While rare, HLH is also potentially life-threatening, so pediatric hematologist-oncologist Michelle Hermiston, MD, PhD, wants pediatricians to understand when and how to think about this hyperinflammatory syndrome. Her talk presents the etiologies, offers pearls on understanding the cytokine storm and delineates when to suspect HLH (think: unexplained, excessive immune response to illness). Hermiston describes keys to the workup, explains why knowing the trigger is essential to effective treatment and discusses which patients should receive a stem cell transplant.
So, um I was asked um to speak today on um hemophage cytic lymphocyte cytosis. Um These are my disclosures. I do sit on external advisory boards for Novartis. So be pharmaceuticals and Maon and accept oops except for Emma puma and refractory. HLH. No drugs are approved for HLH in the United States. So, um today, what I would like to cover is to define HLH as a clinical syndrome that can be caused by multiple ideologies to explain the pathophysiology of HLH and its common manifestations to describe a systematic approach to the patient with suspected HLH and to review treatment options for hyper inflammatory conditions. Oops, there we go. I thought I would start here. Um This is an email from my son a few years ago who's um our family are big hockey fans and you said this is pretty cool blues hockey team is supporting this little girl who had a transplant for this disease called HLH Hemogo something, something I don't know if you know anything about HLH, but it sounds really bad to enjoy the video. And indeed, this is a very rare disease. Um It's like, you know, hopefully a little bit or a lot about it. And I'm able to share that with you today. Um And uh it certainly can be a very bad disease. So let's dig in um and try to um help us all develop a systematic approach to this entity. So what is HLH if we break it down into its Latin words? He is blood foc cytic is of a cell that eats and lymphocytosis is expansion of lymphocytes. What we see um histologically are um uh swollen, mac swollen macrophages who ingest um essentially cells. So white blood cells, there's some platelets in there and there's some red blood cells inside this cell. Um It's important to understand that HLH is not a single disease entity. There is not one test we can send that says, oh this is HLH, it's actually a syndrome which is a clinical manifestation of many different conditions. It's characterized by uncontrolled and massive systemic inflammation involving lymphocytes and macrophages and can be thought of as hyperinflammation that becomes self damaging and often life threatening. This is a figure from a review that we wrote as part of the North American Consortium for Histiocytosis that um shows all the different diseases that can fall under um the umbrella of Hoh Syndrome disease and mimics. And so um the um understanding and the approach, these patients can be quite complex and generally takes a large team of individuals. I find it helpful to take a step back and to try to think about this very simplistically, what is our immune system designed to do? It's role is really to eliminate infected cells or malignant cells. And we know that patients without a functional immune system have increased infections and also increased risk for malignancy, particularly lymphoid malignancies. So, in a normal individual, you have a trigger infection, malignancy once in a while, it's a self antigen if the immune system is confused and has reactivity um to self and autoimmune disease. But any of these triggers can lead to activation of CD eight T cells. These T cells when they are activated, um start to proliferate and they produce interferon gamma that leads to recruitment and activation of neutrophils, mac and macrophages um which are able to clear the virus seems to be the timer. Um The important part of this is that they will produce more cytokines from these infected monocytes um or act um activated cells and that leads to further activation of the T cells. Um These T cells can recognize and um through cytolytic granular release, kill the infected um T cell or the malignant target cell. Once the target is eliminated, this then leads to um no further stimulation for the T cells, most of them will die and a few will go on to become memory T cells. And this protects us the next time we en um encounter that same antigen in individuals with HLH. It's important to recognize that the immune response is appropriately initiated. The challenge is really in the ability to terminate that immune response. And so the process starts appropriately, you can interfere in gamma macrophages get activated, they release their appropriate goodies, IL six TNF and IL 18. Um however, the T cells due to cytolytic defects are unable to stop this immune response. And so you get this very um active and vicious circle with hyper cytic anemia that leads to cell infiltration and destruction of tissues um uh and a very ill