In secondary hemophagocytic lymphohistiocytosis, when is therapeutic plasma exchange indicated and what is the recommended regimen?

Therapeutic Plasma Exchange (PLEX) in Secondary HLH

Therapeutic plasma exchange is NOT a standard or first-line treatment for secondary HLH and is only mentioned as a salvage option for refractory disease in the most recent guidelines.

Primary Treatment Approach for Secondary HLH

The cornerstone of secondary HLH management does not include plasma exchange. Instead, treatment follows this hierarchy 1:

First-Line Treatment

• High-dose corticosteroids (dexamethasone 10 mg/m² or methylprednisolone 1g/day IV for 3-5 days) should be initiated immediately 1, 2
• Treat the underlying trigger simultaneously—this is equally critical as immunosuppression 2, 3
• IVIG (1.6 g/kg over 2-3 days) may be added for its anti-inflammatory effects 1

Second-Line Options (Before Considering PLEX)

• Etoposide for severe HLH with imminent organ failure or refractory disease 1, 4
• Cyclosporine A or tacrolimus 1
• Anakinra (IL-1 inhibition) particularly for MAS-associated HLH 1, 4
• Rituximab for EBV-triggered HLH 1, 4
• Ruxolitinib (JAK2 inhibitor) showing promise in critically ill patients 4, 5

When PLEX May Be Considered

Plasma exchange is only mentioned as a salvage therapy for refractory/relapsed HLH 4. The 2019 Blood guidelines list it among treatment intensification options alongside:

• Chemotherapy intensification
• Alemtuzumab (anti-CD52)
• Cytokine adsorption using filter columns or plasma exchange
• JAK2 inhibitors
• Anti-IFN-γ antibody 4

Critical Context

The guideline groups plasma exchange with "cytokine adsorption using filter columns," suggesting its theoretical role is mechanical removal of inflammatory cytokines 4. However, no specific regimen, frequency, or volume is provided, reflecting the lack of robust evidence for this intervention.

Why PLEX Is Not Standard

The pathophysiology of HLH involves sustained cellular immune activation (activated T-cells and macrophages) rather than primarily circulating antibodies or toxins 6. The cytokine storm originates from continuous cellular production, not just circulating mediators 6. Therefore:

• Corticosteroids and etoposide directly suppress the activated immune cells producing cytokines 1, 4
• Targeted biologics (anakinra, ruxolitinib, emapalumab) block specific cytokine pathways 4, 7
• Plasma exchange only temporarily removes circulating cytokines without addressing the cellular source 4

Recommended Algorithm for Refractory Secondary HLH

If a patient fails first-line therapy (corticosteroids + trigger treatment ± IVIG), escalate in this order 4, 7:

1. Add etoposide (if not already given) at individualized dosing 1, 4
2. Add cyclosporine A or switch to tacrolimus 1
3. Consider targeted biologics: ruxolitinib for critically ill patients 5, anakinra for MAS 7, or emapalumab for refractory cases 4
4. Alemtuzumab for severe refractory disease 4
5. Cytokine adsorption or plasma exchange only as a last resort when all other options have failed 4

Common Pitfalls

• Do not delay corticosteroids while considering plasma exchange—steroids are the proven first-line therapy 2, 7
• Do not use PLEX as first-line therapy—it lacks evidence and delays effective treatment 4
• Do not forget the trigger—treating only the inflammation without addressing the underlying infection, malignancy, or autoimmune disease leads to treatment failure 2, 3
• Monitor for secondary infections aggressively, as they cause significant mortality in HLH patients receiving immunosuppression 1