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. 2025 Oct 14;9(19):4936-4945.
doi: 10.1182/bloodadvances.2024015490.

Characterizing clinically significant extravascular hemolysis in adults with PNH on ravulizumab or eculizumab treatment

Austin G Kulasekararaj  1 , Jong Wook Lee  2 , Christopher J Patriquin  3 , Caroline I Piatek  4 , Alexander Röth  5 , Wilma Barcellini  6 , Robert A Brodsky  7 , Jun-Ichi Nishimura  7 , Ji Yu  8 , Mohammed Mahdi  8 , Régis Peffault de Latour  9
Affiliations

Characterizing clinically significant extravascular hemolysis in adults with PNH on ravulizumab or eculizumab treatment

Austin G Kulasekararaj et al. Blood Adv. .

Abstract

In patients with paroxysmal nocturnal hemoglobinuria (PNH), the complement component 5 (C5) inhibitors ravulizumab and eculizumab control terminal complement activity and intravascular hemolysis, which are drivers of morbidity and mortality. During C5 inhibitor treatment, ongoing C3 fragment deposition on surviving PNH red blood cells may cause clinically significant extravascular hemolysis (csEVH) in some patients. csEVH is not thought to be life threatening but may cause symptomatic anemia and need for transfusion. This post hoc analysis of studies 301 (NCT02946463) and 302 (NCT03056040) evaluated the prevalence of csEVH (symptomatic anemia [hemoglobin levels <9.5 g/dL] with absolute reticulocyte count ≥120 × 109/L) in adult patients with PNH treated with ravulizumab or eculizumab for 6 months (183 days). The association between csEVH and fatigue (measured using the Functional Assessment of Chronic Illness Therapy - Fatigue [FACIT-F] scale) was also evaluated in study 302 patients with stable disease. On day 183 of studies 301 and 302, csEVH prevalence was 23.2% (29/125) and 20.2% (19/94) with ravulizumab and 24.8% (30/121) and 21.3% (20/94) with eculizumab, respectively. All patients in study 302 with csEVH experienced fatigue, which was mostly mild (ravulizumab, 79%; eculizumab, 65%) or moderate (ravulizumab, 21%; eculizumab, 30%). FACIT-F scores remained stable from baseline (ravulizumab, 42.2; eculizumab, 38.3) to day 183 (ravulizumab, 44.3; eculizumab, 38.3), close to general population normative values. This analysis demonstrated that csEVH affected 20% to 25% of patients with PNH, most of whom experienced mild fatigue, with fatigue remaining stable during treatment. Ravulizumab and eculizumab continue to provide benefit to adults with PNH with csEVH.

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Conflict of interest statement

Conflict-of-interest disclosure: A.G.K. has received honoraria from Alexion, AstraZeneca Rare Disease, Amgen, Celgene/Bristol Myers Squibb (BMS), Novartis, and Ra Pharma; is on the board of directors or advisory boards for Alexion, AstraZeneca Rare Disease, Amgen, Celgene/BMS, Novartis, Pfizer, Roche, and Ra Pharma; and has received consultancy fees from Achillion, Akari Therapeutics, Alexion, AstraZeneca Rare Disease, BioCryst, Celgene/BMS, Janssen Pharmaceuticals, Novartis, Novo Nordisk, Pfizer, Roche, and Samsung. J.W.L. has received research funding from Achillion and Alexion, AstraZeneca Rare Disease; served as advisory board member for and received honoraria from Alexion, AstraZeneca Rare Disease; and received consultancy fees from Kyowa Kirin, Novartis, and Sanofi. C.J.P. has received consultancy fees from Alexion, AstraZeneca Rare Disease, BioCryst, Novartis, Roche, Sanofi, Sobi, and Takeda; and received speaker’s bureau fees from Alexion, AstraZeneca Rare Disease, Amgen, Novartis, and Sobi. C.I.P. has received consulting fees from Alexion, AstraZeneca Rare Disease/AstraZeneca, and Rigel; received advisory board fees from Alexion, Annexon Biosciences, AstraZeneca Rare Disease/AstraZeneca, Apellis, Sanofi, Sobi/Dova, Novartis, and Rigel; received research support from Alexion, Apellis, Argenx, AstraZeneca Rare Disease/AstraZeneca, Celgene, Incyte, Oscotec, Rigel, and Sanofi; and received speaker’s bureau fees from Apellis and Sobi/Dova. A.R. has received research funding from Roche; received travel support from AbbVie, Alexion, AstraZeneca Rare Disease, and Sobi; received lecture honoraria from Alexion, AstraZeneca Rare Disease, Amgen, Grifols, Novartis, Roche, Sanofi, and Sobi; and received consultancy fees from Alexion, AstraZeneca Rare Disease, Apellis, BioCryst, Bioverativ, Kira, Novartis, Pfizer, and Sanofi. R.A.B. has received research funding and consultancy fees from Alexion, AstraZeneca Rare Disease; and received honoraria from Alexion, AstraZeneca Rare Disease, American Society of Hematology, Indy Hematology Review, International Society on Thrombosis and Haemostasis Congress, and UpToDate. J.-i.N. has a membership on the board of directors or advisory committees for Alexion, AstraZeneca Rare Disease, Chugai Pharmaceutical Co, and Roche; and has received research funding from Alexion, AstraZeneca Rare Disease. J.Y. is a current employee of and shareholder in Alexion, AstraZeneca Rare Disease. M.M. is a current employee of and shareholder in Alexion, AstraZeneca Rare Disease. R.P.d.L. has served as an advisory board member for and has received consultancy fees, research funding, and speaker’s bureau fees from Alexion Pharmaceuticals Inc. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Distribution of fatigue levels in study 302 at day 183 based on FACIT-F score in patients with csEVH. Mild indicates FACIT-F score ≥40; moderate, FACIT-F score ≥20 to <40; severe, FACIT-F score <20.
Figure 2.
Figure 2.
Change in mean fatigue score over time using FACIT-F score in patients with csEVH from study 302. FACIT-F score ranges from 0 to 52, with a higher score indicating less fatigue.
See this image and copyright information in PMC

Comment in

  • Extravascular hemolysis in PNH.
    Szer J. Szer J. Blood Adv. 2025 Oct 14;9(19):4977-4978. doi: 10.1182/bloodadvances.2025016873. Blood Adv. 2025. PMID: 41026938 Free PMC article. No abstract available.

References

    1. 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. - PMC - PubMed
    1. Risitano AM, Rotoli B. Paroxysmal nocturnal hemoglobinuria: pathophysiology, natural history and treatment options in the era of biological agents. Biologics. 2008;2(2):205–222. - PMC - PubMed
    1. Brodsky RA. Paroxysmal nocturnal hemoglobinuria. Blood. 2014;124(18):2804–2811. - PMC - PubMed
    1. Hill A, DeZern AE, Kinoshita T, Brodsky RA. Paroxysmal nocturnal haemoglobinuria. Nat Rev Dis Primers. 2017;3:17028. - PMC - PubMed
    1. Soliris®. Prescribing information. US Food and Drug Administration; 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125166s431lbl.pdf