Expert Consensus on the Diagnosis and Monitoring of Paroxysmal Nocturnal Hemoglobinuria (PNH): An Algorithmic Approach in an Era of New Treatments.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disorder caused by a defect of glycosylphosphatidyl-anchored proteins, leading to an uncontrolled complement-mediated hemolysis. The advent of complement inhibitors in clinical practice radically changed patients' outcomes and survival. Despite this significant progress, numerous unmet needs persist in clinical practice. A group of Italian experts explored the main challenges currently associated with PNH diagnosis and monitoring and reached a consensus on screening, diagnosis, initial work-up, and monitoring. The following core questions were examined: (i) Which patients need to be tested? (ii) Which test to use, and how do we define positivity? (iii) Which workup is requested for patients with a newly detected PNH clone? (iv) Which monitoring in untreated patients? (v) Which monitoring in C-terminal-inh and C-proximal inh? Each specific clinical question was framed according to the GRADE format. Overall, flow-cytometry for PNH detection was recommended in patients presenting with two or more suggestive signs or symptoms and/or with hematologic conditions known to be associated with PNH clones, including DAT-negative hemolysis, idiopathic venous thrombosis (particularly at atypical sites), and primary bone marrow dysfunction (such as aplastic anemia or myelodysplastic syndrome). A high-sensitivity flow cytometry test in neutrophils and erythrocytes should be preferred (lower limit of quantification 0.01%). Baseline assessment of disease activity (i.e., LDH > 1.5×ULN and PNH signs/symptoms), thrombotic risk, bone marrow (BM) features and imaging for organ dysfunction are suggested. Monitoring comprises blood counts and hemolytic markers with frequency depending on anemia severity and symptoms, as well as annual PNH clone retesting, BM reevaluation in case of cytopenias, and constant education about infectious risk and breakthrough hemolysis in patients on treatment.