In patients with secondary HLH, treatment is adapted to the underlying condition and the severity of the HLH (i.e., graded treatment intensity and duration). In addition to etoposide and glucocorticoids, common drugs directed at secondary HLH include inhibitors of interleukin-1 (e.g., anakinra), interferon-γ (e.g., emapalumab), and Janus kinases (e.g., ruxolitinib), as well as intravenous immune globulin.

In patients with moderate secondary HLH, glucocorticoids with or without intravenous immune globulin may be sufficient, and adding anakinra (2 to 10 mg per kilogram of body weight per day) can be considered. Cyclosporine is not often used in adults, except in those with MAS-HLH. In patients with severe, nonresponsive, or progressive secondary HLH, particularly those with CNS involvement, imminent organ failure, or both, prompt addition of weekly treatment with etoposide is often recommended, at an age-adjusted dose, such as 100 mg per square meter of body-surface area in adolescents and young adults, 75 mg per square meter in adults, and 50 mg per square meter in older adults. The duration of treatment should be determined weekly by evaluating the response.

MAS is a life-threatening hyperinflammatory complication of rheumatic diseases and other autoimmune diseases that is classified as secondary HLH because it shares many clinical and laboratory features with HLH; hence, the term MAS-HLH. In patients with systemic juvenile idiopathic arthritis, MAS-HLH is defined by the presence of a fever, a ferritin level exceeding 684 μg per liter, and any two of the following signs: a platelet count of 181×109 per liter or lower, an aspartate aminotransferase level higher than 48 U per liter, a fasting triglyceride level exceeding 1.76 mmol per liter (156 mg per deciliter), and a fibrinogen level of 3.6 g per liter or lower. Fibrinogen and platelet levels are often higher in MAS-HLH than in other forms of HLH because of the inflammatory nature of this form.

Mortality associated with MAS-HLH is approximately 5 to 10% among children and 10 to 15% among adults. CNS involvement may lead to irreversible neurologic damage. Severe pulmonary disease with a high risk of death may also develop, but the best prevention and treatment are still unknown.

A common first-line approach is the use of high-dose glucocorticoid therapy, such as intravenous pulse methylprednisolone, administered at 30 mg per kilogram per dose (maximum, 1000 mg per dose) once daily for 3 to 5 days, followed by oral or intravenous glucocorticoids. Cyclosporine, given at a dose of 2 to 7 mg per kilogram per day (trough value, 100 to 150 μg per liter), can be added. Interleukin-1–blocking therapy is increasingly used (e.g., anakinra at a dose of 2 to 10 mg per kilogram per day).

In patients with severe disease or CNS involvement despite glucocorticoid therapy and therapy with cyclosporine or anakinra (or both), one or a few moderate weekly doses of etoposide (50 to 100 mg per square meter) can be effective.

In studies pioneered by Imashuku and colleagues in Japan, the risk of death among patients with severe EBV infection was markedly reduced by means of HLH-directed therapy with etoposide and glucocorticoids. More recently, a therapeutic step-up strategy based on clinical and laboratory findings has been suggested. Chronic, active EBV infection is a progressive, fatal disease characterized by organ failure, hypercytokinemia, HLH, and overt lymphomatous or leukemic changes, for which allogeneic HSCT is recommended.

Since secondary HLH develops in approximately 10% of patients with severe dengue fever, with high associated mortality, HLH-directed therapy is worth considering in selected cases. Virus-associated HLH caused by neonatal herpes simplex virus, enteroviruses, or human immunodeficiency virus rarely requires extensive HLH-directed therapy. Treatment of severe influenza-associated HLH has not been well studied. Severe coronavirus disease 2019 (Covid-19) only rarely induces full-blown systemic HLH. HLH induced by intracellular infections, such as tuberculosis, leishmaniasis, or rickettsial disease, usually responds to specific antimicrobial treatment, and therapy based on the HLH-94 or HLH-2004 protocols should typically be avoided.

