Haemophagocytic lymphohistiocytosis is a severe immune system disorder that turns the body’s defense system against itself, creating a storm of inflammation that can damage vital organs and threaten life if not recognized and treated promptly.

Understanding Treatment Goals and Options for HLH

When someone is diagnosed with haemophagocytic lymphohistiocytosis, the main goal of treatment is to stop the immune system from attacking the body and to bring the dangerous inflammation under control. This condition creates what doctors call a cytokine storm, which means that chemical messengers in the body are being produced in such large amounts that they cause widespread damage to organs like the liver, spleen, bone marrow, and even the brain. Without treatment, this damage can progress quickly and become fatal, sometimes within just a few months.^[1]

The approach to treating HLH depends on several factors, including whether the condition is inherited (primary HLH) or triggered by another medical problem like an infection or cancer (secondary HLH). It also depends on how severe the symptoms are, which organs are affected, and whether the patient has already received treatment before. Early diagnosis and rapid treatment are absolutely crucial because the disease can worsen very quickly, leading to organ failure and death if left untreated.^[2]

Medical societies and expert groups have established standard treatment protocols based on years of research and clinical experience. At the same time, scientists are actively investigating new therapies through clinical trials. These newer approaches aim to target specific parts of the immune system more precisely, potentially reducing harmful side effects while still controlling the dangerous inflammation. Some patients may benefit from established treatments, while others might be candidates for newer experimental therapies, especially if standard treatments have not worked or if the disease has come back after initial treatment.^[10]

Standard Treatment Approaches for HLH

The most widely used treatment protocol for HLH is based on guidelines developed by the Histiocyte Society, often referred to as the HLH-2004 protocol. This standard treatment combines immunosuppression (calming down the overactive immune system) with cytotoxic chemotherapy (drugs that kill overactive immune cells). The main medications used in this initial phase are etoposide and dexamethasone, which are given for about eight weeks.^[9]

Etoposide is a chemotherapy drug that works by destroying rapidly dividing cells, including the overactive immune cells that are causing the inflammation in HLH. It targets both T cells and histiocytes, the white blood cells that are malfunctioning in this disease. Dexamethasone is a powerful corticosteroid that suppresses the immune system broadly and helps reduce inflammation throughout the body. Together, these two drugs form the backbone of initial HLH treatment.^[19]

Many treatment teams also add a drug called cyclosporine to the initial regimen. Cyclosporine is an immunosuppressant that works differently from dexamethasone. It specifically blocks the activation of T cells, which play a central role in driving the inflammation in HLH. By preventing these cells from becoming activated and producing harmful cytokines, cyclosporine helps control the disease at a different point in the immune response.^[9]

For patients who improve with the initial treatment and do not have the familial (genetic) form of HLH, doctors may stop therapy after the eight weeks if the disease appears to be fully resolved. However, many patients require continuation therapy, especially those with persistent symptoms, those with the familial form, or those preparing for a bone marrow transplant. Continuation therapy typically involves repeated doses of etoposide given intravenously, pulses of dexamethasone, and daily oral cyclosporine, continuing from week nine onwards until transplantation can be performed or until the disease is fully controlled.^[9]

The side effects of standard HLH treatment can be significant. Etoposide causes suppression of the bone marrow, which leads to low blood cell counts. This means patients are at high risk for infections (due to low white blood cells), bleeding (due to low platelets), and anemia (due to low red blood cells). Patients often need supportive care including blood transfusions, antibiotics to prevent or treat infections, and careful monitoring in the hospital during the most intensive phases of treatment.^[11]

Dexamethasone and other corticosteroids can cause a wide range of side effects, especially with prolonged use. These include weight gain, mood changes, high blood sugar, high blood pressure, increased risk of infections, weakening of bones, and stomach irritation. In children, long-term steroid use can affect growth. Cyclosporine can cause kidney problems, high blood pressure, tremors, excessive hair growth, and gum swelling. Because of these potential side effects, doctors carefully balance the benefits of controlling HLH against the risks of the medications.^[10]

For patients with primary (familial) HLH, or for those with severe disease that keeps coming back, the only potential cure is hematopoietic stem cell transplantation, also called bone marrow transplant. This procedure replaces the patient’s faulty immune system with healthy stem cells from a donor. The transplant is typically performed after the initial treatment has brought the disease under control and the patient’s condition is stable enough to tolerate the procedure. Finding a suitable donor can take time, which is why continuation therapy is important to keep the disease suppressed while waiting for transplant.^[19]

The success of stem cell transplantation depends on many factors, including how well-matched the donor is, the patient’s overall health status, and whether the HLH is fully controlled before the transplant. The transplant itself carries risks, including graft-versus-host disease (where the donated immune cells attack the patient’s body), infections, and organ damage from the high-dose chemotherapy used to prepare for the transplant. Despite these risks, transplantation offers the best chance for long-term survival in patients with familial HLH.^[3]

Emerging Therapies in Clinical Trials

Researchers have been working to develop new treatments for HLH that target specific molecules involved in the cytokine storm, with the goal of reducing the need for traditional chemotherapy drugs like etoposide. One of the most important breakthroughs in recent years has been the development of emapalumab, a drug that specifically targets a cytokine called interferon-gamma. This cytokine plays a central role in driving the inflammation and tissue damage in HLH.^[10]