patient. So, in familial HLH, which is really, I think taught us a lot about this defect. It's quite fascinating that the defects um in families um map to different steps in the cytolytic um pathway. So rab 27 monk 13 monk 18 ory toxin or syn toxin 11 and all of these different proteins are important for movement of the cytolytic Granules to the cell surface. You can also have a um mutation and perfer you can't poke a hole into the target cell and kill it. And with this defect, you have this activated cell that sorry about that um is producing lots of cytokines but unable to kill the target cell. We know that there are at least five types of familial HLH, which historically has been thought of as the genetic kind. Um It's important to point out that FH FHL one is still unknown despite complete sequencing. And despite the fact that two family members in this um uh family um died of an HLH Like syndrome. So we still don't know all of um the genes um and pathways that are important for this disease. There's also a number of HLH associated immune deficiencies such as Sharia Kashi disease, Roselli syndrome, XL um lymphoproliferative disorder, one and two and ITK deficiency. Um And so, in recognizing and thinking about any time you have a child who has an un un um an unexplained or unanticipated, excessive immune response. Um It's important to think about this family of diseases. Historically, we thought of HLH is kind of these two varieties, is a primary HLH or secondary HLH. I think we're coming to appreciate that there's a lot of overlap between these historically, if it was a child, an infant that had disease, we thought it was primary, an older child. We thought secondary. Um interestingly, um the oldest patient in the literature with homozygous perfer mutations presented at age 72. And indeed, as this entity is being recognized more commonly by um our colleagues in internal medicine, we're realizing that primary HLH can happen um in older Children, teenagers and adults. And so it's important to look for an underlying cause because that can change your therapy. Um Doctor Allen's Group at Texas Children's Hospital sequenced, a large number of patients um that presented with an HLH like phenotype and they found a much broader um panel of mutations than had initially been um appreciated in the literature. So, in addition to the familial genes, um they also identified primary immunodeficiency associated genes. Um and um several other immuno immunologically relevant um pathways. And so the current um thinking in the field has really moved to this idea of hygenic um uh genetic contributors to HLH where you may have mutations in a couple of different pathways in terms of cytolytic granule um uh production or movement within cell or preferring killing. And those if they're um digene, meaning you have different mutations that are both heterozygous, it may cripple the pathway but not completely um eliminate its function. And these are patients that may present um without quite full blown um HLH but definitely hyperinflammation um and may be predisposed because this pathway is important for eliminating malignancies um uh to lymphomas in future. Um and adult years. And so this is the approach we currently use to think about this low risk HLH patients, meaning they have no associated mutations require a very large antigenic load. In order to develop an HLH phenotype patients who have classic um familial HLH nonsense bio mutations need very little infection or antigenic stimulation um to develop HLH. And those are the patients that often present early in the middle are patients who have one or two mutations or maybe hypo morphic mutations. It may take more for them to develop HLH. Um But I think any time you have a child who has an unusual presentation of a common childhood illness, thinking about whether they have a predisposition to this disease um is critical um in pediatrics. And so just to summarize, um we now believe there are multiple pathways to HLH or hyperinflammation. It can be the classic cytolytic defects that I just walked you through. Um a more recently emerging category are inflamma zom opathy. In flamas themes are a component of immune cells that are important for also terminating immune responses. This includes Xiap and NLRC four. In this pathway, you get very high levels of il 18. Um You also see this in patients who have autoimmune um disease and what when we call HLH macrophage activation syndrome. Um This pathway leads to uncontrolled persistent activation of lymphocytes. Um and whether you come from this direction or this direction or you just have lots of antigen. Like we see when we use um card T cells um to treat patients with leukemia, you get um very high levels of interfering gamma that leads to macrophage activation and production of cytokines including A L six, il 10 il one beta and TNF alpha. And so this really gets this feed forward loop um of hyperinflammation oops. So, um what do we do about that? Um I do