022.

Parker C, Omine M, Richards S, et al. Diagnosis and management of paroxysmal nocturnal hemoglobinuria. Blood. 2005;106(12):3699–3709. doi: 10.1182/blood-2005-04-1717. PubMed DOI PMC

Sahin F, Akay OM, Ayer M, et al. Pesg PNH diagnosis, follow-up and treatment guidelines. Am J Blood Res. 2016;6(2):19–27. PubMed PMC

Villegas A, Arrizabalaga B, Bonanad S, et al. Spanish consensus statement for diagnosis and treatment of paroxysmal nocturnal haemoglobinuria. Med Clin (Barc) 2016;146(6):278.e1–7. doi: 10.1016/j.medcli.2015.12.012. PubMed DOI

Griffin M, Munir T. Management of thrombosis in paroxysmal nocturnal hemoglobinuria: a clinician's guide. Ther Adv Hematol. 2017;8(3):119–126. doi: 10.1177/2040620716681748. PubMed DOI PMC

Morado M, Freire Sandes A, Colado E, et al. Diagnostic screening of paroxysmal nocturnal hemoglobinuria: prospective multicentric evaluation of the current medical indications. Cytometry B Clin Cytom. 2017;92(5):361–370. doi: 10.1002/cyto.b.21480. PubMed DOI

Devos T, Meers S, Boeckx N, et al. Diagnosis and management of PNH: review and recommendations from a Belgian expert panel. Eur J Haematol. 2018;101(6):737–749. doi: 10.1111/ejh.13166. PubMed DOI

Weitz IC. Nocturnal paroxysmal hemoglobinuria. 2018. https://bestpractice.bmj.com/topics/pt-br/894. Accessed 25 Jan 2021.

Cannizzo E, Raia M, De Propris MS, et al. Features, reason for testing, and changes with time of 583 paroxysmal nocturnal hemoglobinuria clones from 529 patients: a multicenter Italian study. Ann Hematol. 2019;98(5):1083–1093. doi: 10.1007/s00277-019-03644-8. PubMed DOI

Brodsky RA. How I treat paroxysmal nocturnal hemoglobinuria. Blood. 2009;113(26):6522–6527. doi: 10.1182/blood-2009-03-195966. PubMed DOI PMC

Hill A, Kelly RJ, Hillmen P. Thrombosis in paroxysmal nocturnal hemoglobinuria. Blood. 2013;121(25):4985–4996. doi: 10.1182/blood-2012-09-311381. PubMed DOI

Huang Y, Liu X, Chen F, et al. Prediction of thrombosis risk in patients with paroxysmal nocturnal hemoglobinuria. Ann Hematol. 2019;98(10):2283–2291. doi: 10.1007/s00277-019-03770-3. PubMed DOI

Schrezenmeier H, Röth A, Araten DJ, et al. Baseline clinical characteristics and disease burden in patients with paroxysmal nocturnal hemoglobinuria (PNH): updated analysis from the International PNH Registry. Ann Hematol. 2020;99(7):1505–1514. doi: 10.1007/s00277-020-04052-z. PubMed DOI PMC

Hill A, DeZern AE, Kinoshita T, Brodsky RA. Paroxysmal nocturnal haemoglobinuria. Nat Rev Dis Primers. 2017;3(17028):1–29. PubMed PMC

Sun L, Babushok D. Secondary myelodysplastic syndrome and leukemia in acquired aplastic anemia and paroxysmal nocturnal hemoglobinuria. Blood. 2020;136:1. doi: 10.1182/blood.2019000940. PubMed DOI PMC

Kinoshita T, Murakami Y, Morita YS. 4.21—Diseases associated with GPI anchors. In: Kamerling H, editor. Comprehensive glycoscience. Oxford: Elsevier; 2007. pp. 393–419.

