What is the primary treatment for a patient with Paroxysmal Nocturnal Hemoglobinuria (PNH)?

Primary Treatment for Paroxysmal Nocturnal Hemoglobinuria (PNH)

The primary treatment for PNH is complement inhibition with terminal complement C5 inhibitors (eculizumab or ravulizumab), which dramatically reduce intravascular hemolysis, prevent thrombosis, and normalize survival to that of the general population. 1, 2, 3

First-Line Complement Inhibitor Therapy

C5 Inhibitors (Standard of Care)

Eculizumab (Soliris) is the established first-line therapy for PNH patients requiring treatment 1, 3:

• Dosing regimen: 600 mg IV weekly for 4 weeks, then 900 mg at week 5, followed by 900 mg every 2 weeks thereafter 1
• Reduces intravascular hemolysis by 85% and decreases transfusion requirements by 86% 3
• Improves survival to match age- and sex-matched controls (no statistical difference, p=0.46) 3
• Reduces thrombosis risk from 5.6 events per 100 patient-years to 0.8 events per 100 patient-years (p<0.001) 3

Ravulizumab (Ultomiris) is an alternative C5 inhibitor with less frequent dosing 2, 4:

• Administered IV every 8 weeks (compared to eculizumab's every 2 weeks) 4
• Provides durable control of terminal complement activity with 6-year efficacy data 4
• FDA-approved for PNH in patients one month of age and older 2

Crovalimab is the newest C5 inhibitor option 4:

• Administered subcutaneously every 4 weeks 4
• Offers convenience of home administration 4

Critical Safety Requirement: Meningococcal Vaccination

All patients MUST be vaccinated against meningococcal bacteria (serogroups A, C, W, Y, and B) at least 2 weeks before starting complement inhibitor therapy 1, 2:

• If urgent therapy is needed before vaccination can be completed, provide antibacterial prophylaxis and vaccinate as soon as possible 1
• Life-threatening and fatal meningococcal infections have occurred with complement inhibitors 1
• These medications are only available through a restricted REMS program due to infection risk 1

Alternative Complement Inhibitors for Inadequate Response

Approximately 30% of patients develop clinically significant extravascular hemolysis despite C5 inhibitor therapy, requiring alternative approaches 4:

Upstream Complement Inhibitors (for C5 inhibitor-inadequate responders)

Pegcetacoplan (C3 inhibitor) 4, 5:

• Administered subcutaneously twice weekly 4
• Controls both intravascular and extravascular hemolysis 4
• Effective in C5 inhibitor-naive and C5 inhibitor-experienced patients 4
• May require dose adjustments during surgery or infections to prevent breakthrough hemolysis 5

Iptacopan (Factor B inhibitor) 4:

• Administered orally twice daily 4
• Targets alternative complement pathway 4
• Increases hemoglobin and achieves transfusion avoidance 4

Danicopan (Factor D inhibitor) 4:

• Administered orally 3 times daily as add-on to eculizumab or ravulizumab 4
• Combination approach targeting both terminal complement and alternative pathway 4

Important caveat: Breakthrough hemolysis during strong complement triggers (infection, surgery) may be more severe with alternative pathway inhibitor monotherapy compared to C5 inhibitors 4

Essential Supportive Care

Folic Acid Supplementation

• 1 mg daily to support erythropoiesis 6

Red Blood Cell Transfusions

• Indicated for symptomatic anemia 6
• Target hemoglobin of 7-8 g/dL in stable patients 6
• 66% of patients on eculizumab for >12 months achieve transfusion independence 3

Iron Management

• Monitor iron parameters closely - do NOT routinely supplement iron without monitoring 7
• Iron supplementation (oral or IV) only for documented iron deficiency from chronic hemoglobinuria 6
• Ferritin levels increase significantly on eculizumab (median 104 to 528 μg/L, p=0.011), particularly in patients with low reticulocyte production or requiring transfusions 7
• Consider iron depletion therapy if overload develops 7

Anticoagulation for Thrombosis

• Indefinite anticoagulation recommended for patients with prior thrombotic events, as thrombosis risk persists even on complement inhibitors 6, 8
• For Budd-Chiari syndrome (hepatic vein thrombosis): long-term anticoagulation warranted due to severity 8
• For portal vein thrombosis: anticoagulation for at least 6 months, consider long-term based on risk factors 8
• For cerebral thrombosis: immediate anticoagulation plus C5 inhibitor therapy 8

Monitoring on Treatment

Regular monitoring should include 6:

• Hemoglobin and reticulocyte count to assess response 6
• Surveillance for breakthrough hemolysis signs: dark urine, fatigue, abdominal pain 6
• LDH levels (should decrease by ~85% on effective C5 inhibitor therapy) 3, 7

Laboratory phenomenon to recognize: Monospecific direct Coombs test becomes positive in most PNH patients on eculizumab, indicating shift to extravascular hemolysis 7. Positive immunofixation for IgG kappa may occur due to eculizumab presence in serum 7.

When to Refer to Hematology

Immediate hematology consultation is essential for 6:

• Severe hemolysis 6
• Thrombotic events 6
• Inadequate response to C5 inhibitor therapy (persistent anemia, ongoing transfusion requirements) 4