think it's important to think about a large antigenic load and acquired f forms or as triggers um in patients who have a familial predisposition. Um infection is the most common. Um and it really any infection you can think of is probably been reported in the literature. The most common are herpes viruses, uh the hepatitis influenza. And you know, and I think there's starting to be reports around the country. Um of HLH being triggered by measles, um bacteria, mycobacteria parasites, particularly L mania and um uh uh is a com um one that is common in many parts of the world. Um and then fungus, you always need to think about malignancy in these patients and often that can be masked um or difficult to find and then to also think about rheumatologic disease. So how do we approach these patients? The first step is to recognize hyperinflammation. Um uh Doctor William Temple, um Ben Won and Ben Wong um and I um developed a standard operating procedure that we're happy to share um to really help um practitioners in our setting, think about how um these patients. So the first step is to recognize hyperinflammation historically, and this is a, a consult that I get frequently like they've only met four out of eight criteria of HLH is it HLH? And so um I think these uh diagnostic criteria can be helpful but they can also sometimes limit um people from taking the step to appropriate care for a patient. These were designed as um study criteria um inclusion criteria for um the HLH 94 and 2004 cri um clinical trials. And so I think remembering that um these are um more guidelines can be helpful. Um They include either a molecular diagnosis of um genetic HLH which almost um never unless you have a family history. Do you have a presentation or five of eight of these criteria? So, fever spino megaly, cytopenias of two or more cell lines, hypertriglyceridemia or hypothyreosis and elevated ferritin over 500 L invaded, soluble um CD 25 which is the il two receptor and lower absent in case cell activity. I will note that the only place to get this tested. Um Number eight is in Cincinnati. It's a very poor test with very poor sensitivity and specificity and they actually don't send it in their setting. Um And so we generally do not look at this. And um uh currently, um in our practice, um there have been since the HLH 94 and 04 criteria, there have been additional um scoring criteria that have been put forth by different organizations. I think it's helpful to remember that this is not a checklist. Uh um But really just guidelines to help you think about hyperinflammation. Um The important um additions in this are um uh liver irritation and um uh activation or um elevation of liver enzymes which are commonly affected in patients who have hyperinflammation. I think more helpful is to actually appreciate that the signs and symptoms of HLH are really sequela of the cytokine storm and map to specific elevations of specific cytokines. So the fever most likely is really driven by high levels of IO one and IL six which come from macrophages and neutrophils. The pany ofen in late stages is due to hemophage cytosis, but in early stages is actually um more likely due to um suppression of um uh blood uh cell formation um by both TNF alpha and interfering gamma which will um inhibit um hematopoiesis at the stem cell. In early progenitor stages, the high triglycerides are due to high levels of TNF alpha inhibiting lipoprotein lipase, the low fibrinogen and I find this actually one of the most helpful um clues to HLH um is due to activated macrophages leading to um production um and release of plasminogen activators which leads to hyperfibrinolysis. The high so soluble ile A two. sorry about that. Um is due to activated lymphocytes, it shed off a T cell. So that's probably the most specific of these criteria. And then the organ dysfunction and sometimes neurologic symptoms are really due to activation of macrophages within those tissues, infiltration by lymphocytes and subsequent damage. So, when should you think about HLH patients with prolonged fever, patients with unexplained liver inflammation, patients with coag papy, particularly a low fibrogen cytopenias, particularly low platelets. Um because they have the shortest half life can be um a helpful marker to trend high ferritin um and or an elevated soluble il two receptor and then patients with a lymphoid malignancy, especially. Um wanna think about this, if the soluble il two receptor is um out of proportion and elevated relative to the ferritin. Think lymphoid malignancy in those patients and then in general, any sick patient without a good explanation at any age, HLH should at least be in the differential. A few other clues include family history, unexplained death in childhood, unexplained liver disease. We've actually had a couple of patients at HL uh at U CS F where HLH was missed in the initial child who um had liver disease got a transplant and then a subsequent either um presented with another bout