What is the first-line treatment for hemophagocytic syndrome?

Author: Wang Zhao, Chief Physician, Beijing Friendship Hospital, Capital Medical University

Reviewer: Zhang Yu, researcher at Chinese Center for Disease Control and Prevention

The treatment of hemophagocytic syndrome (HLH) is a very complex issue. In general, whether it is primary hemophagocytic syndrome or secondary hemophagocytic syndrome, the first-line treatment recommended by the current international guidelines is the HLH-94 regimen, which is the treatment regimen proposed by the International Histiocyte Society in 1994.

The main components of the HLH-94 regimen are three drugs.

First, hormones, such as dexamethasone; second, VP-16, which is Etoposide; third, cyclosporine A. Of course, immunoglobulin G can also be added. Immunoglobulin G is an important auxiliary drug. If you have good economic conditions, it is better to use it. If you are not rich, it doesn’t matter if you can’t use it. However, the three drugs mentioned above, especially hormones and VP-16, are the most critical therapeutic drugs.

Figure 1 Original copyright image, no permission to reprint

The entire course of HLH-94 treatment is actually 40 weeks. However, in fact, after 8 weeks of induction treatment in the early stage, if the hemophagocytosis is relieved, the key point is to treat the primary disease as soon as possible, without having to continue long-term 32-week maintenance treatment.

To give a simple example, once lymphoma-related hemophagocytic syndrome is under control, the lymphoma should be treated as soon as possible, because after the lymphoma is cured, the hemophagocytic syndrome will also be cured. For example, for primary hemophagocytic syndrome, after the hemophagocytic syndrome is controlled, a transplant should be performed as soon as possible. Long-term maintenance treatment alone is of little significance, because the disease will relapse after stopping the medication. Only by changing the immune system and repairing the gene defect can it be cured. Another example is hemophagocytic syndrome caused by rheumatic autoimmune diseases. After the hemophagocytic syndrome is controlled, the rheumatic autoimmune disease can be treated, and maintenance treatment is not required.

What kind of patients need 32 weeks of maintenance treatment? Those are patients whose primary disease cannot be controlled, or patients who need transplantation but cannot find a suitable donor for the time being. Maintenance treatment may be meaningful, but the key point is still the treatment of the primary disease.

Therefore, the treatment of hemophagocytic syndrome is divided into two stages: first, control of hemophagocytic syndrome; second, treatment of the primary disease. Whether the patient can survive in the end depends mainly on whether the primary disease is controlled. Just like Epstein-Barr virus-related hemophagocytic syndrome, if the Epstein-Barr virus does not turn negative, the patient will relapse sooner or later. Therefore, if the primary disease is controlled, there will be no problem of recurrence and treatment of hemophagocytic syndrome.

If the HLH-94 regimen is not effective in treating hemophagocytic syndrome, a second-line treatment can be used. However, the International Histiocyte Society currently has no fixed recommended regimen for second-line treatment. Ruxolitinib, plasma exchange, high-dose chemotherapy drugs, and even some cytotoxic drugs can be used in combination.

The DEP regimen is commonly used now. The International Expert Consensus on Adult Hemophagocytic Syndrome published in June 2019 and the "Guidelines for the Diagnosis and Treatment of Hemophagocytic Syndrome in China" published in 2022 both recommended the DEP regimen as a salvage treatment option.

The DEP regimen is a combination of doxorubicin liposomes, etoposide, and methylprednisolone, with an active transition to primary disease treatment or hematopoietic stem cell transplantation after the condition is relieved. For patients with Epstein-Barr virus-related hemophagocytic syndrome, pegaspargase or asparaginase can be added to the DEP regimen.

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Ruxolitinib was first used for myelofibrosis, but now it is found that it can be used not only for the treatment of hemophagocytic syndrome, but also for the treatment of GVHD, that is, graft-versus-host disease, and some inflammatory reactions, and the treatment effect is very good. However, how to use it reasonably, including dosage, duration of use, and what types of patients are suitable for it, still needs more research to confirm.

In addition, because hemophagocytic syndrome is caused by a life-threatening inflammatory cytokine storm, the inflammatory cytokine can be removed through plasma exchange, so for some high-risk hemophagocytic syndrome patients, this inflammatory cytokine storm can be controlled through plasma exchange. However, it is transient and only treats the symptoms, not the root cause. The patient will relapse later, so plasma exchange is only considered in emergency situations.

Anti-infection treatment is also an important aspect of treating hemophagocytic syndrome. Many patients with hemophagocytic syndrome do not respond well to treatment and eventually die. In fact, they do not die from the progression of hemophagocytic syndrome, but from infection or certain complications. Therefore, for patients with hemophagocytic syndrome, it is important to prevent infection.

If a patient with hemophagocytic syndrome develops a fever during treatment, we need to monitor and evaluate whether it is an infection or a relapse. Of course, in the treatment of hemophagocytic syndrome, various preventive measures should be taken, including active prevention of bacterial, fungal, even Pneumocystis carinii pneumonia, and some viral infections.