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

First-Line Treatment for Paroxysmal Nocturnal Hemoglobinuria

Eculizumab (or ravulizumab) is the first-line treatment for PNH, as these complement C5 inhibitors are FDA-approved specifically to reduce hemolysis and represent the only disease-modifying therapy that improves survival, reduces thrombotic complications, and eliminates transfusion dependence in the majority of patients. 1, 2

Complement C5 Inhibitors: The Standard of Care

Eculizumab (Soliris)

• FDA-approved for PNH treatment to reduce hemolysis 2
• Dosing regimen for adults: 600 mg weekly for 4 weeks, then 900 mg at week 5, followed by 900 mg every 2 weeks thereafter 2
• Blocks terminal complement-mediated intravascular hemolysis by binding C5 protein with high affinity 3, 4
• Dramatically reduces transfusion requirements from mean 19.3 units/year pre-treatment to 5.0 units/year on therapy 5
• Achieves transfusion independence in 66% of patients treated for more than 12 months 5
• Normalizes survival to match age- and sex-matched controls, representing a fundamental change in disease natural history 5

Ravulizumab (Ultomiris)

• FDA-approved second-generation C5 inhibitor with longer half-life 1
• Administered every 8 weeks (versus every 2 weeks for eculizumab), improving patient convenience 6
• Reduces pharmacokinetic breakthrough hemolysis by establishing more stable anti-C5 concentrations 6
• Equivalent efficacy to eculizumab with superior dosing schedule 6

Critical Pre-Treatment Requirements

Mandatory Meningococcal Vaccination

• Complete meningococcal vaccination (serogroups A, C, W, Y, and B) at least 2 weeks before first dose 2
• If urgent therapy cannot be delayed, provide antibacterial prophylaxis and vaccinate as soon as possible 2
• Complement inhibition increases risk of life-threatening meningococcal infections that can become rapidly fatal 2
• Available only through ULTOMIRIS and SOLIRIS REMS program due to infection risk 2

Thrombosis Management

Anticoagulation Strategy

• For venous thrombosis in unusual sites (Budd-Chiari syndrome, portal vein thrombosis), indefinite anticoagulation is recommended even with complement inhibitor therapy 7
• Complement inhibitors reduce thrombotic events from 5.6 per 100 patient-years to 0.8 per 100 patient-years 5
• Patients without previous thrombosis can safely discontinue warfarin after starting eculizumab 5

Site-Specific Thrombosis Management

• Budd-Chiari syndrome (found in 9-19% of BCS patients with PNH): requires long-term anticoagulation plus hepatology consultation for possible TIPS procedure 7
• Cerebral thrombosis: requires immediate anticoagulation combined with C5 inhibitor therapy and neurological evaluation 7

Suboptimal Response Management

Recognizing Incomplete Response

• Up to 67% of patients may have suboptimal response with persistent anemia due to: 6
  • Incomplete control of intravascular hemolysis
  • Development of C3-mediated extravascular hemolysis (EVH)
  • Concomitant bone marrow failure

Second-Line Options for Suboptimal Responders

• Upstream complement inhibitors (pegcetacoplan, iptacopan, danicopan) efficiently target extravascular hemolysis and improve anemia in patients with inadequate response to C5 inhibitors 6
• These agents block complement cascade at C3, factor B, or factor D levels 6

Common Pitfalls to Avoid

• Do not delay vaccination: Meningococcal vaccination must precede therapy by 2 weeks unless clinical urgency mandates immediate treatment with concurrent antibiotic prophylaxis 2
• Do not discontinue anticoagulation prematurely: Patients with prior thrombosis in unusual sites require indefinite anticoagulation despite complement inhibition 7
• Do not ignore persistent anemia: Transfusion-dependent patients on C5 inhibitors may have extravascular hemolysis requiring upstream complement blockade 6
• Monitor for breakthrough hemolysis: Infections, trauma, and surgery can trigger complement amplification despite therapy 6