of age or had a sibling who presented similarly. And so thinking about that in that population is important. And then a family history of lymphoid malignancies, particularly in males triggers you to think about um excellent lympho proliferative disease, inflammatory bowel disease and um infants, toddler boys also um should be a trigger to think about X LP. Um And then I think serial assessment of laboratory indicators is very helpful in these um patients. Um either declining fibrinogen or an increasing ferritin. Make me nervous a low sed rate with a high um CRP also makes me anxious. The sed rate will be low because you have um decreased fibrinogen. Um but you'll see inflammation from the high CRP. I want to say a couple of words about ferritin. It is an acute phase reactant um and very non-specific but is a good test of macrophage. Um activation or a sign of macrophage activation. There was a retrospective review over two years of all patients with ferritin's greater than 500 at Texas Children's Hospital. They had over a tho um um 1000 samples and 30,000 admissions. Um 10 patients had HLH and 320 were non HLH. Um and they assigned in this study, patients to diagnostic categories by their primary discharge diagnosis. Um and then looked further into the ones where um there was either HLH or it was unknown but had high levels. And I think this is quite striking data, patients who had um an uh ferritin of greater than um 20,000 generally fell into that HLH or unknown um category um more over. Um If you looked at the peak ferritin, the one when you get over that um 15 to 20,000 range, all of those patients were HLH. There's really not many other things that can give you an HLH and that type of um pheno type um other than hyperinflammation and in terms of the predictive value, um the emission ferritin was 74 to 83% accurate. The maximum ferritin actually had 85 to 95% ferritin or accuracy, particularly if it was over 10,000. Um And if you add it in a fever, you get to 90 percent spec um specificity as well as very good um sensitivity. And then um they also very importantly showed in this paper that the rate of change in the ferritin was also indicative of HLH and non HLH, it'll be kind of um consistently elevated. Um But in HLH, you'll see rapid changes and this can be very helpful to trend. Um and to um determine whether or not your interventions are being helpful. There are some clues too that it might not be HLH leukocytosis absence of cytopenias, especially if you have a high platelet count, that's less likely to be HLH. It may be inflammation from another etiology but probably not HLH a high fibrinogen, a normal soluble il two receptor. Since T cells are central to the pathogenesis of this disease, having a high um soluble il two receptor, makes it less likely uh or having a normal soluble io two receptor. Um makes it much less likely since that's really a signal of activated T cells, positive Coombs, lymphadenopathy, normal liver functions and a high sed rate also um can um cast doubt that this is um HLH. So this is um I think a useful approach to the patient with s suspected hyperinflammation. Um you know, so clinical signs and symptoms that make us think about HLH a previous family history um is important. Um in those patients, we wanna do an evaluation for malignancy, rheumatologic disease infection and primary immunodeficiency. And then to really look at the inflammatory markers. If the ferritin or soluble il two receptor are not elevated, it's unlikely to be HLH, other than isolated CNS disease in the context of HLH, which can happen present as confusion but have normal systemic markers. If the inflammatory markers are abnormal, then you want to start going down. Um The approach of is this HLH. And I'll go into that in more detail in a moment. So first up recognize hyperinflammation, we see hyperinflammation in our patient. What should we do next? Um uh The next step is really to identify and treat the trigger. Um People often and we actually wrote this sop because people often um jump down to treating. But um it's really important to understand why this happens. HLH, even in familial situations or in the miri models where you can engineer um a family predisposition syndrome to HLH does not occur spontaneously, you have to infect those mice or give them cancer. Um Same thing with patients that it doesn't occur spontaneously. And so you always want to look for a uh trigger um with every flare. And if you know, sometimes I'll get calls about patients who were doing great. And all of a sudden the ferritin just went back up to 40,000. And in those cases, it's important to send all of the viral studies and to think about what a new trigger might be. Um And so when looking for the trigger, you wanna think about infection malignancy of self antigen. Um And I really think about treating the trigger and why I have it before any other therapy as turning off the bath water if you treat, but with immunosuppressive, but you