Breakthrough hemolysis in paroxysmal nocturnal hemoglobinuria throughout clinical trials: from definition to clinical practice

Abstract Breakthrough hemolysis (BTH) is the hemolytic exacerbation occurring in a patient with paroxysmal nocturnal hemoglobinuria (PNH) on treatment with anticomplement therapies. In this review article, we analyzed the definition, frequency, and severity of BTH events across phase 3 clinical trials with terminal (anti-C5 ravulizumab and crovalimab) and complement inhibitors upstream C5 (anti-C3 pegcetacoplan, alternative-pathway inhibitors iptacopan, and danicopan), as well as from real-world reports. Furthermore, we reviewed the impact of the various compounds on quality of life and patient-reported outcomes. In particular, BTH may occur with all complement inhibitors, with a frequency of 10% to 15% over 6 months with eculizumab, crovalimab, and pegcetacoplan, and <5% with ravulizumab, iptacopan, and danicopan plus anti-C5. By prolonging the follow-up, the frequency of BTH appeared increased in patients treated with pegcetacoplan (nearly 24% at 1 year) as compared with both anti-C5, iptacopan, and double inhibition with danicopan plus anti-C5. BTH risk appears associated with patients’ features, particularly suboptimal response/failure of previous complement inhibitor. Transfusions were required in approximately half of cases and modifications of anticomplement therapy included anticipation of the next anti-C5 dose and addition of eculizumab in patients on proximal inhibitors. Breakthrough thromboses were rare, although anticoagulant prophylaxis should be considered during severe episodes. Complement amplifying conditions were observed in approximately half of cases and were more frequently infections. Treatment adherence, optimization of the administration schedule, anticoagulant prophylaxis, as well as education of patients and physicians remain important factors to prevent BTH and its complications.