It is important to consider HLH in patients with sepsislike critical illness that does not respond to sepsis-directed therapy. In sepsis-associated HLH, treatment with anakinra, in addition to sepsis-directed therapy, has been associated with improved survival. Further studies on the frequency and treatment of sepsis-associated HLH are needed.

Because etoposide is myelosuppressive, it may be difficult to ascertain whether a patient is responding to therapy based on assessment of peripheral blood counts. Regular monitoring of immune activation, via measurement of sCD25, is essential to gauge success of therapy and need for treatment reintensification or alternative salvage approaches. Ferritin tends to lag sCD25 and may not fully normalize for many months in some patients despite resolution of HLH. Patients with HLH frequently reactivate as steroids are weaned (typically around week 6 of the HLH94 protocol), so close clinical and regular laboratory monitoring should continue as long as patients are receiving treatment. Salvage therapy for HLH has been reviewed in recent years. To date, most published experience has been with alemtuzumab, but emapalumab, an IFN-_γ_ blocking monoclonal antibody, was recently approved for refractory or recurrent HLH, and is the first drug ever approved by the US Food and Drug Administration for the treatment of HLH. Based on the importance of IFN-_γ_ signaling in HLH, ruxolitinib is being investigated currently in several trials ({"type":"clinical-trial","attrs":{"text":"NCT03795909","term_id":"NCT03795909"}}NCT03795909, {"type":"clinical-trial","attrs":{"text":"NCT02400463","term_id":"NCT02400463"}}NCT02400463, {"type":"clinical-trial","attrs":{"text":"NCT03533790","term_id":"NCT03533790"}}NCT03533790).–

Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening syndrome classified into primary HLH and secondary HLH. Secondary HLH is always caused by autoimmune disease, infections, or cancer. The first-line therapy for secondary HLH is the HLH 2004 protocol, including dexamethasone, etoposide, and supportive therapy. However, up to 30% of patients, especially pediatric patients, remain unresponsive to first-line treatment, and the mortality rate reaches 50% in children with HLH. Furthermore, some children who have special conditions, such as an active virus infection, are not suitable for immunosuppressants treatment. Recently, several HLH-promoting cytokines have been identified, including interferon-γ, interleukin-2, and interleukin-6. Janus kinase 1 and 2 control the signaling of many cytokines, notably interferon-γ, interleukin-2, and interleukin-6. Janus kinase 1 and 2 inhibitors, such as ruxolitinib, have been successfully used to treat HLH in mice. Here, we report that a boy, diagnosed with HLH and high titer of hepatitis B virus-DNA copies, improved quickly, and the cytokine storm of HLH was alleviated after receiving ruxolitinib. Five days after ruxolitinib treatment, entecavir was introduced and serum titer results of hepatitis B virus-DNA returned negative. With 3 months of ruxolitinib treatment and following-up 1 year, the boy's situation maintained sustained remission. In this study, it is suggested that ruxolitinib might be a first-line drug, which could alleviate the cytokine storm of HLH. This treatment may be ushering in the age of glucocorticosteroid-free HLH treatment, which is particularly meaningful for children because it avoids the side effects of glucocorticosteroid.

Objective: To provide an overview of clinical sequelae and emerging treatment options for hemophagocytic lymphohistiocytosis (HLH).

Data Sources: A literature search was conducted using the search terms "hemophagocytic lymphohistiocytosis," "hemophagocytic syndrome," "macrophage activation syndrome," and "treatment" on Ovid and PubMed from January 1, 2017, through September 28, 2022.

Study Selection And Data Extraction: Relevant clinical trials, meta-analyses, case reports, review articles, package inserts, and guidelines to identify current and emerging therapeutic options for the management of HLH.