don't treat the trigger. Um The water is just gonna keep flowing out of the bathtub. So found your trigger or at least have done your best to look for it. And sometimes you can't find anything but it, it's important to look exhaustively for that. Third step is really to calm the hyperinflammation. I think of treating HLH in two phases. The first phase being induction therapy, you want to gain control of the damaging immune hyper um activation, treat the underlying infectious trigger and li limit organ damage and mortality. The second step is really the definitive therapy and this is only when indicated. Um and its goal is really to prevent potentially um fatal future recurrences by correcting the underlying immune defect with the transplant. So, this is the current um approach to HLH therapy. Uh It involves high dose steroids, um twice weekly and then once weekly opic side. And if a patient has CNS um manifestations, intersec methotrexate and hydrocortisone once their immune system has calmed down. And um ensuring they don't have a coagulopathy ns safe to do a lumbar puncture. Um This was based on HLH 94 the HLH 2004 study um tested whether psychos sporin in a um would make a difference in a randomized fashion and there was actually no difference but more seizures in the psychos sporin arm So we do not use that in our practice. Um The goal of this therapy is really to um control hyperinflammation. Historically, um people follow this similar to what we do in oncology as a protocol and you had to get every single dose. And on time, I think over the last decade, there's been um a shift in this thinking and that what we really need to do this isn't an underlying on oncologic disease. It's really hyperinflammation. And so you want to live, get the patient and treat them appropriately. Some patients will be controlled on steroids alone and most patients will actually not need eight weeks of the topaz side. And so we've really moved towards treating patients based on um what they um their uh level of inflammation dictates with. That said the overall outcomes for patients with HLH have not improved all that much until very recently. Um And are not great. Um You know, we can cure um generate long term cures with transplant in about um 60 to 70% of patients. But that means that there's a lot of patients um that we need to develop better approaches or um be able to manage um their reactivation or persistence of the disease better. So what can we use to treat HLH in addition to, you know, big gun steroids and a topic side. Um If we think about the pathophysiology, there's a whole lot of um different um approaches that are currently being tested and I think it's an exciting time um for these patients. Um these include agents just to lum or siltuximab that inhibit IL six and Tanner se that inhibits TNF alpha. Um uh an Akira um which can affect um IO one. there are agents that may be helpful from the tissue in in uh injury, standpoint, Emma paum blocks interference, gamma jack inhibitors. Um and I'll go into more detail and these can affect um cytokine signaling pathway um and act at both the T cell and the macrophage level. If it's an EBV infection, we have some possibilities. And so it's an exciting time, I think in terms of new approaches for um these patients. So um a few words on Emma puma, um which is um an interferon gamma blockading um antibody. It acts both on circulating interferon gamma as well as interfering gamma that is bound to the um patients um who uh in the pivotal trial. Um So a single arm um phase 12 study um who failed HLH conventional therapy could receive this and the computer it's gonna remind itself. Um and the patients um had an overall 12 month survival of about 73%. So still not 100% but certainly active in a number of patients. If you um looked at um uh all treated patients again, it was about 70%. And um if patients could get to transplant, they actually did quite well a second possibility um is Anakinra which is a il one receptor antagonist. There are limited case series showing response. Um It is relatively benign and that it doesn't increase your infection risk um and will not mask the um malignancy while you're um waiting to get a, a pet CT um to look at that which is different from um using um hy Doster or a topic side. It also crosses the blood brain barrier and so it can be excellent for patients with CNS disease. Um And we have had good luck um using this as a steroid sparing agent um or as um a way to get patients off of steroids while we're bridging them to transplant, um particularly those um kids who have isolated CNS disease. So, um another useful agent to think about ruxolitinib has also recently emerged on the scene. This is a potent re um reversible inhibitor of Jack 12 signaling, which is the key regulator of cytokine signaling. Um It um is a pathway that is used by multiple different cytokines. So it can affect both the T cells and the macrophages and neutrophils. It is an oral agent and