Brodsky RA, Young NS, Antonioli E, et al. Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Blood. 2008;111(4):1840–1847. doi: 10.1182/blood-2007-06-094136. PubMed DOI

Hillmen P, Muus P, Dührsen U, et al. Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria. Blood. 2007;110(12):4123–4128. doi: 10.1182/blood-2007-06-095646. PubMed DOI

Lee JW, Sicre de Fontbrune F, Wong Lee Lee L, et al. Ravulizumab (ALXN1210) vs. eculizumab in adult patients with PNH naive to complement inhibitors: the 301 study. Blood. 2019;133(6):530–539. doi: 10.1182/blood-2018-09-876136. PubMed DOI PMC

Kulasekararaj AG, Hill A, Rottinghaus ST, et al. Ravulizumab (ALXN1210) vs. eculizumab in C5-inhibitor-experienced adult patients with PNH: the 302 study. Blood. 2019;133(6):540–549. doi: 10.1182/blood-2018-09-876805. PubMed DOI PMC

Tomazos I, Hill A, Royston M. Ravulizumab and eculizumab reduce transfusions in adult patients with paroxysmal nocturnal hemoglobinuris: evidence from three real-world databases: TRINETX US EMR, TRINETX US CLAIMS and KOMODO HEALTH. E-poster EP1337. In: Presented at the virtual EHA 2021; 9–17 June.

Kulagin A, Klimova O, Rudakova T, et al. Benefits and limitations of long-term eculizumab treatment for paroxysmal nocturnal hemoglobinuria (PNH): real-world data from large cohort study in Russia. Blood. 2018;132(1):2589. doi: 10.1182/blood-2018-99-120139. DOI

Burke JP, Sahli B, Broderick K, Gleason PP. Paroxymsal nocturnal hemoglobinuria real-world effectiveness of C5 inhibitors and cost assessment 2021. https://www.primetherapeutics.com/wp-content/uploads/2021/10/4085-B_PNH-C5-Assessment-1.pdf. Accessed 17 Jan 2022.

Hillmen P, Szer J, Weitz I, et al. Pegcetacoplan versus eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2021;384(11):1028–1037. doi: 10.1056/NEJMoa2029073. PubMed DOI

de Latour RP, Szer J, Weitz IC, et al. Pegcetacoplan versus eculizumab in patients with paroxysmal nocturnal haemoglobinuria (PEGASUS): 48-week follow-up of a randomised, open-label, phase 3, active-comparator, controlled trial. Lancet Haematol. 2022;9(9):e648–e659. doi: 10.1016/S2352-3026(22)00210-1. PubMed DOI

Wong RS, Navarro JR, Comia NS, et al. Efficacy and safety of pegcetacoplan treatment in complement-inhibitor naïve patients with paroxysmal nocturnal hemoglobinuria: results from the phase 3 Prince study. Blood. 2021;138:606. doi: 10.1182/blood-2021-147493. DOI

Gomez-Almaguer D, Wong R, Dumagay T, et al. S303: Effect ofpegcetacoplan on quality of life in complement-inhibitor naive patients with paroxysmal nocturnal hemoglobinuria: results from the phase 3 Prince study. HemaSphere. 2022;6:606. doi: 10.1097/01.HS9.0000844104.86321.a6. DOI

Montan I, Löwe B, Cella D, et al. General population norms for the functional assessment of chronic illness therapy (FACIT)-fatigue scale. Value Health. 2018;21(11):1313–1321. doi: 10.1016/j.jval.2018.03.013. PubMed DOI

Desai D, Panse J, Daguindau N, et al. MDS-112 Normalization of hematologic and health-related quality of life markers in patients with paroxysmal nocturnal hemoglobinuria treated with pegcetacoplan and baseline hemoglobin at or above 10 g/dL. Clin Lymphoma Myeloma Leuk. 2022;22:S305.

Desai D, Wong R, Fishman J, et al. MDS-254 A matching-adjusted indirect comparison of the efficacy of pegcetacoplan using PRINCE trial data versus ravulizumab and eculizumab in complement inhibitor naive-patients with paroxysmal nocturnal hemoglobinuria. Clin Lymphoma Myeloma Leuk. 2022;22:S306–S307.

