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

Treatment of Paroxysmal Nocturnal Hemoglobinuria (PNH)

Eculizumab is the primary treatment for paroxysmal nocturnal hemoglobinuria (PNH) and should be initiated promptly upon diagnosis to reduce mortality and prevent life-threatening complications. 1

Understanding PNH

PNH is a rare acquired clonal hematopoietic disorder characterized by:

• Chronic complement-mediated intravascular hemolysis
• Increased risk of thrombosis
• Bone marrow dysfunction
• Fatigue and reduced quality of life

First-Line Treatment: Complement Inhibition

Eculizumab Therapy

• Mechanism: Humanized monoclonal antibody that binds to complement protein C5, preventing formation of the terminal complement complex C5b-9 that mediates cell lysis 2
• Administration: Intravenous infusion
• Vaccination requirement: Patients must receive meningococcal vaccination at least 2 weeks before starting eculizumab due to increased risk of Neisseria meningitidis infection 1

Clinical Benefits of Eculizumab

1. Survival benefit: Normalizes survival to that of the general population 3
2. Reduction in thrombosis: Decreases thrombotic events from 5.6 to 0.8 events per 100 patient-years 3
3. Hematologic improvement:
   • Rapidly reduces intravascular hemolysis (within 1 week)
   • Achieves transfusion independence in approximately 66% of patients treated for >12 months 3
   • Stabilizes hemoglobin levels 2
4. Quality of life improvement:
   • Reduces fatigue and dyspnea
   • Improves overall quality of life scores 4

Monitoring During Treatment

• Regular LDH levels to assess hemolysis control
• Complete blood counts
• Renal function tests
• Surveillance for breakthrough hemolysis
• Monitoring for meningococcal infection

Management of Specific PNH Complications

Thrombosis Management

• For patients with SVT (splanchnic vein thrombosis) and PNH:
  • Long-term eculizumab treatment is indicated 1
  • Anticoagulation may be required in addition to eculizumab

Anemia Management

Despite eculizumab treatment, some patients may have residual anemia due to:

• Underlying bone marrow dysfunction
• Residual intravascular hemolysis
• C3-mediated extravascular hemolysis 5

For persistent anemia:

• Consider red blood cell transfusions for symptomatic anemia
• Evaluate for concurrent bone marrow disorders

Limitations and Emerging Therapies

Limitations of Eculizumab

• Complete normalization of hemoglobin occurs in only about one-third of patients 5
• Some patients continue to require transfusions despite treatment
• Risk of breakthrough hemolysis

Emerging Therapies

• Novel terminal complement inhibitors: Target C5 like eculizumab but with longer duration of action and subcutaneous administration 5
• Proximal complement inhibitors: Target earlier steps in complement cascade (anti-C3, anti-factor D, or anti-factor B agents) 5
  • May prevent both intravascular and C3-mediated extravascular hemolysis
  • Available in oral or subcutaneous formulations
  • Being studied as monotherapy or in combination with eculizumab

Common Pitfalls in PNH Management

1. Delayed diagnosis and treatment: PNH should be considered in cases of unexplained hemolysis, thrombosis (especially in unusual sites), or cytopenias
2. Inadequate meningococcal vaccination: Must be completed before initiating eculizumab
3. Failure to recognize breakthrough hemolysis: Regular monitoring of LDH and hemoglobin is essential
4. Overlooking bone marrow dysfunction: Some patients may have concurrent aplastic anemia or myelodysplasia
5. Premature discontinuation of anticoagulation: Carefully evaluate thrombotic risk before stopping anticoagulation in patients on eculizumab

Eculizumab has revolutionized the treatment of PNH by addressing the fundamental complement-mediated hemolysis, reducing thrombotic risk, and improving survival to levels comparable with the general population.