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

Treatment for Paroxysmal Nocturnal Hemoglobinuria (PNH)

Eculizumab is the first-line treatment for patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) to reduce hemolysis, prevent thrombotic events, and improve survival. 1

Diagnosis and Evaluation

• Flow cytometry to evaluate loss of GPI-anchored proteins is essential for confirming PNH diagnosis 2
• Complete blood count with peripheral smear and reticulocyte count should be performed to assess the degree of hemolysis 2
• Laboratory evaluation should include LDH, haptoglobin, and direct antibody test (Coombs test) to characterize the hemolytic process 2
• Testing for complement levels (C3, C4, CH50) may be helpful in evaluating the complement system involvement 2

First-Line Treatment

• Eculizumab (Soliris), a C5 complement inhibitor, is FDA-approved for PNH treatment with the following dosing regimen: 1

  • For adults: 600 mg weekly for the first 4 weeks, followed by 900 mg for the fifth dose 1 week later, then 900 mg every 2 weeks thereafter
  • Dosing should be administered at the recommended time points or within two days of these points

• Ravulizumab (Ultomiris), a longer-acting C5 inhibitor, is also FDA-approved for PNH with less frequent dosing (every 8 weeks) 3, 4

Pre-Treatment Requirements

• Meningococcal vaccination (for serogroups A, C, W, Y, and B) must be administered at least 2 weeks prior to starting eculizumab or ravulizumab 1
• If urgent therapy is required before vaccination can take effect, antibacterial prophylaxis should be provided 1
• Patients must be enrolled in the ULTOMIRIS and SOLIRIS REMS program due to increased risk of serious meningococcal infections 1

Clinical Benefits of Complement Inhibition

• Significant reduction in intravascular hemolysis (87% reduction in one study) 5
• Reduced transfusion requirements with 66% of patients achieving transfusion independence after 12 months of treatment 6
• Dramatic decrease in thrombotic events from 5.6 events per 100 patient-years before treatment to 0.8 events per 100 patient-years on treatment 6
• Improved survival comparable to age- and sex-matched normal controls 6
• Improvement in chronic kidney disease in 41% of patients within 12 weeks 5
• Rapid improvement in fatigue and dyspnea within 1-2 weeks of treatment initiation 5

Monitoring and Follow-up

• Regular monitoring of hemoglobin, LDH, and clinical symptoms is necessary to assess treatment efficacy 2
• Patients should be monitored for signs of breakthrough hemolysis, especially during infections or other complement-activating conditions 4
• Vigilance for early signs of meningococcal infection is critical due to increased risk with complement inhibition 1, 7

Special Considerations

• For patients with PNH undergoing allogeneic hematopoietic stem cell transplantation (HSCT), eculizumab may be used prophylactically in the post-transplant period to prevent hemolysis and thrombosis 8
• For patients with both PNH and Budd-Chiari syndrome, long-term anticoagulant therapy in addition to eculizumab is indicated 2
• Patients with PNH clones who develop thrombosis should receive indefinite anticoagulation in addition to complement inhibitor therapy 2

Treatment Limitations and Emerging Therapies

• Up to 2/3 of patients may have suboptimal response due to incomplete control of intravascular hemolysis, C3-mediated extravascular hemolysis, or concomitant bone marrow failure 4
• Newer complement inhibitors targeting upstream components (C3, factor B, factor D) are in development to address these limitations 4
• Pegcetacoplan (anti-C3), iptacopan (anti-factor B), and danicopan (anti-factor D) show promise for patients with suboptimal response to C5 inhibitors 4

Potential Adverse Effects

• Serious meningococcal infections (life-threatening if not recognized and treated early) 1
• Development of human anti-human antibodies (rare) 7
• Breakthrough hemolysis during infections or other complement-activating conditions 4

PNH treatment has been revolutionized by complement inhibitors, transforming a previously life-threatening disease into a chronic condition with survival rates approaching those of the general population when properly treated.