Peffault de Latour R, Roeth A, Kulasekararaj A, et al. Oral monotherapy with iptacopan, a proximal complement inhibitor of factor B, has superior efficacy to intravenous terminal complement inhibition with standard of care eculizumab or ravulizumab and favorable safety in patients with paroxysmal nocturnal hemoglobinuria and residual anemia: results from the randomized, active-comparator-controlled, open-label, multicenter, Phase III Apply-PNH Study. Blood. 2022; 140(Supplement 2):LBA-2-LBA.

Kulasekararaj AG, Griffin M, Langemeijer S, et al. Long-term safety and efficacy of ravulizumab in patients with paroxysmal nocturnal hemoglobinuria: 2-year results from two pivotal phase 3 studies. Eur J Haematol. 2022;109(3):205–214. doi: 10.1111/ejh.13783. PubMed DOI PMC

Cooper JP, Farah RJ, Stevenson PA, et al. Hematopoietic cell transplantation for paroxysmal nocturnal hemoglobinuria in the age of eculizumab. Biol Blood Marrow Transplant. 2019;25(7):1331–1339. doi: 10.1016/j.bbmt.2019.01.033. PubMed DOI PMC

KamranzadehFumani H, Zokaasadi M, Kasaeian A, et al. Allogeneic hematopoietic stem cell transplantation for paroxysmal nocturnal hemoglobinuria: a retrospective single-center study. Hematol Oncol. 2017;35(4):935–938. doi: 10.1002/hon.2367. PubMed DOI

Mei M, Gupta R, O'Donnell M, et al. Post-allogeneic hematopoietic stem cell transplantation eculizumab as prophylaxis against hemolysis and thrombosis for patients with hematologic disorders associated with paroxysmal nocturnal hemoglobinuria clones. Biol Blood Marrow Transplant. 2019;25(5):e183–e185. doi: 10.1016/j.bbmt.2019.01.025. PubMed DOI

Shasheleva DA, Maschan AA, Shelikhova LN, et al. Hematopoietic stem cell transplantation with alpha/beta T-lymphocyte depletion and short course of eculizumab in adolescents and young adults with paroxysmal nocturnal hemoglobinuria. Ter Arkh. 2018;90(7):57–64. PubMed

Vallet N, de Fontbrune FS, Loschi M, et al. Hematopoietic stem cell transplantation for patients with paroxysmal nocturnal hemoglobinuria previously treated with eculizumab: a retrospective study of 21 patients from SFGM-TC centers. Haematologica. 2018;103(3):e103–e105. doi: 10.3324/haematol.2017.182360. PubMed DOI PMC

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):1833–1839. doi: 10.1016/j.bbmt.2020.05.024. PubMed DOI

Peffault de Latour R, Schrezenmeier H, Bacigalupo A, et al. Allogeneic stem cell transplantation in paroxysmal nocturnal hemoglobinuria. Haematologica. 2012;97(11):1666–1673. doi: 10.3324/haematol.2012.062828. PubMed DOI PMC

Vinogradova MA, Kulagin AD, Shmakov RG. Pregnancy in paroxysmal nocturnal hemoglobinuria: from survival to life. TA. 2022;94(7):859–864. doi: 10.26442/00403660.2022.07.201714. PubMed DOI

Alashkar F, Saner FH, Vance C, et al. Pregnancy in classical paroxysmal nocturnal hemoglobinuria and aplastic anemia–paroxysmal nocturnal hemoglobinuria: a high-risk constellation. Front Med. 2020;7(543372):1–7. PubMed PMC

Al-Dosari Y, Al-Zahrani H, Al-Mohareb F, Hashmi S. Pregnancy with paroxysmal nocturnal hemoglobinuria: a case series with review of the literature. Saudi J Med Med Sci. 2021;9(2):178–189. doi: 10.4103/sjmms.sjmms_4_20. PubMed DOI PMC

Fassett MJ, Hernandez Lopez AL. Treatment of paroxysmal nocturnal hemoglobinuria in pregnancy with eculizumab: a case report. Case Rep Women's Health. 2021;30(1):e00294. doi: 10.1016/j.crwh.2021.e00294. PubMed DOI PMC