has excellent bioavailability, but you need to make sure your patient can actually absorb um a drug before you give this. Um It has a short half life um which allows for dose titration um and probably um affects HLH through um multiple different mechanisms. It has been FDA approved um for other um diseases and has known defined toxicity profiles in Children and um has um been shown to be um pretty safe and well tolerated. Um We are currently testing this agent in the North American Consortium for Histiocytosis. Um And I think this is um interesting um animal data that shows that interfering gamma is crucial for initiating HLH. Um. Um And in this, in this experiment, they took mice that were predisposed to h by um having perfer mutations and then bred them with animals that lack different cytokines. And what they found is that um interfering gamma is really the key driver um in um helping these um animals survive when you give them a trigger to get them. It h however, there's been subsequent studies that have shown that other um pathways are still important. So, interfere on gamma deficient mice who have a predisposition to HLH will still die with LC MD infection. Um And um other um cytokines um can actually be more protective in these animals. So um it's not um a complete interferon gamma only driven disease. We um studies have also shown that um neutrophils are important in this disease. So, in this study, um they used animals that um had a per mutation and um gave them um CMV infection to trigger disease. Um If you didn't give them any intervention, the animals would die if you treated them only with an anti interferon gamma antibody, about half of the mi mice. Um so come to disease. However, if you gave them ralli nib, you could rescue the animals. And what was interesting is that it really seemed to be um the effect of Rex ait nib on in um the neutrophils that was important because if you um took away neutrophils with an antibody in these um mice, um some of them would survive about the same numbers. The interfering gamma might um uh mice that received interfering gamma. If you gave interfering gamma plus um uh the antil antibody, then you actually got quite nice responses in these animals. And so um Rex soit nib um is an agent that certainly deserves more testing in Children. Um We also have data um and this comes from my own laboratory that um uh affecting um Jack Sat signaling with rexy litum can um um maybe protect animals by synergize with the steroids. So we have found that if you give um T cells, um uh if you grow T cells from a human being, a normal human being in the presence um of increasing levels of cytokine, they become resistant in this top line um to killing with dexamethasone. And so even at very high doses, and so um from that, and that's due to the fact that these cells actually in the presence of steroids increase a pro survival protein called BC L two. Um And um you can reverse this effect um in the context of um ruxolitinib. And so this is just nicely showing this that when you have cells that are grown in the presence of IL two, which we know is elevated in patients with HLH, they're resistant to dexamethasone. But if you give even tiny levels um of ralli nib, you can reverse this resistance and make them more sensitive. Um And so we are now um actually testing this in the context of a clinical trial. Um There is a group in China that recently reported um a lovely study showing um uh that this seems to also be active in humans. And that if you give ralli nib, you can definitely improve the outcomes of these patients to up to 80% which is much better than any of the historical studies. Um And so we do have this study open um at our center. Um and um are starting to um use this approach in Children. The next step, once you've gotten the patient stabilized, the inflammation um calmed is to determine if there's an underlying defect in the immune system so that if there is you can prevent future episodes of HLH by replacing the immune system. So the approach that we usually take for this is to do what we call rapid functional screening. So we um send cells for flow cytometry for Perrin CD 107 A mobilization sap and XIAP, which um are both the of the markers for the excellent lymphoproliferative disorders. Um If the perfer is de decreased, we will then um sequence for perfer mutations. If the CD 1078 is decreased, that actually picks up almost all of the, and I'll show you how that essay works. Um pathway uh all of the different pathways or mutate proteins that are mutated in the pathway for cytic granular re release. Um And then um the SAP and X IP will tell you about the XL one P one and two linked um disorders. If we see any of these functional test abnormal, then we will um because genotype dictates phenotype, we'll do confirmatory genetic testing. It's also important to have this information. So that if we have to do a transplant on a patient, we wanna make sure that any sibling or parent donors do