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

Paroxysmal Nocturnal Hemoglobinuria (PNH): Overview and Management

What is PNH?

PNH is a rare acquired clonal hematopoietic stem cell disorder caused by a somatic mutation in the PIGA gene, resulting in deficiency of glycosylphosphatidylinositol (GPI)-anchored complement regulatory proteins (CD55 and CD59), which leads to complement-mediated destruction of blood cells. 1, 2

Pathophysiology

• The PIGA gene mutation occurs in multipotent hematopoietic stem cells, causing deficient synthesis of GPI anchors 3
• Without GPI anchors, complement regulatory proteins CD55 and CD59 cannot attach to cell membranes 1
• This absence renders red blood cells, granulocytes, monocytes, and platelets vulnerable to complement-mediated lysis 3
• The result is chronic intravascular hemolysis as the primary manifestation 3

Clinical Manifestations

The classic triad of PNH consists of hemolytic anemia, pancytopenia, and thrombosis. 1

Key clinical features include:

• Intravascular hemolytic anemia with evidence of hemolysis on peripheral smear 4
• Thrombosis in unusual sites, particularly splanchnic veins (hepatic, portal, mesenteric) 4, 5
• Bone marrow failure frequently associated with aplastic anemia or myelodysplastic syndrome 1, 6
• End-organ damage manifestations: fatigue, chest pain, dyspnea, renal impairment, pulmonary hypertension 6
• Recurrent infections and cytopenias 1

Epidemiology and Natural History

• Prevalence of PNH clone is approximately 16 per million 3
• Average age of onset is early 30s, though can present at any age 3
• With supportive care alone, mortality rate is approximately 35% 6
• Before targeted therapy, PNH had >50% mortality 7
• Thrombosis is the major cause of mortality, particularly intra-abdominal thrombosis 1

Diagnostic Approach

When to Suspect PNH

Test for PNH in patients with:

• Unexplained intravascular hemolysis with negative direct antiglobulin test 4
• Venous thrombosis in unusual sites, especially splanchnic veins (Budd-Chiari syndrome occurs in 9-19% of PNH patients) 4, 5
• Cytopenias associated with bone marrow failure syndromes 4
• Young patients with hypoplastic myelodysplastic syndrome and normal cytogenetics 4

Diagnostic Testing Algorithm

Initial laboratory evaluation:

• Complete blood count with differential and reticulocyte count 4
• Peripheral blood smear examination for hemolysis 4
• Hemolysis markers: LDH (elevated), haptoglobin (low), bilirubin (elevated), free hemoglobin 4
• Renal function tests and coagulation profile 4

Confirmatory testing:

• Flow cytometry for GPI-anchored proteins is the gold standard diagnostic test 2
• Evaluate PNH clone size in granulocytes and red blood cells 4

Additional testing for patients with thrombosis:

• JAK2V617F mutation testing 4
• Thrombophilia screening 4

For patients with cytopenias:

• Bone marrow aspiration and biopsy 4
• Cytogenetic analysis 4

Risk Stratification

Patients with >60% PNH granulocytes have significantly higher thrombosis risk and require more aggressive management. 4, 5

Treatment

First-Line Therapy: Terminal Complement Inhibitors (C5 Inhibitors)

C5 inhibitors are the standard first-line therapy for PNH, as they reduce thrombosis risk, extend survival to match healthy controls, and improve quality of life. 2, 6

FDA-Approved C5 Inhibitors

Eculizumab (Soliris): 8

• Dosing for adults with PNH: 600 mg IV weekly × 4 weeks, then 900 mg at week 5, then 900 mg IV every 2 weeks thereafter
• Most extensive long-term safety and efficacy data available 2
• Reduces intravascular hemolysis, thrombosis risk, and transfusion requirements 6

Ravulizumab (Ultomiris): 9

• Dosing for adults with PNH: Weight-based loading dose followed by maintenance dosing every 8 weeks
• Longer-acting C5 inhibitor with less frequent dosing 2
• Six-year data demonstrate durable control of terminal complement activity 2

Crovalimab: 2

• Administered subcutaneously every 4 weeks
• Most recently FDA-approved C5 inhibitor 2