Horányi D, Várkonyi A, Nagy GR, et al. Rare case of a pregnancy in a woman with paroxysmal nocturnal hemoglobinuria. Case Rep Orv Hetil. 2016;157(23):916–918. doi: 10.1556/650.2016.30430. PubMed DOI

Lauritsch-Hernandez LS, Kraehenmann F, Balabanov S, Kimmich N. Eculizumab application during pregnancy in a patient with paroxysmal nocturnal hemoglobinuria: a case report with review of the literature. Clin Case Rep. 2018;6(8):1582–1587. doi: 10.1002/ccr3.1634. PubMed DOI PMC

Miyasaka N, Miura O, Kawaguchi T, et al. Pregnancy outcomes of patients with paroxysmal nocturnal hemoglobinuria treated with eculizumab: a Japanese experience and updated review. Int J Hematol. 2016;103(6):703–712. doi: 10.1007/s12185-016-1946-x. PubMed DOI

Rodríguez-Ferreras A, Velasco-Roces L. Eculizumab-related abortion in a woman with paroxysmal nocturnal hemoglobinuria: a case report. J Reprod Infertil. 2019;20(4):252–255. PubMed PMC

Czyż J, Szukalski Ł, Szukalska A, et al. Eculizumab treatment in pregnant women with paroxysmal nocturnal hemoglobinuria: a Polish experience. Adv Clin Exp Med. 2022;31(6):707–710. doi: 10.17219/acem/150600. PubMed DOI

Kelly RJ, Höchsmann B, Szer J, et al. Eculizumab in pregnant patients withparoxysmal nocturnal hemoglobinuria. New Engl J Med. 2015;373(11):1032–1039. doi: 10.1056/NEJMoa1502950. PubMed DOI

Choi CW, Jang JH, Kim JS, et al. Efficacy of eculizumab in paroxysmal nocturnal hemoglobinuria patients with or without aplastic anemia: prospective study of a Korean PNH cohort. Blood Res. 2017;52(3):207–211. doi: 10.5045/br.2017.52.3.207. PubMed DOI PMC

Dudina G. A mini-review on paroxysmal nocturnal hemoglobinuria and a case of eculizumab treatment of PNH in elderly MDS patient. Cell Ther Transplant. 2017;6(1):48–54. doi: 10.18620/ctt-1866-8836-2017-6-1-48-54. DOI

Giannotta JA, Fattizzo B, Barcellini W. Paroxysmal nocturnal hemoglobinuria in the context of a myeloproliferative neoplasm: a case report and review of the literature. Front Oncol. 2021;11(1):1–8. PubMed PMC

Lee JW, Peffault de Latour R, Brodsky RA, et al. Effectiveness of eculizumab in patients with paroxysmal nocturnal hemoglobinuria (PNH) with or without aplastic anemia in the International PNH Registry. Am J Hematol. 2019;94(1):e37–e41. doi: 10.1002/ajh.25334. PubMed DOI

Shakir A, Narula S, LaGrow A, Nusrat S. Two roads diverge: treatment choice in coexisting severe aplastic anemia and paroxysmal nocturnal hemoglobinuria. J Med Cases. 2020;11(6):182–184. doi: 10.14740/jmc3478. PubMed DOI PMC

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(8):e345–e347. doi: 10.3324/haematol.2017.183046. PubMed DOI PMC

Raghupathy R, Derman O. Response of paroxysmal nocturnal hemoglobinuria clone with aplastic anemia to rituximab. Case Rep Hematol. 2012;2012:106182. PubMed PMC

DeZern AE, Jones RJ, Brodsky RA. Eculizumab bridging before bone marrow transplant for marrow failure disorders is safe and does not limit engraftment. Biol Blood Marrow Transplant. 2018;24(12):e26–e30. doi: 10.1016/j.bbmt.2018.07.032. PubMed DOI PMC

Parker CJ. Management of paroxysmal nocturnal hemoglobinuria in the era of complement inhibitory therapy. Hematology Am Soc Hematol Educ Program. 2011;2011(1):21–29. doi: 10.1182/asheducation-2011.1.21. PubMed DOI

DeZern AE, Dorr D, Brodsky RA. Predictors of hemoglobin response to eculizumab therapy in paroxysmal nocturnal hemoglobinuria. Eur J Haematol. 2013;90(1):16–24. doi: 10.1111/ejh.12021. PubMed DOI PMC

Ekinci O, Dogan A, Demircioglu S, et al. Clinical features and responses to eculizumab of paroxysmal nocturnal hemoglobinuria patients: a single-center experience. Med Sci. 2019;8(3):624–627.

