Characterization of Breakthrough Hemolysis in Patients With Paroxysmal Nocturnal Hemoglobinuria: An International Multicenter Experience

Abstract

Breakthrough hemolysis (BTH) is defined as a hemolytic exacerbation in a patient with paroxysmal nocturnal hemoglobinuria (PNH) treated with complement inhibitors (CIs). In the current era of several terminal and proximal inhibitors, there are no guidelines for defining BTH and its severity, and clinical management is not standardized. This retrospective, observational, and multicentric study evaluated BTH frequency and severity in PNH patients treated with complement inhibitors from 2007 until February 2025 at 10 centers across Italy (9 centers) and the United Kingdom (1 center). A total of 271 BTH events occurred in 102 out of 198 patients (51%), with 36/198 (18%) patients experiencing 3 or more BTH episodes over the 18-year follow-up. Most events (55%) were prompted by infections, and 24 (10%) were linked to poor compliance with oral alternative pathway inhibitors. BTH was clinically severe in about half of patients, requiring transfusion in 46%, CI dosing adjustment in 17%, and anticoagulant prophylaxis in 16%. Overall, 5 (2%) breakthrough thrombotic events occurred in patients not on prophylaxis, all during an infection. BTH incidence was 0.19 events per patient-year, maximal with proximal inhibitors (0.4 events per patient-year), and lower for anti-C5 (0.18 per patient-year). By logistic regression analysis, the main predictors of BTH were more severe disease at diagnosis (increased LDH and a shorter time to first complement inhibitor), treatment with proximal inhibitors, and poorer EBMT response category.

Keywords: breakthrough hemolysis; danicopan; eculizumab; iptacopan; paroxysmal nocturnal hemoglobinuria; pegcetacoplan; ravulizumab; thrombosis.

FIGURE 1

Incidence of breakthrough hemolysis (BTH) according to the complement inhibitor utilized, by Kaplan –Meier method. [Color figure can be viewed at wileyonlinelibrary.com]

FIGURE 2

Predictors of breakthrough hemolysis by Receiver Operating Characteristics (ROC) analysis. Variables with a statistically significant association (p < 0.05) with BTH occurrence included female gender (OR = 2.75, p < 0.001), increased LDH levels at diagnosis (OR = 1.14, p = 0.005), a shorter time from diagnosis to the first CI (OR = 1.003, p = 0.001), the administration of proximal inhibitors (OR = 4.85 compared to eculizumab, p = 0.0004), and poorer responses to CI (linear trend with OR = 4.62 and p = 0.0005 for worse responses compared to complete and major responses). Conversely, PNH/MDS was less commonly associated with BTH events compared to classic hemolytic and PNH/AA (OR = 0.26, p = 0.004). These variables resulted in an AUC = 0.82, sensitivity = 0.79, specificity = 0.67.