Most of the criteria are non-specific, she added. “There really is no gold standard to tell you that a patient has HLH.â€
Dr. McClain said that many of the criteria established by the HLH-94 and HLH-2004 studies are outdated and do not include new clinical and laboratory features that have been found to be much more important. He and other members of NACHO have established an algorithm for the diagnostic workup of HLH in newly presenting patients that includes markers of immune activation (sCD25, granzyme B expression, CXCL9) and genetic testing (multigene panel or whole exome) to establish risk of HLH recurrence.3
Ensuring Prompt Treatment
Patients who experience flares associated with HLH are, in effect, having an inflammatory storm, Dr. Jordan explained. The goal of treatment, therefore, is to halt any underlying trigger and control the overactive immune system.
The current standard of care for HLH (etoposide and corticosteroids) was established by the HLH-94 study. This study looked at children ages 15 or younger who fulfilled diagnostic criteria of HLH and had no prior treatment with chemotherapy or cyclosporine. HLH-2004 confirmed that patients with HLH could be rescued with a combination of etoposide and dexamethasone.
“Etoposide is good at killing activated T cells,†Dr. Jordan said, but Dr. McClain noted that the use of steroids in this setting can be tricky.
“The high-dose steroids have to be tapered down gradually and, as we decrease the dose, we often end up releasing control of the immune system,†Dr. McClain explained. “Sometimes, we are forced to put patients back on steroids while we consider alternative treatments.â€
In 2018, the U.S. Food and Drug Administration (FDA) approved the monoclonal antibody emapalumab, which binds and neutralizes interferon-gamma, for adult and pediatric patients with recurrent or refractory HLH.6 This approval was based on a single-arm study in 27 children who received emapalumab with background dexamethasone. The overall response rate was 65%.7 The investigators also noted that emapalumab was not associated with any organ toxicity, though 10 patients developed severe infections during treatment.
However, Dr. McClain noted that emapalumab is not equally effective for all patients. In adults, Dr. Berliner added, its use is even a bit controversial.
“In the trial used to support its approval, the drug was never given to anyone over the age of 12,†Dr. Berliner noted. “The result is that there has only been scattershot use of emapalumab in adults.â€
In fact, the European Medicines Agency recommended against marketing authorization for emapalumab for pediatric patients in 2020.8 The agency wrote that “the results of the study were not considered sufficient to conclude that [emapalumab] was effective in treatment of primary HLH.†Because patients received other medicine and symptoms varied over time, “it was not possible to conclude that the response seen in some patients was due to the effect of [emapalumab],†the agency continued. “Furthermore, the effect of emapalumab could not be sufficiently supported by available data on how the medicine works, and the role of interferon gamma in how primary HLH develops is not fully understood.â€
Other therapies are being explored for HLH, including JAK inhibitors. Animal studies of the JAK1/2 inhibitor ruxolitinib showed significant decreases in clinical and laboratory manifestations of HLH, with improved survival in mice infected with lymphocytic choriomeningitis virus.9
There are no published clinical trials of JAK inhibition in HLH, but case reports in children and adults have shown that HLH can be successfully treated with ruxolitinib, Dr. Berliner said.
There are also ongoing trials in France looking at the anti-CD52 monoclonal antibody alemtuzumab for refractory HLH, Dr. Jordan added. Still, all of these treatments are acting as a bridge to transplantation because “if a patient has a cytotoxic deficiency, they will keep developing episodes of hyperinflammation,†he explained. “Immune suppression is necessary to control these episodes and it is too risky for someone to stay in that state indefinitely.â€
Determining who should undergo transplantation is also controversial, Dr. Berliner said, aside from adults with lymphoma-associated HLH. Anyone with active HLH cannot receive a transplant, but otherwise, she is fairly aggressive with recommending transplant.
“Usually, we transplant anyone who has had an episode of HLH that was associated with multiorgan failure, but whose disease has gone into remission,†Dr. Berliner said. “That is highly variable though, and depends on how comfortable the transplant service is with transplanting these patients.â€
Increasing Incidence or Increasing Recognition?
Due to its overlapping presentation with other inflammatory syndromes and the possibility of missed diagnoses, determining the exact incidence of HLH is nearly impossible. However, experts agreed that the reported incidence is definitely increasing. For example, in the Swedish national registry, incidence of primary HLH increased from 1.2 cases per million in 2006 to 1.5 cases per million in 2011.2
Whether this growing number reflects an actual increase in cases or simply a greater awareness of the syndrome is unclear.
“Genetic deficiencies are at the heart of this syndrome, but there are many other patients who meet the criteria,†Dr. Jordan said. “These are the patients who appear to be increasingly recognized, and many of those are adults.â€
Dr. Berliner agreed. “When I saw my first [adult] patient with HLH, there were close to zero references about HLH in PubMed when I looked it up. Now there are hundreds.â€
This increased recognition is happening outside of hematology, too. Many patients with HLH will show up to the hospital when they are critically ill and initially be treated by an intensivist in the intensive care unit, explained Dr. Jordan, or by infectious disease specialists who are often consulted in cases of prolonged unexplained fevers. Other patients may present with liver failure and see someone on the gastrointestinal service first and, in rare cases, individuals may present with neurologic involvement and see a neurologist first.
However, he noted, most patients present with cytopenias and end up in the care of a hematologist fairly quickly.
From there, a patient’s management may be shared among other specialists depending on the category of the disease, Dr. Berliner said. For example, if a patient has a malignancy-associated HLH, a hematologist/oncologist will be involved, while a patient with HLH caused by infection will likely be comanaged with an infectious disease specialist. Those with macrophage activation syndrome may be comanaged with rheumatologists, she said.
Dr. Berliner said she believes the increased awareness around HLH may be only part of the reason that clinicians are seeing more patients with the syndrome. “The world is also changing,†she said. “We have many more biologic and immunosuppressive drugs, and many new organisms. It is not clear whether or not some of these factors are contributing to a possible increase [in patients experiencing immune dysregulation].â€
In fact, the question of whether there is increased incidence or increased recognition is one she poses at the beginning of her lectures on HLH.
“I suspect the answer may be ‘both,’†she said. “These patients are very sick and it is hard for me to imagine that everybody escaped notice for all those years because the findings tend to be nonspecific. On the other hand, it is possible that HLH was just diagnosed as other things.â€
In the age of COVID-19, it is possible that even more cases of HLH are going unrecognized. The cytokine release syndrome, or cytokine storm, associated with COVID-19 looks much like HLH, Dr. Berliner explained. “I don’t think patients with COVID-19 [and the associated cytokine storm] truly have HLH, but they certainly might fulfill a lot of the criteria for it,†she said. “That is just another one of the reasons HLH is so difficult to diagnose.†—By Leah Lawrence