← Blood, Sweat and Smears - A Machaon Diagnostics Podcast
Blood, Sweat and Smears - A Machaon Diagnostics Podcast
HLH, CXCL9 and Clinical Decision-Making with Dr. Joe Rocco
00:47:33
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- [00:06]
A
Hello and welcome to Blood, Sweat and Smears, your macheon diagnostics podcast with tag team hosts, including Our medical director, Dr. Brad Lewis, senior director Bjorn Stromses, that's me. And other guest hosts. We hope you find these podcasts interesting and informative. Thank you for listening. And away we go.
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B
Foreign.
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C
Welcome, everybody. Welcome back to Matrian's Blood, Sweat and Smears podcast on topics in benign hematology. This is Brad Lewis. Once again, I have again the extraordinary pleasure of being able to talk with Joe Rocco. Joe Rocco is an assistant clinical investigator at the niaid. He'll tell you a bit about how he got there. He runs their hemophagocytic lymphohistiocytosis, their HLH unit. Perhaps the only person in the world who sees nothing but hlh. That's really all he does. And has recently come out with, I think, a fairly extraordinary study looking at a way to stratify HLH into a subgroup that may be very, very treatable. And he's gonna talk a bit about that. Joe, you can take it from here. I'd love you to start with sort of how you came to be doing something like this.
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B
Yeah, absolutely. I mean, it's fantastic to be here. There is nothing I love more than talking about hlh, so I more than happy to take the opportunity. And yeah, lots of people ask me sort of, how did I get here? Because it is a little bit unique and I think it's very rare that sort of people maybe remember the first case of something they saw. Maybe they can sometimes put their finger on it. I actually remember the first case of HLH I read about. It was the. It was in the New England Journal. Every journal they have a case series. And I was reading this case. I was like, this is absolutely fascinating. This adult lady with a complex syndrome with fevers and high ferritins and low blood counts, and she got the diagnosis at the end of HLH was the first time I ever heard of it. And then I read the educational portion. I was like, well, why did she get that? What was causing the hlh? Throughout medical school and residency and even in my first year of fellowship at nih, you know, we would see these cases of HLH being brought up and they were always so complex and often younger patients. I'm an adult physician, so these patients were in their 20s, 30s, 40s, 50s, you know, 60s is young nowadays. And so many times we would have all the consult services involved, everyone would be there, and we do the workup, we wouldn't find anything obvious, or we would, but the patients would be too sick to get. Get treatments, and we would say what treatment is best? What do we do this, what do we do that? And amazingly, even at the nih, on our NIAD rounds with world experts in every immunologic condition you could think of, people were still not sure what was the best thing to give. And that was a huge motivation for me, after seeing so many of these patients and not being sure what to do to say, someone has to learn more about this. And. And I have to thank my fantastic mentors at the NIH, Arenas, Reddy, and Dr. Holland, because they actually, when I sold this pitch to them, they were like, you should come here and do that. And that's what I've been doing since. And we have a natural history protocol where we bring these patients in from all over the D.C. metro area and all over the country, sometimes the world, and we try and figure out why is this happening and how can we treat it better.
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C
Can anybody refer patients to your natural history study?
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B
Yeah, we take calls from anyone around the country. And really, like when I was on a call with someone from the Netherlands the other day, kind of hard to transfer someone in the ICU on four pressers from the Netherlands to the United States, but, you know, we're always willing to help, discuss cases and if it's possible, where we've lifelighted patients in from far as Florida and Georgia before. So always happy to help. Super.
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C
All right, so let's start off talking a bit about hlh, one of the problems you actually already alluded to. But docs in the real world find themselves standing there in the ICU looking at this patient and thinking he is sick, as could be he's going to die. I don't have a clue what's going on. When should they begin thinking about the possibility of hlh? And then in a moment, I'll ask you to talk about other things they should think about perhaps at the same time.