not ha um carry the same mutation um before um choosing a donor for a transplant. And so this is looking on the flow cytometry based assay for looking at Perrin. Um So, in a normal person, um when you activate their cells, they have an increase in this expression of Perrin and a patient who has a perfer deficiency that um increase in perfer does not happen. Um And then this is the CD 107 A um de uh degranulation essay. So CD 107 A normally lives on the cytolytic Granules. If you stimulate those cells, the cytolytic Granules fuse with the cell surface and you get this big increase in CD 107 A expression. And so this will pick up any defect in the pathway to getting these Granules to the cell surface. Um And so this is how this looks. So this is the controls. When you stimulate them, you get all this CD 107 A on the cell surface. And it doesn't happen in a patient who has a no mutation. Um and on 13, which is one of the pathways in them. If you can determine that a patient has um ho uh an HLH genetic mutation, then the next step is really to um replace the immune system. Um And um I think there's always controversy in the field over whom to transplant. Um I think that the simple litmus test is to simply ask the question, would this patient be better safer or healthier with a different immune system? Is their own immune system helping or hurting them? Um The current recommendations in the literature are um to transplant patients with familial HLH, including CNS only disease to transplant patients who have recurrent or refractory HLH, even if you can't find the gene defect. Um And then to consider transplantation in patients who have abnormal functional testing, even if we can't yet find the disease with um gene defect with our current sequencing technology. Um if they have pre um recurrent self damaging inflammation. Um So this is the approach that we take. Um when we have a patient with HLH, we will start to do the testing. Um And then we give enough therapy to keep their disease in control and to prevent um damage until we can get them to transplant. And we generally try to get them to transplant within um, uh a couple of months. Once their immune system has calmed down, sometimes we can't get the immune system completely calm. And um, the consensus in the field is those patients are good to take to transplant regardless. And that's really based on this finding that the earlier you transplant patients, the better they do um because they have less um organ damage. Um And um just to say that transplanting HLH is more challenging than many other immune defects because the inflammation and the predisposition to organ damage. So how do we transplant these patients? Um uh Well, I appreciate this audience is primarily um general pediatricians. I do think it's helpful to understand what we think about as transplants. Um In case one of your patients has to go down this pathway, what we're really doing. I think from a transplanted perspective is trying to balance graft persistence and survival with toxicity of the transplant conditioning. There are essentially three different types of conditioning regimens. We can do, we can do what we call mac or myeloablative conditioning. This is very aggressive chemotherapy, often with total body irradiation. And the goal is to completely eliminate the bone marrow in the patient so that there's no chance of autologous recovery. Oops apologize. My computer has a mind of its own today. Um The idea is that you prevent rejection by removing host um uh host graph versus host potential by opening up the marrow niches. Um More recently, additional approaches have been developed including um RT C which is reduced toxicity, myeloablative conditioning where we use um modern approaches to um to target our diseases so that we get myelo a but less organ toxicity. Um And there are different regimens that can be used for that. And then the third approach is reduced intensity conditioning in patients with HLH. We're not trying to eliminate malignancy, we just want to give them an immune system. And so the idea is that if you um do less um intense um therapy just to make space for the new um cells that might be sufficient. So what is the data tell us? Um There has not been a randomized control trial comparing these different approaches. Um The um Cibmtr which is on the International Cooper for transplant. And um patients did compare a retrospective comparison of 261 HLH patients. 96 got mylo blade of very intense conditioning. 