| Category (diagnostic criterion/biomarker/therapy) | Details (threshold/dose/regimen) | Performance/outcome stats | Notes/implementation | Source (URL+year) | Context citation id |
|---|---|---|---|---|---|
| HLH-2004 diagnostic criteria | Diagnosis commonly requires **5 of 8 criteria**; thresholds include fever **≥38.5°C**, ferritin **>500 µg/L**, cytopenias in ≥2 lineages (Hb **≤9 g/dL**, platelets **<100 ×10^9/L**, neutrophils **<1 ×10^9/L**), plus hypertriglyceridemia/hypofibrinogenemia, splenomegaly, hemophagocytosis, elevated sCD25, low/absent NK activity | Widely used classification framework; no single test sufficiently sensitive/specific on its own | Standard entry framework in both pediatric and adult literature; bone marrow hemophagocytosis is **not mandatory** for early screening | HiHASC guideline 2024 https://doi.org/10.1016/S2665-9913(23)00273-4; Infectious Disease Reports 2024 https://doi.org/10.3390/idr16020012 | (pqac-00000009, pqac-00000011) |
| HScore | Published diagnostic cutoff **>169 points**; reduced cutoff **>134** may be used when bone marrow data unavailable | In one adult-center study/classification approach, HScore-based HLH definition used **>169**; HiHASC notes HScore is most relevant for quick adult screening | Includes fever, organomegaly, cytopenias, ferritin, triglycerides, fibrinogen, marrow hemophagocytosis, and prior immunosuppression | Wimmer 2024 https://doi.org/10.5282/edoc.33899; Scientific Reports 2024 https://doi.org/10.1038/s41598-024-82760-6 | (pqac-00000008, pqac-00000015) |
| Ferritin screening biomarker | Quick-screen ferritin plus CBC/fibrinogen/triglycerides/LFTs/LDH; pediatric “very high” ferritin threshold often **>10,000 µg/L**; adult thresholds in practice often **2,000–10,000 µg/L** | In pediatric data, ferritin **>10,000 µg/L** had **90% sensitivity** and **98% specificity** for HLH | HiHASC recommends serial ferritin; “3Fs” initial screen = fever, falling counts, raised ferritin | HiHASC guideline 2024 https://doi.org/10.1016/S2665-9913(23)00273-4 | (pqac-00000009, pqac-00000010, pqac-00000030) |
| Ferritin frequency in adult HLH cohort | Ferritin **≥500 µg/L** in **100% (62/62)**; **≥2,000 µg/L** in **97% (60/62)**; **>6,000 µg/L** in **73%** | Shows ferritin is highly prevalent but not alone diagnostic | Useful as screening/monitoring biomarker in adults | Wimmer 2024 https://doi.org/10.5282/edoc.33899 | (pqac-00000012, pqac-00000013, pqac-00000037) |
| sCD25 biomarker | HLH-2004 marker; commonly used threshold **≥2400 U/mL** | Raised in **97%** of pediatric HLH in cited data; combined **sCD25 >3900 U/mL + ferritin >1000 ng/mL** yielded **84% sensitivity** and **81% specificity** for malignancy-associated HLH; adult cohort frequency **88% (53/60)** | Often not rapidly available; specificity/sensitivity poorer in critical care settings | HiHASC guideline 2024 https://doi.org/10.1016/S2665-9913(23)00273-4; Wimmer 2024 https://doi.org/10.5282/edoc.33899 | (pqac-00000009, pqac-00000010, pqac-00000012) |
| CRP + ferritin adjunctive differential aid | CRP **<130 mg/L** combined with HScore **>136** or ferritin **>15,254 µg/L** | CRP **<130 mg/L + HScore >136** improved specificity from **85.2% to 96.3%**; CRP **<130 mg/L + ferritin >15,254 µg/L** increased specificity from **88.9% to 100%** for HLH vs AOSD/COVID cytokine storm | Useful when cytokine panels unavailable | Scientific Reports 2024 https://doi.org/10.1038/s41598-024-82760-6 | (pqac-00000015) |
| HLH-94 regimen | **8-week induction**: dexamethasone **10 mg/m²/day** with 50% taper every 2 weeks + etoposide **150 mg/m²** twice weekly for 2 weeks, then weekly for 6 weeks; intrathecal methotrexate/hydrocortisone for CNS disease | Historical pre-etoposide 5-year OS about **20%**; became standard backbone for severe HLH | Adult practice still often extrapolated from pediatric protocols | Cancers 2023 https://doi.org/10.3390/cancers15061839 | (pqac-00000018) |
| HLH-2004 regimen / long-term outcomes | Upfront cyclosporine added to etoposide+dexamethasone backbone; HSCT indicated for familial/genetic, relapsing, or severe/persistent disease | In **369 children**, **230/369 (62%)** alive at median 5.2 years; **5-year survival 61% (56–67%)**; pre-HSCT mortality **19%** vs **27%** in HLH-94; post-HSCT 5-year survival **66%** overall, **70%** in verified FHL | Confirmed efficacy of etoposide/dexamethasone; upfront CSA did **not** significantly improve overall outcome | Blood 2017 https://doi.org/10.1182/blood-2017-06-788349 | (pqac-00000018) |
| HSCT | Curative intent for primary/familial HLH and relapsed/severe persistent disease | In adult review, reduced-intensity conditioning OS reported around **50%** with fludarabine/melphalan and **75%** with alemtuzumab preconditioning; however **20–30%** may die before transplant in some series | HLA typing recommended for persistent disease, CNS involvement, or predisposing mutations | Cancers 2023 https://doi.org/10.3390/cancers15061839 | (pqac-00000016, pqac-00000018) |
