Diagnostic Criteria and Treatment Options for Hemophagocytic Lymphohistiocytosis (HLH)

Diagnostic Criteria for HLH

The diagnosis of HLH should be based on the HLH-2004 diagnostic criteria, which requires either a molecular diagnosis consistent with HLH or fulfillment of 5 of 8 specific clinical and laboratory parameters, while treatment should follow the HLH-94 protocol with modifications based on the underlying trigger and patient characteristics 1, 2
The diagnosis of HLH can be established if either of the following is fulfilled: molecular diagnosis consistent with HLH or at least 5 of the following 8 criteria: fever, splenomegaly, cytopenias, hypertriglyceridemia and/or hypofibrinogenemia, hemophagocytosis, low or absent NK cell activity, ferritin ≥500 μg/L, soluble CD25 ≥2400 U/mL 1, 3
Hyperferritinemia should always prompt consideration of HLH in the differential diagnosis, with levels >10,000 μg/L being highly suspicious in adults 1
Hemophagocytosis alone is neither sensitive nor specific for HLH and may be present in other conditions such as septicemia 4, 5

Primary (Genetic) HLH is caused by mutations affecting lymphocyte cytotoxicity and immune regulation, most common in children but can occur in adolescents and young adults 2, 4, 5
Secondary (Acquired) HLH is most common in adults, triggered by infections, malignancies, autoinflammatory/autoimmune disorders, or immunotherapies 2, 1, 3

In all patients with HLH, screen peripheral blood and bone marrow for blasts 6, 5
Imaging studies recommended: chest X-ray, ultrasound and/or CT of abdomen and enlarged lymph nodes, consider CT, MRI, and in special cases, PET for patients with elevated likelihood of malignancy 6, 5, 4, 3

The HLH-94 protocol is the recommended standard treatment for HLH, including dexamethasone, etoposide, cyclosporine A, and intrathecal therapy 2
Treatment should be tailored according to the underlying condition and HLH-triggering factor 2
For primary (genetic) HLH, complete HLH-94 protocol followed by allogeneic hematopoietic stem cell transplantation (alloSCT) is recommended 2
For malignancy-associated HLH, combined approach with HLH-directed and malignancy-directed therapy is recommended, with etoposide-containing regimens showing better survival 2, 7
For infection-associated HLH, anti-infectious treatment is pivotal, and consider anti-B-cell therapy (rituximab) for highly replicative EBV infection 2, 7

Factors associated with higher mortality include malignancy-associated HLH (particularly T-cell lymphoma) 2, 3
T-cell lymphoma-associated HLH has a worse prognosis than B-cell lymphoma-associated HLH 3
Survival rates for malignancy-associated HLH are generally poor, with 30-day survival rates of 56-70% and median overall survival of 36-230 days 3
The HLH-94 protocol has improved survival from nearly uniformly fatal to >50% long-term survival 2