Data Synthesis: Genetic disorders and secondary causes may trigger HLH in both children and adults. Notable improvements in the diagnosis of HLH were seen with implementation of the HLH-2004 standard diagnostic criteria; however, timely and accurate identification of HLH remain significant barriers to optimal management. Multiagent immunochemotherapy are the backbone of aggressive therapy for acutely ill patients with HLH.

Relevance To Patient Care And Clinical Practice: The global coronavirus 2019 (COVID-19) pandemic and emerging immune effector cell therapies have served to highlight the concerns with immune dysregulation and subsequent HLH precipitation. Without prompt identification and treatment, HLH can be fatal. Historically, the clinician's armamentarium for managing HLH was sparse, with etoposide-based protocols serving as the standard of care. Relapsed or refractory disease portends a poor prognosis and requires additional treatment options. Second- or subsequent-line options now include hematopoietic stem cell transplantation, emapalumab, alemtuzumab, anakinra, ruxolitinib, and tocilizumab.

Conclusions: Improvements in diagnostic methods and novel immunosuppressive treatment strategies, including noncytotoxic immunochemotherapy, have transformed the therapeutic landscape. Unfortunately, many unanswered questions remain. Additional studies are required to optimize dosing, schedules, treatment sequences, and indications for novel treatment options.

Purpose Of Review: The approach to treating patients with hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) has shifted in recent years with the aim to limit exposure to genotoxic agents, such as etoposide, yet dampen hyperinflammation by targeting the activity of specific HLH/MAS-associated cytokines. In this review, we discuss recent efforts to reduce the dose of etoposide and/or incorporate cytokine-targeted therapies for the treatment of HLH/MAS.

Recent Findings: There is emerging evidence that reduced-dose etoposide and/or cytokine-targeted therapies, including agents that neutralize or inhibit signaling induced by interferon gamma, interleukin (IL)-1, IL-18, and IL-6, can effectively ameliorate the clinical and laboratory manifestations of HLH/MAS and improve overall outcomes.

Summary: The application of novel regimens containing lower doses of etoposide and/or cytokine-directed agents to treat HLH/MAS holds potential to dampen inflammation while minimizing therapy-associated toxicities. Nevertheless, further research is needed to better understand, which patients represent the most appropriate candidates to receive cytokine-targeted therapies, elucidate the optimal timing and dose of these therapies, and decipher whether they should be administered alone or in combination with conventional HLH-directed therapies, such as dexamethasone and standard-dose or reduced-dose etoposide.

Primary (familial/hereditary) and secondary (non-familial/hereditary) hemophagocytic lymphohistiocytosis (HLH) are hyperinflammatory and hypercytokinemic syndromes. Secondary HLH includes infection- (eg viral/bacterial/fungal/parasitic) and non-infection- (eg collagen disease or malignancy) related diseases. Viral HLH is the major type among all age groups. Secondary viral HLH and primary HLH must be differentiated carefully because primary HLH can be associated with viral infection(s), and the outcome is dismal without a timely diagnosis and hematopoietic stem cell transplantation (HSCT). Epstein-Barr virus (EBV)-related HLH (EBV-HLH) is the most common type of viral HLH in childhood. For non-EBV-HLH, appropriate treatment of viral infection, followed by immunomodulatory agent(s) such as corticosteroids, intravenous immunoglobulin or cyclosporine A, is usually successful; however, recent SARS-CoV-2-related HLH may become life-threatening. EBV-HLH may occur heterogeneously associated with the primary infection, with chronic active EBV infection or with underlying primary HLH. Although immunomodulatory agent(s) are effective in the majority of EBV-HLH cases, management differs from that of non-EBV-HLH because severe and refractory cases may require etoposide-containing HLH-1994/2004 regimens or other experimental agents. The novel agent, emapalumab (an anti-IFN-γ monoclonal antibody) can be used to treat EBV-HLH cases to avoid the risk of secondary malignancy due to etoposide. Finally, HSCT is required for refractory EBV-HLH cases and can also be curative in some other cases.