| Emapalumab (anti-IFNγ) | FDA-approved salvage therapy for **primary HLH**; pediatric phase 3 used IV emapalumab until HSCT (4–12 weeks anticipated) | Pediatric trial data cited in adult review: **ORR 65%** and **70%** proceeded to HCT; adult phase 2/3 study enrolled only **7** and was **terminated** | Most evidence strongest in pediatric pHLH; adult sHLH role remains uncertain | Cancers 2023 https://doi.org/10.3390/cancers15061839; NCT03312751; NCT03985423 | (pqac-00000016, pqac-00000028, pqac-00000029) |
| Ruxolitinib dose-escalation salvage | General-dose phase typically **10–15 mg twice daily**, escalated up to **20 mg twice daily** in refractory HLH | In **8** refractory patients, **4/8 (50%)** achieved better remission after escalation; median best response time **18.5 days**; estimated **2-month OS 75%**; **no grade ≥3** adverse events reported | Escalation may help nonresponders to initial dose; sCD25 **10,000 pg/mL** cutoff predicted response (AUC **0.8125**) | Frontiers in Immunology 2023 https://doi.org/10.3389/fimmu.2023.1211655 | (pqac-00000019, pqac-00000020) |
| Anakinra (IL-1 blockade) | Anti-cytokine option mainly used in MAS/rheumatologic HLH | Retrospective data cited in adult review: **75% OS** in rheumatologic-associated MAS vs **17%** in other sHLH causes | More favorable evidence in MAS than malignancy-associated HLH | Cancers 2023 https://doi.org/10.3390/cancers15061839 | (pqac-00000016) |
| Alemtuzumab salvage | Anti-CD52 salvage therapy, sometimes combined with DEP | Salvage response **64%**; DEP+alemtuzumab series reported **CR 27%** and **PR 49%** | Infection risk is high; generally rescue/bridge strategy | Cancers 2023 https://doi.org/10.3390/cancers15061839 | (pqac-00000016) |
| NCT03312751 emapalumab trial | **Phase 3**, open-label, single-group, pediatric **primary HLH**; **35** enrolled; **COMPLETED** | Primary endpoint: overall response at Week 8/EOT; secondary endpoints included OS, HSCT outcomes, glucocorticoid reduction, PK/PD markers (IFNγ, CXCL9/CXCL10, sCD25) | Key registration study informing emapalumab use in pHLH | ClinicalTrials.gov NCT03312751 (results posted 2024); https://clinicaltrials.gov/study/NCT03312751 | (pqac-00000028) |
| NCT03985423 adult emapalumab trial | **Phase 2/3**, open-label, adult HLH (malignancy- and non-malignancy-associated), **7** enrolled; **TERMINATED** | Primary endpoint: overall response at Week 4 | Excluded primary HLH; terminated by sponsor decision | ClinicalTrials.gov NCT03985423; https://clinicaltrials.gov/study/NCT03985423 | (pqac-00000029) |
| NCT04120090 ruxolitinib salvage trial | **Phase 3**, open-label, refractory/relapsed HLH, ages **1–75 y**, **80** planned; status **UNKNOWN / last known recruiting** | Primary outcomes: CR/PR response rate and **1-year PFS**; secondary outcomes include OS and AEs | Compares low- vs high-dose ruxolitinib; includes adult and pediatric dosing | ClinicalTrials.gov NCT04120090; https://clinicaltrials.gov/study/NCT04120090 | (pqac-00000026) |
| NCT03795909 ruxolitinib + dexamethasone | **Phase 1/2**, pediatric refractory/secondary HLH, **50** planned; status **UNKNOWN** | Primary outcome at 2 weeks based on ferritin-defined disease activity | Family HLH excluded; ruxolitinib + dexamethasone vs placebo + dexamethasone | ClinicalTrials.gov NCT03795909; https://clinicaltrials.gov/study/NCT03795909 | (pqac-00000027) |
| NCT04551131 response-adapted ruxolitinib regimen | **Phase 1/2**, St. Jude, **10** planned; **ACTIVE_NOT_RECRUITING** | Used in pediatric/young patient development program; outcomes include response-adapted use | Referenced in adult review as ongoing US trial | ClinicalTrials.gov NCT04551131; https://clinicaltrials.gov/study/NCT04551131 | (pqac-00000021, pqac-00000022) |
| NCT05762640 first-line ruxolitinib in pHLH | **Phase 2**, primary HLH, **20** planned; **RECRUITING** | First-line ruxolitinib strategy under study | Tests whether JAK inhibition can move earlier in pHLH care pathway | ClinicalTrials.gov NCT05762640; https://clinicaltrials.gov/study/NCT05762640 | (pqac-00000022) |
| NCT06951971 emapalumab + ruxolitinib | **Phase 2/3**, single-arm, ages **1–70 y**, **30** planned; **NOT_YET_RECRUITING** | Primary outcome: **60-day overall survival** | Dose-modified combination regimen; allows rescue/bridge to allo-HSCT | ClinicalTrials.gov NCT06951971; https://clinicaltrials.gov/study/NCT06951971 | (pqac-00000022) |


*Table: This table compiles the main quantitative diagnostic thresholds, biomarker performance data, standard regimens, salvage therapies, and key registered trials for HLH from the retrieved evidence. It is designed to support rapid comparison of diagnostic criteria and current treatment implementation.*