What is Hemophagocytic Lymphohistiocytosis (HLH)?

From the Guidelines

Hemophagocytic lymphohistiocytosis (HLH) is a rare but life-threatening condition that requires prompt treatment with immunosuppressive therapy, including dexamethasone and etoposide, to prevent multi-organ failure and improve outcomes. HLH can be primary (genetic) or secondary (acquired), with the latter typically triggered by infections, malignancies, or autoimmune diseases 1. The hallmark of HLH is uncontrolled activation of T lymphocytes and macrophages, resulting in a cytokine storm that damages tissues throughout the body. Patients typically present with persistent high fever, enlarged liver and spleen, cytopenias (low blood counts), high ferritin levels, high triglycerides, low fibrinogen, and hemophagocytosis (immune cells engulfing other blood cells) on bone marrow examination.

Diagnosis and Treatment

Diagnosis requires meeting specific criteria established by the HLH-2004 protocol, including clinical, laboratory, and histopathological findings 1. Treatment must begin promptly and includes immunosuppressive therapy with dexamethasone (typically starting at 10 mg/m² daily) and etoposide (150 mg/m² twice weekly for 2 weeks, then weekly), along with treating any underlying triggers. For primary HLH, hematopoietic stem cell transplantation is often necessary for long-term survival. The mortality rate remains high, especially if diagnosis is delayed, because the hyperinflammatory state rapidly leads to multi-organ failure.

Secondary HLH

Secondary HLH is commonly triggered by infections or malignancies, and may also be induced by autoinflammatory/autoimmune disorders 1. The treatment of secondary HLH depends on the underlying trigger and may require individualized modified HLH-94–like treatment. Addition of IV immunoglobulin (IVIG) may be considered, as it has anti-inflammatory potential.

HLH in Adults

HLH has become more widely recognized in adults, with all ages affected 1. Patients often suffer from recurrent fever, cytopenia, liver dysfunction, and a sepsis-like syndrome that may rapidly progress to terminal multiple organ failure. The diagnosis and management of secondary forms of HLH in adults remain challenging due to the heterogeneity of inciting factors and clinical outcomes.

Key Considerations

• Early recognition and aggressive treatment are essential to improve outcomes in HLH.
• Treatment decisions must be made on a case-by-case basis, taking into account the underlying trigger and the patient's clinical presentation.
• Genetic analyses and functional testing may be necessary to determine whether a patient has an inherited form of HLH.
• Secondary infections are a major cause of fatality and HLH during chemotherapy, and patients require broad antimicrobial prophylaxis and close monitoring to detect recurrent malignant disease.

From the Research

Definition and Characteristics of HLH

• Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome characterized by cytokine dysregulation and uncontrolled activation of T lymphocytes and macrophages 2.
• It can be categorized as primary when associated with specific genetic mutations or secondary when associated with infections, malignancies, or autoimmune disorders 2.
• Clinical features of HLH include unexplained fever, hepatosplenomegaly, pancytopenia, and severe hyperferritinemia 2, 3.

Diagnosis and Treatment of HLH

• The HLH-2004 criteria are widely used to diagnose this condition, but there is growing concern that its application may result in undertreatment of certain patients 4.
• Treatment of primary HLH has become standardized based on the HLH-2004 protocol using cyclosporine, etoposide, and dexamethasone with or without intrathecal methotrexate followed by hematopoietic stem cell transplantation 2, 5.
• Treatment of secondary HLH is directed at control of the underlying condition, and if unsuccessful, cytotoxic agents such as those in HLH-2004, steroids, intravenous γ-globulin, or targeted immune therapy have been used 2.
• Immunotherapy targeting CD52 expressed on immune effector cells of HLH is a rational therapeutic approach in patients too ill for traditional cytotoxic chemotherapy 2.

Prognosis and Outcome of HLH

• Laboratory markers measured on day 7 of therapy can predict outcomes, with the most potent unfavorable marker being improvement in soluble CD25 (sCD25) of less than 25% from pretherapy levels 6.
• The presence of ≥3 unfavorable markers, including absolute sCD25 level, platelet count, absolute lymphocyte count, and blood urea nitrogen, is strongly associated with pre-BMT mortality 6.
• The 5-year probability of survival for patients with HLH is around 61%, with pre-HSCT mortality being a significant concern 5.