Steroids in HLH - Dexamethasone Dosing

HLH-94 Protocol (most widely used)

Continuation/Maintenance Therapy (post-week 8, bridge to HSCT)

• Dexamethasone: 10 mg/m²/day for 3 days, given every 2nd week (pulse dosing)
• Etoposide: 150 mg/m² once in alternate weeks
• Cyclosporine A added from week 9 (trough target ~200 µg/L)

HLH-2004 Protocol (modified)

Special Notes

• Malignancy-associated HLH: Treatment of the underlying malignancy (usually an etoposide-containing lymphoma regimen) should begin immediately. Dexamethasone (5-10 mg/m²) combined with an anti-CD52 agent (alemtuzumab) may be used for refractory adult HLH.
• CNS involvement (children): Intrathecal methotrexate 12 mg/dose at weeks 3-4 (rarely needed in adults).
• Liver dysfunction: Initial etoposide dose reduction is appropriate; dexamethasone doses are generally maintained.
• Renal failure: May require dose reduction.
• Cytopenias: Treatment should NOT be withheld for cytopenias alone - they often reflect disease activity, not drug toxicity.
• Adults: Often do not tolerate bi-weekly etoposide dosing; it is common to hold one of the initial four doses or start directly with weekly dosing.

Why Dexamethasone (not prednisolone)?

Diagnosis of HLH

Step 1 - Think of the Diagnosis

• Unexplained fever + cytopenias + multiorgan failure
• Markedly elevated ferritin (useful as a rapid screening test)
• Failure to improve despite antibiotics

HLH-2004 Diagnostic Criteria

2024 Update (Histiocyte Society): NK cell activity has been removed from the criteria. Now only 5 of the remaining 7 criteria need to be fulfilled.

Molecular/Genetic Diagnosis (Primary/Familial HLH)

• Absent perforin expression by flow cytometry → suggests PRF1 variants
• Defective CD107a degranulation → suggests UNC13D, STXBP2, STX11, RAB27A variants

The HScore (for Secondary HLH)

• Score >169: ~93% probability of HLH
• Score >250: ~99% probability of HLH
• Particularly useful in adults when sIL-2R is unavailable

Note: For secondary HLH, many centers accept 4 of 8 fulfilled criteria (rather than 5) as sufficient for diagnosis.

Initial Diagnostic Workup

• CBC with differential (cytopenias)
• Full metabolic panel + LFTs
• Fasting triglycerides
• Fibrinogen
• Ferritin (markedly elevated; >10,000 µg/L is highly suggestive)
• Soluble IL-2 receptor (sCD25) where available

• EBV (serology + PCR) - most common viral trigger
• CMV, HSV, HIV, parvovirus B19, adenovirus
• Blood cultures (bacterial, fungal, mycobacterial)
• Consider tuberculosis workup

• Bone marrow biopsy/aspirate - look for hemophagocytosis (macrophages engulfing red cells, white cells, or platelets)
• Note: Hemophagocytosis is neither sensitive nor specific - it can be absent early and present in other conditions

• CT/ultrasound to confirm splenomegaly and hepatomegaly

• Autoimmune screen (ANA, anti-dsDNA) for macrophage activation syndrome (MAS)
• CT chest/abdomen/pelvis + PET for lymphoma (malignancy is the trigger in >50% of adult cases)

Key Diagnostic Pearls

• Ferritin >10,000 µg/L has high specificity for HLH in the right clinical context
• In adults, lymphoma is the trigger in >50% of cases - always exclude it
• HLH can be present even if <5 criteria are met, particularly at disease onset - treat on strong clinical suspicion if needed
• The underlying trigger (infection, autoimmune disease, malignancy) can itself satisfy some HLH-2004 criteria, complicating interpretation

Treatment of HLH

1. Suppress the hyperinflammation (stop the cytokine storm)
2. Identify and treat the underlying trigger

A. Standard Immunochemotherapy

HLH-94 Protocol (most widely used, including in adults)

HLH-2004 Protocol (modified)

• Cyclosporine A (CsA) started from Day 1 (not week 9), at 6 mg/kg/day, targeting trough level of 200 µg/L
• Intrathecal MTX given with prednisone (for children with CNS involvement)

Continuation/Maintenance Therapy (post Week 8, bridge to HSCT)

B. Treatment Tailored to Underlying Trigger

C. Salvage / Refractory Disease

Alemtuzumab (anti-CD52)

• Monoclonal antibody that destroys mature T cells
• Used as bridge to HSCT in eligible patients
• Also reduces GVHD risk post-HSCT and is incorporated into conditioning regimens
• Pre-HSCT survival is ~90% with etoposide or alemtuzumab in experienced centers

Emapalumab (anti-IFN-γ) - FDA Approved for refractory pediatric HLH

• Dose: 1 mg/kg IV every 3-4 days, with escalation up to 10 mg/kg based on response/toxicity
• Given with dexamethasone 5-10 mg/m²
• FDA approved for refractory/recurrent primary HLH in children
• Adult data limited; may be useful under expert supervision

Ruxolitinib (JAK1/2 inhibitor)

• NOT FDA approved for HLH
• Inhibits multiple inflammatory cytokines
• Possible adjunct therapy under expert supervision, especially for intractable symptoms
• Being studied in clinical trials

D. Hematopoietic Stem Cell Transplantation (HSCT)

• Patient must be in remission at time of HSCT (active HLH at transplant → poor outcomes due to overwhelming GVHD)
• Reduced-intensity conditioning gives superior outcomes
• Successful HSCT is curative
• Overall survival now ~80% with modern therapy; ~85-90% post-HSCT in experienced centers

E. Key Practical Points

• Do NOT withhold treatment for cytopenias - they reflect disease activity, not drug toxicity
• Adults often cannot tolerate bi-weekly etoposide - it is acceptable to hold one of the first four doses or start immediately with weekly dosing
• Significant liver dysfunction: reduce initial etoposide dose and increase as function improves
• Renal failure: dose adjustments may be required
• CNS involvement in adults is much less common than in children - intrathecal MTX is rarely needed
• Treatment should be initiated under specialist/expert supervision