Critical Safety Requirement for C5 Inhibitors

MANDATORY meningococcal vaccination (serogroups A, C, W, Y, and B) at least 2 weeks before starting therapy, unless urgent treatment is needed. 8

• If urgent therapy required, provide antibacterial prophylaxis and vaccinate as soon as possible 8
• Patients remain at increased risk for invasive meningococcal disease even after vaccination 8
• Monitor for early signs of meningococcal infection and evaluate immediately if suspected 8
• Available only through REMS program due to meningococcal infection risk 8

Second-Line Therapy: Proximal Complement Inhibitors

Approximately 30% of patients on C5 inhibitors develop clinically significant extravascular hemolysis with ongoing transfusion requirements or symptomatic anemia. 2

For these patients, proximal complement inhibitors are indicated:

Pegcetacoplan (C3 inhibitor): 2, 10

• Administered subcutaneously twice weekly
• Inhibits both intravascular and extravascular hemolysis 2
• Effective in both C5 inhibitor-naive and C5 inhibitor-experienced patients 2
• Increases hemoglobin and achieves transfusion avoidance 2
• May require dose adjustments during surgery or infections to prevent breakthrough hemolysis 10

Iptacopan (Factor B inhibitor): 2

• Administered orally twice daily
• Controls both intravascular and extravascular hemolysis 2
• Effective as monotherapy in C5 inhibitor-naive and experienced patients 2

Danicopan (Factor D inhibitor): 2

• Administered orally 3 times daily
• Used as add-on therapy to eculizumab or ravulizumab, not as monotherapy 2
• Targets both terminal complement and alternative pathway 2

Important Treatment Considerations

Breakthrough hemolysis risk:

• Can occur with any complement inhibitor during strong complement triggers (infection, surgery, trauma) 2, 10
• May be more severe with alternative pathway inhibitor monotherapy compared to C5 inhibitors 2
• Requires close monitoring and potential dose adjustments during high-risk periods 10

Treatment adherence concerns:

• Self-administered subcutaneous and oral therapies raise concerns about adherence 6
• Uncontrolled terminal complement due to non-adherence can be life-threatening 6

Management of Thrombosis in PNH

Anticoagulation Strategy

For venous thrombosis in unusual sites (Budd-Chiari, portal vein), indefinite anticoagulation is recommended even with complement inhibitor therapy. 5

Site-Specific Management

Budd-Chiari Syndrome (hepatic vein thrombosis): 5

• Long-term anticoagulation warranted due to severity
• Hepatology consultation for consideration of transjugular intrahepatic portosystemic shunt (TIPS) in selected cases
• PNH found in 9-19% of Budd-Chiari patients 5

Portal vein thrombosis: 5

• Anticoagulation for at least 6 months, with consideration for long-term treatment
• Monitor carefully for variceal bleeding risk in patients with portal hypertension

Cerebral venous and arterial thrombosis: 5

• Immediate anticoagulation along with C5 inhibitor therapy required
• Neurological evaluation and appropriate imaging necessary

Special Clinical Situations

Pregnancy: 5

• Associated with high maternal mortality in PNH patients, making it a relative contraindication
• If pregnancy occurs, specialized management with hematology and maternal-fetal medicine required
• Continue complement inhibitor therapy throughout pregnancy

Surgery: 5, 10

• Requires careful planning with dose adjustments of complement inhibitors 10
• Preference for epidural over general anesthesia when possible 5
• Close monitoring for breakthrough hemolysis perioperatively 10

Catheter-related thrombosis: 5

• Requires vigilant monitoring
• May benefit from prophylactic anticoagulation

Supportive Care

While not a substitute for complement inhibitor therapy, supportive measures include:

• Transfusion support for severe anemia 6
• Folic acid supplementation 1
• Management of renal impairment and pulmonary hypertension 6
• Treatment of associated bone marrow failure syndromes 1

Prognosis with Modern Therapy

With C5 inhibitor therapy, survival of PNH patients now approaches that of healthy controls. 2, 6

• Significant improvements in hemoglobin levels 6
• Reduced transfusion requirements 6
• Decreased thrombosis risk 6
• Improved quality of life 6
• Greater overall survival compared to supportive care alone 6