What is the diagnosis and treatment approach for Hemophagocytic Lymphohistiocytosis (HLH)?

From the Guidelines

Hemophagocytic Lymphohistiocytosis (HLH) should be diagnosed and treated promptly using the HLH-2004 criteria and protocol, with a focus on addressing the underlying trigger and hyperinflammation, as delayed treatment can lead to high mortality rates due to progressive multi-organ failure. The diagnosis of HLH requires either genetic confirmation or fulfillment of five out of eight clinical and laboratory criteria, including fever, splenomegaly, cytopenias, hypertriglyceridemia or hypofibrinogenemia, hemophagocytosis, low/absent NK cell activity, elevated ferritin, and high soluble CD25 levels 1.

Key Considerations in HLH Diagnosis and Treatment

• The HLH-2004 protocol is the standard approach, using dexamethasone (initially 10 mg/m² daily, tapering over 8 weeks), etoposide (150 mg/m² twice weekly for 2 weeks, then weekly), and cyclosporine (target trough levels 200 μg/L) 1.
• For CNS involvement, intrathecal methotrexate may be added.
• Supportive care includes antimicrobial prophylaxis, IVIG for hypogammaglobulinemia, and transfusion support.
• In secondary HLH, treating the underlying condition (infection, malignancy, autoimmune disease) is crucial.
• For primary (genetic) HLH, allogeneic hematopoietic stem cell transplantation is ultimately necessary for cure.
• Salvage therapies for refractory cases include alemtuzumab, anakinra, or ruxolitinib.

Special Considerations

• In cases of EBV-HLH, the addition of rituximab to HLH-directed therapy may be effective in clearing the reservoir of virus, and monitoring of ferritin, sCD25, cell counts, and EBV DNA may guide the number of rituximab doses 1.
• The prognosis for EBV-HLH has improved greatly when treated promptly using HLH-94 protocols, but the variable severity of EBV-HLH demands graded intensity and length of treatment.

Treatment Approach

• The decision to start HLH-directed treatment depends on clinical judgment and assessment of organ function, and pulsed corticosteroids and elements of HLH-94 may be used 1.
• A clear indication for immediate administration of etoposide is severe HLH presenting with imminent organ failure.
• Individualized modified HLH-94–like treatment has been suggested in secondary HLH.
• The extent and duration of HLH-directed therapy depend on the severity of HLH and the underlying trigger.

From the Research

Diagnosis of Hemophagocytic Lymphohistiocytosis (HLH)

• The diagnosis of HLH is often challenging due to the diverse clinical manifestations and the presence of several diagnostic mimics 2.
• The HLH-2004 protocol is used in the diagnosis of HLH, which was originally developed for the pediatric population, but still forms the basis of the diagnosis of HLH in adults 2.
• Laboratory markers, such as soluble CD25 (sCD25), platelet count, absolute lymphocyte count, and blood urea nitrogen, can be used to predict outcomes and identify patients at risk for early mortality 3.

Treatment Approach for HLH

• The treatment of HLH is primarily based on the HLH-94 protocol, which involves suppressing the inflammatory response 4, 2.
• The treatment includes immunosuppressive and cytotoxic therapy aiming at clinical remission, followed by hematopoietic stem cell transplantation (HSCT) in patients with familial, persistent, or recurrent disease 4.
• Etoposide and dexamethasone are commonly used in the treatment of HLH, but some patients may require salvage or alternative therapeutic approaches 3, 5.
• Alemtuzumab, a targeted immune therapy, has been used to treat HLH in patients who are too ill for traditional cytotoxic chemotherapy 6.
• The treatment needs to be modified in adults depending on the underlying cause and comorbidities 2.

Prognosis and Outcome

• The prognosis of HLH is generally poor, warranting rapid diagnosis and aggressive management 2.
• The estimated 5-year probability of survival for patients with HLH is around 54% 4.
• Patients with familial disease have a poorer prognosis, with a 5-year survival of around 50% 4.
• Early response markers, such as improvement in sCD25, can predict survival after etoposide-based therapy of HLH 3.