Marek Ussowicz ^1* Dawid Przystupski ¹ Patrycja Mensah-Glanowska ² Agnieszka Piekarska ³

• ¹ Wroclaw Medical University, Wrocław, Poland
• ² Department of Hematology, Jagiellonian University Medical College, Kraków, Lesser Poland, Poland
• ³ Department of Haematology and Transplantology, Faculty of Medicine, Medical University of Gdansk, Gdańsk, Pomeranian, Poland

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, complement-driven, acquired hemolytic anemia with specific presentations of hemoglobinuria, abdominal pain, fatigue, and thrombosis.Objective: This review covers current therapeutic strategies, including anticomplement therapy and allogeneic hematopoietic cell transplantation (alloHCT), emphasizing that the approach should be tailored to disease subtypes.Results: The outcome of alloHCT varies depending on disease severity, thrombotic history, and response to prior therapies. The non-transplant PNH therapies include anti-C5 monoclonal antibodies that reduce terminal complement activation (eculizumab, ravulizumab, and crovalimab) and proximal complement pathway inhibitors such as the C3 inhibitor pegcetacoplan, the complement factor B inhibitor iptacopan, and the complement factor D inhibitor danicopan. While complement inhibitors have revolutionized treatment, alloHCT remains the only curative therapy, particularly for patients who are refractory to medical management or those with severe cytopenia. This manuscript outlines the conditioning regimens used in HCT and summarizes recent studies showing that overall survival rates improve with less toxic conditioning protocols.Conclusions: HCT can be used in PNH management, particularly for patients who are resistant to or without access to complement-targeted therapies. Any potential cure offered with alloHCT must be counterbalanced by the significant risk of the procedure, including graft-versus-host disease and transplant-related mortality, particularly in patients with comorbidities. In the case of severe aplastic anemia with an associated PNH clone, immunoablative protocols based on ATG serotherapy with fludarabine and Cy are recommended. In classic PNH patients, the tendency to use reduced toxicity protocols with fludarabine has been well documented. A treosulfan/fludarabine-based regimen can be recommended, but there is no consensus as to the choice of drugs with optimal efficacy in this context.