What is the recommended treatment for patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) findings?

Paroxysmal Nocturnal Hemoglobinuria (PNH): Diagnosis and Treatment

Diagnostic Workup

When PNH is suspected, immediately obtain flow cytometry to evaluate loss of GPI-anchored proteins on peripheral blood cells, which is the gold standard for diagnosis. 1

Essential laboratory evaluation includes:

• Complete blood count with peripheral smear showing evidence of hemolysis (schistocytes, macrocytosis) 1
• Markers of hemolysis: elevated LDH, low haptoglobin, elevated indirect bilirubin, elevated reticulocyte count 1
• Flow cytometry to quantify the proportion of GPI-negative cells in neutrophils and red blood cells 1
• Direct antibody test (Coombs) to exclude autoimmune hemolytic anemia 1
• Renal function tests and urinalysis for hemoglobinuria 1
• Complement testing (C3, C4, CH50) to evaluate complement activity 1

Additional workup to exclude other causes:

• Bone marrow biopsy and aspirate to evaluate for aplastic anemia or myelodysplastic syndrome 1
• Viral studies (CMV, EBV, HHV6, parvovirus) 1
• Nutritional assessments (B12, folate, iron) 1
• Evaluation for thrombophilia if thrombotic events present 1

Treatment Recommendations

Complement Inhibitor Therapy (First-Line)

For patients with PNH and clinically significant hemolysis, initiate eculizumab (or ravulizumab) as first-line therapy to reduce intravascular hemolysis and prevent thrombotic complications. 2, 3

Eculizumab dosing for PNH in adults: 2

• 600 mg IV weekly for 4 weeks
• 900 mg IV at week 5
• 900 mg IV every 2 weeks thereafter

Ravulizumab is an alternative long-acting C5 inhibitor approved for PNH treatment 3

Critical Pre-Treatment Requirements

All patients MUST receive meningococcal vaccination (serogroups A, C, W, Y, and B) at least 2 weeks before starting complement inhibitor therapy. 2, 3 This is non-negotiable due to the dramatically increased risk of life-threatening meningococcal infection with complement blockade.

If urgent therapy is required before vaccination can provide immunity:

• Administer vaccines immediately 2
• Provide prophylactic antibiotics (typically ciprofloxacin or penicillin) until 2 weeks post-vaccination 1, 2
• Monitor closely for signs of meningococcal infection (fever, headache, neck stiffness) 2

Evidence for Complement Inhibitor Efficacy

The evidence supporting eculizumab is moderate quality but consistent:

• Reduces intravascular hemolysis: LDH levels decrease from mean 3111 IU/L to 594 IU/L (P=0.002) 4
• Decreases transfusion requirements: median transfusion rate reduced from 1.8 to 0.0 units per patient per month (P=0.003) 4
• Improves survival: 6-year overall survival 92% with eculizumab versus 80% in historical controls (HR 0.38, P=0.037) 5
• Reduces thrombotic events: 4% with eculizumab versus 27% in untreated patients 5
• Improves quality of life: significant improvement in fatigue scores and health-related quality of life measures 6, 4

A Cochrane review noted the evidence comes from one small trial with risk of bias, but the clinical benefits are substantial enough to support use 6

Supportive Care Measures

While awaiting or alongside complement inhibitor therapy:

• Folic acid supplementation 1 mg daily to support erythropoiesis 1
• Red blood cell transfusions for symptomatic anemia (target hemoglobin 7-8 g/dL in stable patients) 1
• Anticoagulation should be strongly considered for patients with prior thrombotic events, as thrombosis risk persists even on eculizumab 5
• Iron supplementation (oral or IV) may be needed for iron deficiency from chronic hemoglobinuria 1

Management of Severe Hemolysis or Thrombosis

For grade 3-4 hemolysis with clinical consequences (renal insufficiency, severe anemia):

• Permanently discontinue any immune checkpoint inhibitors if hemolysis is immune-related 1
• Begin eculizumab therapy 900 mg weekly for 3-4 doses, then 1200 mg at week 5, then 1200 mg every 2 weeks 1
• Provide red blood cell transfusions according to existing guidelines for life-threatening anemia 1
• Hematology consultation is mandatory 1

Monitoring on Treatment

Regular monitoring should include:

• Hemoglobin and reticulocyte count to assess response 1
• LDH levels to monitor hemolysis (though some extravascular hemolysis may persist) 4, 7
• Transfusion requirements as a clinical endpoint 4
• Signs of breakthrough hemolysis (dark urine, fatigue, abdominal pain) 2
• Surveillance for meningococcal infection (fever, headache, altered mental status) 2

Special Considerations and Pitfalls

Common pitfall: Assuming eculizumab eliminates all hemolysis. While it blocks intravascular hemolysis, extravascular hemolysis of C3b-opsonized cells can continue, and some patients remain transfusion-dependent 6, 4

Thrombosis risk persists: Even on eculizumab, patients with prior thrombotic events remain at higher risk and may require ongoing anticoagulation 5

Breakthrough hemolysis: Can occur with infections or complement-amplifying conditions; may require dose adjustment or additional supportive care 2

Pregnancy considerations: PNH patients have increased maternal and fetal risks; eculizumab can be continued during pregnancy with close monitoring 2

Allogeneic stem cell transplantation: Remains the only curative option for PNH but carries significant morbidity; eculizumab can be used prophylactically post-transplant to prevent hemolysis during engraftment 8

REMS Program Requirement

Eculizumab is only available through the ULTOMIRIS and SOLIRIS REMS program due to meningococcal infection risk. 2 Prescribers must enroll in this restricted program, and patients must be counseled about infection risks and the need for immediate evaluation if fever or signs of infection develop.