Managing HLH

Two main management goals for patients with HLH

Hemophagocytic lymphohistiocytosis (HLH) requires appropriate recognition and timely treatment to prevent irreversible organ damage.¹

The 2 main goals for managing patients with HLH include^1,2:

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Controlling hyperinflammation

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Limiting toxicities and further organ damage

Addressing the trigger

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For patients whose testing results suggest a genetic etiology for their HLH, the ultimate goal is hematopoietic stem cell transplantation (HSCT), which is the only curative treatment.^1,2

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For patients whose testing results suggest an alternate trigger such as infection, malignancy, or rheumatologic disease, the underlying condition should be treated first to see if the hyperinflammation resolves.²

Treatment approaches for controlling hyperinflammation in primary HLH

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First-line therapy for patients with HLH involves broad immunosuppression using etoposide and steroids.³

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In cases of incomplete response to first-line therapy, other options include therapies that target specific cytokines involved in HLH immune dysregulation.³

A retrospective study:

Early response markers predict survival after etoposide-based therapy of HLH⁴

A retrospective, multi-institutional study was conducted to identify biomarkers associated with pre-HSCT mortality risk in patients with primary HLH treated with etoposide-based therapy. This chart review analyzed 14 biomarkers in 89 patients and assessed survival to HSCT or ~1 year if no HSCT was pursued.*

Inclusion criteria⁴

Patients of any age, (average range, 0 months-23.5 years) who had been diagnosed with familial or reactive HLH, and treated for at least 2 weeks (or until time of death if previously occurred) using HLH-94/HLH-2004 protocols.

Exclusion criteria⁴

Initial therapy with antithymocyte globulin, HLH secondary to unidentified malignancy, and insufficient data for detailed assessment of outcome.

Study limitations⁴

• Retrospective chart review that was observational in nature and reflects data outside of a controlled clinical trial with prospective endpoints; therefore, causality cannot be established
• Missing data that were imputed in several instances
• High rate of patients who transferred institutions after starting HLH-directed therapy (n=57)
• These data employ descriptive statistics to summarize a given dataset and are not powered to detect between group differences in the outcomes of interest
• Outcomes should be interpreted with caution alongside physician clinical judgment and other relevant lab assessments

Outcomes and definitions⁴

Primary endpoint: survival to HSCT, or 1 year if no HSCT.

Pre-HSCT mortality: failure to achieve either primary endpoint.

Overall survival: evaluated at 5 years post-diagnosis or last follow up.

5 key prognostic biomarker tests that may predict pre-HSCT mortality⁴
 

sCD25=soluble cluster of differentiation 25; sIL-2Rα=soluble interleukin 2 receptor alpha.

sCD25 demonstrated the strongest association with pre-HSCT mortality risk⁴

• The authors concluded that sCD25 and its improvement from baseline is the strongest predictor of mortality
• Serial monitoring of sCD25 may be a consideration in clinical practice
• Given the lack of rapid sCD25 availability, additional day 7 prognostic markers were characterized in this study

Prognostic indicators observed at day 7⁴

This retrospective study found that:

Day 7 markers illustrate pre-HSCT mortality risk^4,‡

• ≥2 prognostic biomarkers—patients demonstrated a 30-fold increase in pre-HSCT mortality risk (OR, 30.7; 95% CI, 5.9-118.1)
• ≥3 prognostic biomarkers—patients had a pre-HSCT mortality rate of 100% (OR, +infinity; 95% CI, 19.5-infinity)

^*The 14 biomarkers that were analyzed included sCD25, ferritin, hemoglobin, platelet count, absolute neutrophil count, absolute lymphocyte count, absolute monocyte count, fibrinogen, alanine transaminase, total bilirubin, creatinine, blood urea nitrogen, lactate dehydrogenase, and triglycerides.

^†sCD25 improvement: (difference between baseline and day 7 value)/baseline value.

^‡Analysis presents results from a multi-institutional, retrospective study of patients diagnosed with HLH and evaluated between 2010 and 2019 at Cincinnati Children’s Hospital Medical Center (CCHMC), Arkansas Children’s Hospital (ACH), or Schneider Children’s Medical Center of Israel (SCMCI).