Kulasekararaj AG, Hill A, Langemeijer S, et al. One-year outcomes from a phase 3 randomized trial of ravulizumab in adults with paroxysmal nocturnal hemoglobinuria who received prior eculizumab. Eur J Haematol. 2021;106(3):389–397. doi: 10.1111/ejh.13564. PubMed DOI PMC

Füreder W, Valent P. Switching from high-dose eculizumab to ravulizumab in paroxysmal nocturnal hemoglobinuria: a case report. Hemasphere. 2020;4(4):e455. doi: 10.1097/HS9.0000000000000455. PubMed DOI PMC

Peipert JD, Kulasekararaj AG, Gaya A, et al. Patient preferences and quality of life implications of ravulizumab (every 8 weeks) and eculizumab (every 2 weeks) for the treatment of paroxysmal nocturnal hemoglobinuria. PLoS ONE. 2020;15(9):e0237497. doi: 10.1371/journal.pone.0237497. PubMed DOI PMC

Yenerel MN, Sicre de Fontbrune F, Piatek C, et al. Phase 3 study of subcutaneous versus intravenous ravulizumab in eculizumab-experienced adult patients with PNH: primary analysis and 1-year follow-up. Adv Ther. 2022;40:18. PubMed PMC

Araten DJ, Belmont HM, Schaefer-Cutillo J, et al. Mild clinical course of COVID-19 in 3 patients receiving therapeutic monoclonal antibodies targeting C5 complement for hematologic disorders. Am J Case Rep. 2020;21(1):e927418. PubMed PMC

Genthon A, Chiarabini T, Baylac P, et al. Severe COVID-19 infection in a patient with paroxysmal nocturnal hemoglobinuria on eculizumab therapy. Leuk Lymphoma. 2021;62(6):1502–1505. doi: 10.1080/10428194.2020.1869963. PubMed DOI

Schüller H, Klein F, Lübbert M, Prager EP. Hemolytic crisis in a patient treated with eculizumab for paroxysmal nocturnal hemoglobinuria possibly triggered by SARS-CoV-2 (COVID-19): a case report. Ann Hematol. 2021;100(3):841–842. doi: 10.1007/s00277-020-04318-6. PubMed DOI PMC

Shikdar S, Borogovac A, Mohamad E, Khawandanah M. COVID19 infection in a patient undergoing treatment for paroxysmal nocturnal hemoglobinuria (PNH) with ravulizumab. Thromb J. 2021;19(1):75. doi: 10.1186/s12959-021-00330-6. PubMed DOI PMC

Gralinski LE, Sheahan TP, Morrison TE, et al. Complement activation contributes to severe acute respiratory syndrome coronavirus pathogenesis. MBio. 2018;9(5):e0175318. doi: 10.1128/mBio.01753-18. PubMed DOI PMC

Dingli D, Matos JE, Lehrhaupt K, et al. The burden of illness in patients with paroxysmal nocturnal hemoglobinuria receiving treatment with the C5-inhibitors eculizumab or ravulizumab: results from a US patient survey. Ann Hematol. 2022;101(2):251–263. doi: 10.1007/s00277-021-04715-5. PubMed DOI PMC

Cella D, Sarda SP, Hsieh R, et al. Clinically meaningful and long-term improvements in fatigue with the C3 inhibitor pegcetacoplan in paroxysmal nocturnal hemoglobinuria: post-hoc analyses from the PEGASUS study week 48. In: Abstract LPB0118. Presented at the ISTH congress, July 17–21, 2021; Philadelphia.

