Biologic Hemophagocytic Lymphohistiocytosis Treatment Protocols to Combat Cytokine Storms


cytokineRecent developments in biologic therapies may bring an end to the off-label use of chemotherapy and other salvage therapies  in hemophagocytic lymphohistiocytosis. Image Source: Wikimedia Commons user: Bill Branson

Cancer may be the darling of the research world, but there are other, rarer diseases that require just as much care and attention as researchers forge their way towards a cure. Hemophagocytic Lymphohistiocytosis (HLH) is a poorly understood, devastating illness with a high mortality rate. Perhaps the most upsetting part is that there is no “gold standard” treatment protocol. The illness itself, which elicits a cytokine storm that ravages the body, has two separate sources: primary HLH is associated with a genetic predisposition which is often diagnosed in young children, while secondary HLH is associated with other infections or diseases and may be acquired later on. Currently, most treatment options rely on off-label uses of other therapeutics.

In March of 2016, the FDA granted breakthrough therapy designation to an orphan immunotherapy drug. This particular designation exists to expedite the development and review of therapies in high need situations where preliminary clinical trial results are promising. NI-0501 is a human anti-interferon-gamma (IFNγ) monoclonal antibody that aims to neutralize the biological activity of the IFNγ, which may play a pivotal role in the pathogenesis of HLH.1 Not only does this new therapeutic have the potential to treat both forms of the illness, but by studying the underlying mechanisms of its function, NI-0501 carries the potential to assist researchers with further research into the causes of HLH. Fortunately, modern lab software has made leaps forward in recent years. With the use of innovative lab software, scientists will have an easier time modelling and tracking these mechanisms, and  inching ever closer to a treatment or, perhaps, a cure.

Off-Label Chemotherapy Use and Off-Target Effects

Previously, one of the most common treatments for HLH was chemotherapy, which is notoriously dangerous and fraught with side effects. The first treatment protocol was developed in 1994, using a chemotherapy regimen (epipodophyllotoxin and corticosteroids) in conjunction with cyclosporine A (CSA) immunotherapy. Bone marrow or hematopoietic stem-cell transplant (HSCT) was recommended for those with familial HLH all those who did well in chemotherapy and had a readily available donor.2

This treatment regimen may appear grim, but it was major progress for a previously untreatable illness. In 2004, the protocol was “revamped”. It is still aimed at treating those under the age of 18 and the changes made were minimal, but since these studies were conducted, stem cell therapies have grown and are better understood. Lab software, such as predictive technologies that assist in tracking and predicting side effects and efficacy, are making it possible for researchers to deliver better results.

Occasionally, patients cannot undergo chemotherapy and HSCT. Many salvage therapies have been used over the years, and it would be a gross understatement to say that they are “less than desirable.” These therapies span a broad range of approaches, from removal of cytokines via plasmapheresis (to reduce cytokine storms), to recombinant human thrombopoietin therapy and splenectomies, to liver transplants. These approaches are last-ditch efforts. While many salvage therapies may reduce the symptoms of the disease they have a variety of horrible off-target results. By studying the ways in which many of these final attempt therapies work, scientists may elucidate mechanisms to target in newer therapies. However, the data is limited due to the disease’s rarity, and the subsequent low numbers of patients who are also unable to undergo the recommended treatment.  Modern lab software may be able to fill analysis gaps, preventing haphazard treatment protocols and helping investigators to create targeted medications.

Using Innovative Software to Develop Ways to Specifically Target Cytokines

As research has progressed in this area, scientists have identified interleukins—groups of cytokines—that contribute to HLH. Researchers have implicated two main families of interleukins that play starring roles in HLH:, IL-1 and IL-6, which are also seen in higher concentration in a number of other illnesses. A number of therapeutics directed at these cytokines have been developed:

  • Anakinra is a recombinant form of human IL-1Ra and it functions by blocking binding to IL-1R via competitive inhibition. Although the precise effect is unknown, and regardless of the startling lack of phase III clinical trials, it is widely used, particularly in patients resistant to corticosteroid and cyclosporine. Moving forward, scientists may use modern lab software to assess the mechanisms that allow it to be effective in some patients.
  • A monoclonal antibody therapy, canakinumab, which has a high affinity for IL-1β, is commonly used. This is yet another poorly understood medication as it tends to function in some patients and may have caused flare-ups in others, though, this was later deemed  unlikely to be statistically insignificant.3
  • Rilonacept, incorporates the extracellular domains of IL-1R type I and IL-1R accessory protein in combination with a portion of human IgG. This therapeutic neutralizes both IL-1ɑ and IL-1β. More research will need to be done to hone this therapeutic, and with the aid of modern lab software, it will be more straightforward to identify the domains that need to be modified.
  • Tocilizumab, has been designed for IL-6-mediated signalling. Unfortunately, it appears to have negligible effects on the symptoms of secondary HLH. Lab software has now advanced to a point where underlying mechanisms may be more easily elucidated leading to better targeted monoclonal antibody therapies. By small modifications to either tocilizumab or canakinumab, researchers have the opportunity to make a more effective biologic medication for HLH.

There is a desperate need for innovative software to better design targeted antibodies, such as the above, and to assist with the design of therapeutic proteins. Researchers are aware that many of the aforementioned therapeutics work in particular populations, but not all, and there aren’t sure of the causes one way or another. Investigators need to be able model, in silico, the potential for effectiveness of these therapeutics, then track commonalities between patient populations that respond better to different therapeutics. Modern lab software offers assisted analysis to help researchers identify domains that bind to troublesome cytokines, and adequately analyze sequences so that they can be optimized for use in patients.

As seen in many previous studies, the HLH patient base is highly heterogeneous. Fortunately, this may mean that there are multiple potential cures waiting in the wings. The key to a better treatment, or, hopefully, a cure, will be using innovative lab software to work through all of the data to find better underlying mechanisms, or to play matchmaker with biomarkers, genetics and therapeutics. There is an urgent need for better therapeutics for this illness; rapid and efficient analysis and processing is the key to saving patients. BIOVIA offers an innovative suite of solutions supported by a common platform that helps researchers to rapidly move biotherapeutic candidates from bench to bedside. These solutions have key capabilities in documentation and data management, which will help investigators better analyze the therapeutic capacity of monoclonal antibodies and provide real-time project tracking. Please contact us today to learn more about how our software options can support the efforts of your lab.

  1. “Novimmune’s NI-0501 Granted Breakthrough Therapy Designation by US FDA for Treatment of Patients With Primary Hemophagocytic Lymphohistiocytosis (HLH),” March 16, 2016,
  2. “Hemophagocytic lymphohistiocytosis: review of etiologies and management,” June 12, 2014,
  3. “Macrophage activation syndrome in the era of biologic therapy,” March 24, 2016,