28 got reduced toxicity conditioning with three drugs called flu Methylin and thiotepa. Um And 14 patients got targeted, um reduced targeted conditioning with bus soften and flu dine. And then 100 and 23 patients actually got reduced intensity conditioning and this were the key results. So the patients who got flu view, which is the intermediate um uh targeted conditioning actually had the best overall and event free survival that was followed by the patients who got also reduced um intensity therapy. Um And then the patients who got the most intense MYOB blade of actually did quite poorly, mainly due to toxicity. And the patients who got the reduced intensity also did more poorly. Um um often due to graft failure. And so um this is sh graft failure is shown here. Um You have the least um failure if you use flu view. Um and the most if you use the reduced intensity um conditioning with flu flu and Meylan. Um and so kind of looking at all of that data, the recommendation consensus from the authors of the paper were that a flu mill thiotepa regimen might optimize the balance between toxicity and ensuring sustained donor engraftment for HLH. Um Our feeling at U CS F because we are very fortunate to have um an amazing pharmacist, Janelle on Boyle who can do targeted um dosing for us is that we've had since we've moved to targeted and dosing and added in a drug called TUUM. We've had few um uh graft failures. Um And we also prophylaxis patients for liver injury with um a drug called defibrotide. Um and we use an an anti day um cytokine cocktail on day zero to also calm down their immune system. And so this has led to very good outcomes for these Children, but certainly, um, more study is needed and, and really at an international level, given the rarity of this disease. So in the last, um, few minutes before questions, um I just wanna talk a little bit about where the field is moving to and the unmet needs in HLH. So, you know, we know to treat the trigger to calm the hyperinflammation and that ideally you wanna replace the defective immune system. Historically, survival has been stuck at 60% even with um to 70% even with Emma pum tux uh ruxolitinib, the jack inhibitor might get us a little higher. The dust generally are due to an inability to control hyperinflammation or secondary infections due to profound immunosuppression. We know from animal studies that you only need about 30% functional T cells uh in order to calm the inflammation. And so this raises the very intriguing idea to correcting t correct T cell therapy alone. Be sufficient for at least a subset of these patients um very excited. Um in that um we um are gonna be testing that at U CS F. Um Jennifer Doudna um leads the innovative genomics Institute and um she was the recipient of the Nobel Prize for developing CRISPR Cas editing where we can go in and fix um precisely gene defects. And so um we are working with um David Win's lab um um at the IG I, um it's also an infectious disease specialist in internal medicine at U CS F to really try to, to test this um in patients. And so the idea will be to use CRISPR cast gene editing to um repair the gene defect in um patients who have um familial HLH. Um and then see if these T cells can sufficiently control the patients. Um either if they have recurrent bouts of this or as a bridge um to gene edited um hematopoietic stem cells. Um This approach is very exciting to us and that it may um spare patients a lot of the toxicity of transplants in chemotherapy. Um uh and the um in increased infection risk that comes with um profound immune suppression. So stay tuned. This is in the early stages. We're hoping to be um to the point of being able to treat patients in about three years. So, takeaways um HLH is a syndrome of excessive inflammation. There can be many different triggers. Always think about autoimmunity infection and malignancy. You need to recognize and accurately diagnose HLH treat the trigger or you just keep having um uh firing um the um inflammation, calm the hyperinflammation. Um And I think there really is a move away from following a protocol but rather treating the patient and giving them only the amount of anti inflammatories that are necessary to um keep them safe. And then ultimately replacing the immune system when appro appropriate. Um And in italics, you know, I think we need more data to really know how to um and clinical trials are necessary to best treat these patients. Um But I think it's an exciting time and that there are new approaches on the horizon. Um I want to think a number of collaborators, particularly from the um nacho consortium um and patients and families. Um And then, um uh I'm always happy to talk to um referring physicians um about these patients. And we do have an immuno uh dysregulation conference every other Thursday. Um We always, we um well, we present our own um patients who are complicated in a multidisciplinary setting. And um we occasionally will have um teams from outside institutions present at this conference just to get um additional. But um I find it takes a village to really think carefully about these kids and the best approaches. So um always can feel free to email us. Um And we're happy to add that to our um uh conference schedule and we can also pull this team together um in very short notice. Um It's usually Friday afternoons because that's when these kids often present um uh to discuss um therapeutic approaches for them. And I will stop there.