European Commission. Health at a glance: Europe 2020: state of health in the EU cycle. https://ec.europa.eu/health/system/files/2020-12/2020_healthatglance_rep_en_0.pdf. Accessed 25 Jan 2022.

de Villiers MR, de Villiers PJ, Kent AP. The Delphi technique in health sciences education research. Med Teach. 2005;27(7):639–643. doi: 10.1080/13611260500069947. PubMed DOI

Risitano AM, Peffault de Latour R. How we(’ll) treat paroxysmal nocturnal haemoglobinuria: diving into the future. Br J Haematol. 2022;196(2):288–303. doi: 10.1111/bjh.17753. PubMed DOI PMC

Nakayama H, Usuki K, Echizen H, et al. Eculizumab dosing intervals longer than 17 days may be associated with greater risk of breakthrough hemolysis in patients with paroxysmal nocturnal hemoglobinuria. Biol Pharm Bull. 2016;39(2):285–288. doi: 10.1248/bpb.b15-00703. PubMed DOI

de Castro C, Grossi F, Weitz IC, et al. C3 inhibition with pegcetacoplan in subjects with paroxysmal nocturnal hemoglobinuria treated with eculizumab. Am J Hematol. 2020;95(11):1334–1343. doi: 10.1002/ajh.25960. PubMed DOI PMC

Shammo J, Gajra A, Patel Y, et al. Low rate of clinically evident extravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria treated with a complement C5 inhibitor: results from a large, multicenter, US real-world study. J Blood Med. 2022;13:425–437. doi: 10.2147/JBM.S361863. PubMed DOI PMC

Patriquin CJ, Kiss T, Caplan S, et al. How we treat paroxysmal nocturnal hemoglobinuria: a consensus statement of the Canadian PNH Network and review of the national registry. Eur J Haematol. 2019;102(1):36–52. doi: 10.1111/ejh.13176. PubMed DOI

de Castro C, Hillmen P, Szer J, et al. CT-286: Results of the PEGASUS phase 3 randomized trial demonstrating superiority of the C3 inhibitor, pegcetacoplan, compared to eculizumab in patients withparoxysmal nocturnal hemoglobinuria. Clin Lymphoma Myeloma Leuk. 2020;20(1):S216–S217. doi: 10.1016/S2152-2650(20)30783-7. DOI

Sakai K. Even mild hemolysis in paroxysmal nocturnal hemoglobinuria could severely compromise the quality of life due to long-term sustained intolerant fatigue. Leuk Res Rep. 2020;14(1):100224. PubMed PMC

Cella D, Sarda SP, Hsieh R, et al. Changes in hemoglobin and clinical outcomes drive improvements in fatigue, quality of life, and physical function in patients with paroxysmal nocturnal hemoglobinuria: post hoc analyses from the phase III PEGASUS study. Ann Hematol. 2022;101(9):1905–1914. doi: 10.1007/s00277-022-04887-8. PubMed DOI PMC

Nishimura J, Yamamoto M, Hayashi S, et al. Genetic variants in C5 and poor response to eculizumab. N Engl J Med. 2014;370(7):632–639. doi: 10.1056/NEJMoa1311084. PubMed DOI

Nishimura J, Kanakura Y. The C5 gene polymorphism in patients with PNH. Rinsho Ketsueki. 2015;56(2):103–110. PubMed

Nishimura J-I, Yamamoto M, Hayashi S, et al. A rare genetic polymorphism in C5 confers poor response to the anti-C5 monoclonal antibody eculizumab by nine Japanese patients with PNH. Blood. 2012;120(21):3197. doi: 10.1182/blood.V120.21.3197.3197. DOI

Ishiyama K, Nakao S, Usuki K, et al. Results from multinational phase 3 studies of ravulizumab (ALXN1210) versus eculizumab in adults with paroxysmal nocturnal hemoglobinuria: subgroup analysis of Japanese patients. Int J Hematol. 2020;112(4):466–476. doi: 10.1007/s12185-020-02934-6. PubMed DOI

Tamura S, Hori Y, Hiroi T, et al. Pegcetacoplan for refractory paroxysmal nocturnal haemoglobinuria associated with the C5 genetic variant. Br J Haematol. 2021;1(1):1–3. PubMed