Treating primary HLH
Managing the cytokine storm in primary HLH
Getting patients to transplant
For patients with primary hemophagocytic lymphohistiocytosis (HLH), a successful hematopoietic stem cell transplantation (HSCT) is the only cure. Before HSCT can be performed, prompt and effective treatment is necessary to calm hyperinflammatory symptoms.1-3
Primary HLH treatment has 3 main goals:
Stabilize the patient
Subdue hyperinflammation to prevent irreversible organ damage1
Minimize treatment toxicities
Reduce negative effects of broad-spectrum medications4,5
Prepare for transplant
Condition the patient for HSCT, the only curative treatment for primary HLH1
The primary HLH treatment landscape
First-line treatment options seek to control hyperinflammation through broad immune suppression.6
Monitoring response to conventional therapy7
At day 7 of treatment with the HLH-94 or HLH-2004 protocols, it was observed that these 5 prognostic biomarkers were identified in a retrospective chart review. Patients of any age, diagnosed with HLH/macrophage activation syndrome and treated with the HLH-94/HLH-2004 protocols for at least 2 weeks (or to the time of death if it occurred earlier) were eligible for analysis. Exclusion criteria included initial therapy with antithymocyte globulin, HLH secondary to an unidentified malignancy, and insufficient data for a detailed outcome assessment. This review assessed survival to HSCT or ~1 year if no HSCT was pursued in 89 patients.
Study limitations: This was a 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 were imputed in several instances. Fifty-seven patients transferred institutions after starting HLH-directed therapy. These data use descriptive statistics to summarize a dataset and are not powered to detect between group differences in the outcomes. Causality cannot be established based on these data. Outcomes should be interpreted with caution alongside physician clinical judgment and other relevant lab assessments.
5 key prognostic biomarker tests
Biomarker | Thresholds at day 7 |
sCD25/sIL-2Rα | <25% improvement from baseline* >17,000 U/mL |
Platelet count (PLT) | <25 x 109/L |
Absolute lymphocyte count (ALC) | <0.35 x 109/L |
Blood urea nitrogen (BUN) | ≥20 mg/dL |
*Day 1 was defined as the first day of etoposide administration. Baseline (pretreatment) laboratory markers were defined as the peak pathologic value obtained within 7 days of treatment initiation.
sCD25 testing is not available at all institutions and may take longer to receive results.
sCD25=soluble cluster of differentiation 25; sIL-2Rα=soluble interleukin 2 receptor alpha.
Information on sCD25 prognostic utility7
- The authors concluded that sCD25 levels and their improvement from baseline were identified as a predictor of pre-HSCT 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 assessed
This retrospective study found that7:
Each of the 5 markers were predictive of pre-HSCT mortality
The effect of multiple unfavorable prognostic indicators was additive
Patients with poor prognostic indicators at day 7 demonstrated increased pre-HSCT mortality risk
Early response assessment7
sCD25 improvement from baseline <25%†
sCD25
>17,000 U/mL
PLT
<25 x 109/L
ALC
<0.35 x 109/L
BUN
≥20 mg/dL
≥3 poor prognostic indicators?
Consider response adaptive therapy
†sCD25 improvement: (difference between baseline and day 7 value)/baseline value.
‡Analysis presents results from a multi-institutional, retrospective chart review of patients diagnosed with HLH, treated with etoposide-based therapy, 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).
Analysis presents results from the author's independent conclusions.