What is the first-line treatment for Paroxysmal Nocturnal Hemoglobinuria (PNH)?

First-Line Treatment for Paroxysmal Nocturnal Hemoglobinuria (PNH)

Eculizumab is the first-line treatment for patients with paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis and associated complications. 1

Understanding PNH

PNH is a rare, acquired hematopoietic stem cell disorder characterized by:

• Complement-mediated chronic hemolysis due to lack of glycosylphosphatidylinositol (GPI)-anchored complement regulatory proteins 2
• Increased risk of life-threatening thrombosis 3
• Potential for chronic kidney disease (66% of patients) 2
• Significant fatigue and reduced quality of life 4

First-Line Treatment Options

Anti-C5 Complement Inhibitors

1. Eculizumab (Soliris)

   • FDA-approved for PNH to reduce hemolysis 1
   • Dosing regimen: 600 mg weekly for first 4 weeks, followed by 900 mg for fifth dose, then 900 mg every 2 weeks thereafter 1
   • Demonstrated benefits:
     • 87% reduction in hemolysis 2
     • Improvement in anemia 2
     • Reduction in transfusion requirements 2, 4
     • Improvement in fatigue and dyspnea within 1-2 weeks 2
     • Improvement in chronic kidney disease in 41% of patients 2
     • Normalization of D-dimer levels (thrombosis marker) 2

2. Ravulizumab (Ultomiris)

   • FDA-approved for PNH in adults and pediatric patients one month of age and older 5
   • Extended dosing interval (every 8 weeks vs. every 2 weeks for eculizumab) 3
   • Provides more stable C5 inhibition with reduced breakthrough hemolysis 3, 6
   • Long-term data shows durable control of terminal complement activity and intravascular hemolysis for up to 6 years 6
   • Five-fold reduction in mortality risk compared to untreated patients 6

Important Considerations

1. Meningococcal Vaccination

   • Mandatory vaccination against meningococcal infection (serogroups A, C, W, Y, and B) at least 2 weeks prior to initiating complement inhibitor therapy 1
   • If urgent therapy is needed before vaccination, antibacterial prophylaxis must be provided 1

2. Treatment Limitations

   • Approximately 30% of patients on C5 inhibitors develop clinically significant extravascular hemolysis with ongoing transfusion requirements 7
   • Breakthrough hemolysis can occur during complement-amplifying conditions (infections, trauma, surgery) 3, 6

Emerging Treatment Options

For patients with suboptimal response to C5 inhibitors:

• Crovalimab: Subcutaneous anti-C5 administered every 4 weeks 7
• Pegcetacoplan: Anti-C3 inhibitor that targets both intravascular and extravascular hemolysis 3, 7
• Iptacopan: Oral factor B inhibitor that controls both types of hemolysis 3, 7
• Danicopan: Oral factor D inhibitor used as add-on to C5 inhibitors 3, 7

Treatment Algorithm

1. Confirm PNH diagnosis through flow cytometry to detect GPI-anchor deficient blood cells
2. Evaluate for meningococcal vaccination and administer at least 2 weeks before starting complement inhibitor 1
3. Initiate eculizumab or ravulizumab as first-line therapy 5, 1
4. Monitor for:
   • Breakthrough hemolysis (LDH levels)
   • Transfusion requirements
   • Thrombotic events
   • Renal function
5. Consider alternative or additional therapies if suboptimal response occurs (persistent anemia, transfusion dependence) 3, 7

Common Pitfalls and Caveats

• Failure to recognize PNH in patients with unexplained hemolysis, thrombosis, or bone marrow failure 8
• Inadequate meningococcal vaccination before initiating complement inhibitor therapy 1
• Not monitoring for breakthrough hemolysis during infections or other complement-activating conditions 3, 6
• Overlooking extravascular hemolysis in patients with persistent anemia despite C5 inhibitor therapy 3, 7
• Discontinuing therapy without close monitoring, as this can lead to rapid hemolysis and potential thrombotic events 1