Emapalumab is a monoclonal antibody that binds to interferon-gamma and neutralizes it, preventing it from activating immune cells and triggering the cascade of inflammation. This drug has been tested in clinical trials specifically for primary HLH in patients who did not respond well to standard treatment, whose disease came back after initial treatment, or who could not tolerate the standard drugs. In 2018, emapalumab became the first and only targeted therapy specifically approved for primary HLH, representing a major advance in the field.^[9]

The clinical trials of emapalumab showed promising results. In a pivotal Phase II/III study, the drug was given to children and adults with primary HLH who had refractory, recurrent, or progressive disease or who were intolerant to conventional therapy. The treatment led to improvements in many patients, with a significant number achieving a response that allowed them to proceed to stem cell transplantation. The drug is given as an intravenous infusion, typically twice per week initially, with the dose adjusted based on the patient’s response.^[10]

Because emapalumab blocks interferon-gamma, which is important for fighting certain infections, patients receiving this drug are at increased risk for infections and must receive preventive antibiotics. The most common side effects include infections, fever, and high blood pressure. Despite these risks, emapalumab has provided a valuable new option for patients who have run out of other treatment choices.^[12]

Another area of active research involves drugs that block other cytokines involved in the HLH cytokine storm. Interleukin-1 (IL-1) is another inflammatory molecule that contributes to HLH, particularly in cases associated with inflammatory conditions. Drugs called IL-1 inhibitors, such as anakinra, have been studied in clinical trials and case reports. Anakinra blocks the receptor for IL-1, preventing this cytokine from activating immune cells. Some studies have shown benefit in patients with secondary HLH, especially when it occurs in the setting of conditions like Still’s disease or in patients who develop a similar syndrome called macrophage activation syndrome.^[10]

Interleukin-6 (IL-6) is yet another cytokine that has been implicated in HLH. Drugs that block IL-6 or its receptor, such as tocilizumab and siltuximab, are being investigated in clinical trials. These medications are already approved for other inflammatory conditions and have shown some promise in treating HLH in small studies and case reports. They work by preventing IL-6 from binding to its receptor on immune cells, thereby reducing inflammation and the production of other inflammatory molecules.^[10]

Recent research has also focused on reducing the dose of etoposide or finding ways to deliver treatment more safely. Some clinical trials have tested lower doses of etoposide in combination with other immunosuppressive drugs, with the goal of maintaining effectiveness while reducing side effects like bone marrow suppression and increasing the risk of secondary cancers. Early results suggest that dose-reduced regimens may be effective in some patients, particularly those with less severe disease or secondary HLH.^[12]

Another promising area involves using drugs that target specific molecules on the surface of immune cells. For example, researchers are studying antibodies that target CD52, a protein found on lymphocytes and monocytes. Alemtuzumab is one such antibody that has been used in small studies of HLH patients. By depleting these cells, the drug can help reduce the inflammation and organ damage. However, like other immunosuppressive treatments, it increases the risk of infections.^[10]

Ruxolitinib, a drug that blocks enzymes called JAK kinases, is also being explored in clinical trials for HLH. JAK kinases are involved in signaling pathways used by many cytokines, including interferon-gamma. By blocking these enzymes, ruxolitinib can reduce the effects of multiple cytokines at once. Small studies have shown benefit in some patients with HLH who did not respond to standard treatment, and larger trials are underway to better understand its role.^[10]

Clinical trials for HLH are conducted in specialized centers around the world, including major pediatric hospitals in the United States, Europe, and other regions. Many trials are available for both children and adults, though the majority of HLH cases occur in childhood. Patients interested in participating in clinical trials should speak with their healthcare team about whether they might be eligible and what trials are currently recruiting patients. Being part of a clinical trial not only provides access to cutting-edge treatments but also contributes valuable information that may help future patients.^[18]

The trials typically proceed through several phases. Phase I trials test the safety and appropriate dosing of a new drug in a small number of patients. Phase II trials assess whether the drug appears to be effective and continue to monitor safety in a larger group. Phase III trials compare the new treatment to the current standard treatment in a randomized fashion, to determine if the new approach is better, as good, or worse than existing options. Some recent HLH trials have combined Phase II and Phase III elements, especially for very rare conditions where it is difficult to enroll large numbers of patients.^[10]

Most common treatment methods

• Immunosuppressive chemotherapy
  • Etoposide combined with dexamethasone forms the standard initial treatment for eight weeks
  • Targets overactive immune cells and reduces inflammation throughout the body
  • Often combined with cyclosporine for additional immunosuppression
  • Continuation therapy with these drugs may be needed beyond the initial phase
• Targeted cytokine blockade
  • Emapalumab blocks interferon-gamma, a key driver of inflammation in HLH
  • First approved targeted therapy specifically for primary HLH with refractory or recurrent disease
  • IL-1 inhibitors like anakinra being studied for secondary HLH and macrophage activation syndrome
  • IL-6 inhibitors such as tocilizumab under investigation in clinical trials
• Hematopoietic stem cell transplantation
  • Bone marrow transplant is the only potential cure for primary (familial) HLH
  • Replaces faulty immune system with healthy donor stem cells
  • Performed after disease is controlled with chemotherapy and patient is stable
  • Requires finding a matched donor and careful preparation
• Novel immunomodulatory agents
  • JAK kinase inhibitors like ruxolitinib block signaling of multiple inflammatory cytokines
  • Antibodies targeting specific immune cell markers such as alemtuzumab (anti-CD52)
  • Reduced-dose etoposide regimens being tested to minimize side effects
  • Combination therapies using multiple targeted drugs under investigation