Not So Benign
Hemophagocytic Lymphohistiocytosis: A Rare Yet Clinically Significant Syndrome

Hemophagocytic lymphohistiocytosis (HLH) is a rare syndrome characterized by dysregulation and overstimulation of the immune system leading to hyperinflammatory responses.¹  It was initially documented in scientific literature in the mid 1900s²  as a pediatric disease but has become increasingly recognized in adults.¹ 

HLH can be familial (primary) or acquired (secondary, sporadic).¹  Both types necessitate immune stimulation or a triggering condition for symptoms to manifest, although in a subset of patients, no trigger can be identified. Due to the rarity of HLH, there is frequently a diagnostic delay, contributing to its high mortality.

The pathophysiology of HLH involves abnormal overactivation of the immune system coupled with a deficiency in downregulation of activated macrophages and lymphocytes mediated by natural killer (NK) cells and cytotoxic T lymphocytes (CTLs).³  In a state of normal immune regulation, NK cells and CTLs downregulate macrophage activation via perforin-dependent cytotoxic pathways. The genetic underpinnings of familial HLH often involve mutations in perforin-mediated pathways⁴  or genes associated with congenital immunodeficiency syndromes.⁵  These mutations are typically inherited in autosomal recessive or compound heterozygous patterns, although studies have reported monoallelic mutations in patients classified as having sporadic HLH, suggesting a gene dosage effect.⁶ 

Acquired HLH is characterized by the absence of a known genetic cause. It can be triggered by immune dysfunction secondary to infections, particularly Epstein-Barr virus (EBV), in 25 to 34% of cases; malignancies, especially lymphomas, in 52 to 60% of cases; and autoimmune conditions in 3 to 8% of cases.^7,8  The term macrophage activation syndrome (MAS)-HLH is reserved for patients with HLH secondary to systemic autoimmune disease, such as Still’s disease, lupus, and vasculitis, as treatment approach may differ.⁹  Approximately 6% of cases are classified as idiopathic.⁷  Therapeutic interventions for these associated autoimmune conditions including chemotherapy, immunotherapy, and chimeric-antigen receptor (CAR) T cell therapy, which induce immune deficiency, have also been associated with an HLH-like syndrome that differs from “true” HLH.¹⁰ 

Familial HLH is seen exclusively in children, and incidence varies by geographical location.¹  Acquired HLH is more common in adults, with a mean age of 49 years at onset¹¹  and increasing incidence over time.¹² 

Individuals with HLH typically present with unremitting fevers, cytopenias, and hepatosplenomegaly.¹  The nonspecific nature and overlap of these symptoms with those of other conditions contribute to diagnostic challenges and delays in HLH management.

Mortality can be as high as 100% without HLH treatment and can occur within a month of diagnosis. With treatment, survival improves to approximately 60 to 70% in pediatric patients¹³  but remains low in adults (~30%).¹⁴ 

The clinical diagnosis of HLH is based on diagnostic criteria utilized in research studies, notably the HLH-2004 study.¹⁵  Diagnosis can be made either based on molecular findings consistent with HLH or the presence of five out of the following eight criteria: fever; splenomegaly; cytopenias affecting two or more lineages; hypertriglyceridemia and/or hypofibrinogenemia; hemophagocytosis in the bone marrow, spleen, or lymph nodes; ferritin levels greater than 500 μg/L; soluble IL-2R levels greater than 2,400 U/mL; and low or absent NK cell activity.^1,9,15 

Despite the defined criteria, the diagnosis of HLH remains challenging given the non-specificity of symptoms and their overlap with those of other conditions such as sepsis. For instance, although ferritin levels over 10,000 are more than 90% sensitive and specific for HLH in children, hyperferritinemia is less predictive of HLH in adults.¹⁶ 

Therapy for HLH involves treating the underlying trigger, if identified, and suppressing the overactive immune system. Consequently, treatment for HLH may vary based on the underlying trigger.⁹  Responses to treatment can be monitored by tracking trends in clinical symptoms (fever curve and splenomegaly, etc.) and laboratory values such as ferritin, sIL-2R, and fibrinogen.⁹  Following diagnosis, ferritin levels in particular correlate with disease activity.¹ 

In the pediatric population, the standard of care for HLH is the HLH-94 protocol, which incorporates etoposide and dexamethasone during weeks 1 through 8, followed by cyclosporine A and dexamethasone as a bridge to bone marrow transplantation for individuals without resolution and those with familial HLH. This protocol has demonstrated a long-term survival rate of approximately 60%,¹³  mostly in children. Etoposide exhibits selective action against activated T cells, mitigating subsequent cytokine release.¹⁷  Etoposide-based regimens have been extrapolated to the treatment of adult HLH.⁹  In cases of EBV-associated HLH, addition of rituximab may be considered to target B-cell reservoirs of EBV.^9,18 

Hematopoietic stem cell transplant is recommended for individuals with familial HLH as well as those with relapse or refractory acquired HLH, with documented improvements in outcomes.^9,13,19  Reduced-intensity conditioning (RIC) regimens are preferred, as they have demonstrated superior outcomes when compared with myeloablative regimens.²⁰ 

Alemtuzumab, an anti-CD52 monoclonal antibody, is employed as salvage therapy in HLH refractory to etoposide-based regimens, serving as a bridge to transplant.^1,21 

Emapalumab, an anti-interferon gamma monoclonal antibody, received FDA approval as second line therapy for familial HLH in children and adults. In the pediatric population, this has been associated with overall response and survival rates of approximately 60% and 74% at 12 months, respectively, with nearly all patients having undergone allogeneic transplant.^22,23  There are no published data demonstrating the efficacy of emapalumab in adult patients with HLH.

Ruxolitinib, a janus kinase (JAK) inhibitor, is currently under evaluation in clinical trials as a potential alternative or adjunct to etoposide-based regimens for the management of relapsed or refractory HLH and has demonstrated promising results in preliminary studies.^24,25 

HLH is a rare albeit increasingly recognized syndrome associated with high mortality. Early diagnosis plays a pivotal role in HLH management. While distinguishing between familial and acquired HLH is not an immediate requirement to initiate treatment, it is necessary for determining long-term management strategies after the acute phase of treatment. Identifying the underlying trigger of an HLH episode is essential, as adjunctive therapies in the acute setting may vary depending on associated disorders. In general, outcomes for HLH have significantly improved, yet there remains a need for further advancements in research and treatment strategies, especially for adult patients.

Drs. Osei and Berliner indicated no relevant conflicts of interest.