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B
Yeah, I think the ideal time to start thinking about HLH is actually before the patient's in the icu, if possible. But obviously in certain cases, they end up there very early on. You know, I think the three biggest things I at least keep on my mind is I really like, you know, this is in a lot of the textbooks, the term unrelenting fevers, because that's really what they are. A sepsis patient can come in with a day or two of fevers, get antibiotics, and it goes away. You know, maybe it takes a couple of days, but you see the downtrend, you see changes starting to happen. HLH is not the case. These patients are just fevering for days, weeks. Some of our patients come in over months and present more like fuos, but the fevers are so unmistakable. But sometimes it starts a little more subtle and it's a more B symptom, like thing of just fatigue, night sweats, weight loss. The trajectory of the presentation of this disease, which we're really starting to describe now, can be so variable. They all end in the ICU on the verge of death. But I'm hoping as we get better at recognizing it, we can do it before they get there. So fevers, these unrelenting fevers or B symptoms is certainly something to keep your ears up for. And I think the cytopenias are a big thing. And I'll pick out maybe the most specific cytopenia is actually probably a low white count. Do we see patients with HLH with a high white count? We do, but they are less likely to be on this sort of full blown HLH spectrum when we'll get into a little bit more of the pathogenesis of it. Of course, the most sensitive marker is probably low hemoglobin, low platelets. But again, there's a lot of reasons you can have low hemoglobin, low platelets. If you have that and the white count's 30. I'm thinking less on the HLH spectrum, but not completely impossible. And then of course you have ferritin. I have a love hate relationship with ferritin because it is very sensitive marker. I think it has some utility in the higher it is, the more likely it's HLH to some degree. But I don't necessarily think that it's. The higher it is, the more likely it's severe hlh. I think that is definitely not true. Some of the HLHs, especially in rheumatologic patients, which we've elucidated in some of our studies, have ferritins well into the hundred thousands and, and a little bit of steroids and Anakinra and they cool right off. Whereas some of the absolutely sickest lymphoma, lymphoproliferative disease, hlhs will have a ferritin of a couple thousand and they're extraordinarily difficult to treat. So good diagnostically, but not necessarily the higher it is, the worse the patient is, which I think sometimes people get caught in that loop.
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C
Excellent. All right, so Somebody begins to think about the possibility of hlh. What tests would you have them order prior to giving you a call or as they call you? Obviously, some are obvious, but we'd love to hear you go through the list.
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B
Yeah, and I think this. I think this is an area of active, dynamic change. I think the first thing we need to do in this sort of just recognizing hlh, and I think that I want to really focus on that recognizing HLH side of things and not the diagnosing HLH side of things. Because hlh, especially in the adults, I don't think of it as an independent diagnosis. I think of it more as a lot of people throw out different terms. I like the term spectrum, the HLH spectrum. I like the term syndrome to some extent because it certainly has a relatively distinct clinical phenotype, really characterized by the fevers, high ferritin, low blood counts. But the ultimate question is, what's driving it in the recognition phase? I think sending the important lab tests that everyone thinks of, liver function tests, triglycerides, fibrinogen, those things are always worth sending. Looking for hepatosplenomegaly. I think if you're getting near the HLH spectrum, you need a pan scan, because things like lymphoma are always on the diagnosis, big liver, big screen will drastically change your approach. And what I think is by far, actually, the two most important labs at this point in time is CxCl9 and the soluble interleukin 2 receptor, also known as soluble CD25. And we can talk about how we specifically think of them. But I want to point out CXCL9 specifically, because when I say CXCL9, the first thing that residents of med students do is say, ooh, what does that do? And even I say, oh, I don't know what it does. It's a chemokine. It does something. But CXCL9 in this setting is really serving as a surrogate marker for the most important cytogine in hlh, which is interferon gamma. And when I think of what I would call true hlh, or, you know, really at the far end of the HLH spectrum as indefinitely hlh. It's a pathologic activation of T cells, making way too much interferon gamma.
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C
But just first, to put in a small plug from Aegeon, when you say getting the CXCL9 and the Siltour, you mean getting it now, having it next week or next month is good. For the death certificate, but less useful.
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B
For the patient 100% getting it now and getting it back quickly. And the sicker the patient is, the actually more important that it is. Which is why recognizing the syndrome a little earlier is. And sending it can actually work in your favor for a lot of reasons. But when they're getting to the icu, the differentiating abilities of it actually becomes greater. Where you could drastically change your treatment based on that CXCL9 value. So you really need it ASAP.
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C
So you'll talk more about the CXCL9 I think in just a moment. But one of the things that sometimes comes up is, well, I think it might be hlh, but maybe I'll wait for it to mature a little bit so that the tests are more diagnostic. We what about getting a CXCL9 early on in the, in the course?
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B
Yeah, I think that's one thing that we've really started to see in our cohort very strikingly it is a very dynamic marker. But in these patients that are presenting with a sort of slower onset of symptoms, and by slower onset, I mean, you know, maybe months, but more likely weeks of fevers, the days of fevers, it becomes a little bit more difficult because those patients do usually go downhill very quickly if they do have hlh. So there's no waiting for it to mature in that setting. The more subtle, maybe subacute presentations, I think sending the CXCL9 early, if you're like eh, it could be. Let me wait and see. Those patients almost always have a very high cxcl9. If this is an evolving HLH process and by very high, we can talk about cutoffs, but I'm saying well over 10,000, probably in the 20, 30,000 range, we've caught patients sort of brewing these unrelenting fevers. They could walk into an emergency room and be discharged because they look pretty good, but their fevers and they're profoundly fatigued and they're cytopenic. We send a CXCL9 and it's 100,000 and you know, within two to three days they're on their way to the ICU without intervention. So I think sending it earlier has a lot of utility in these questionable cases.
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C
Great.
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B
Yeah.
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C
And again, as I mentioned earlier on the CXCL9 and the Siltu are both 24 hour turnarounds. If you send it here to Machan almost no matter where you are in the country. What about other tests? You get along at the same time. Other tests you might suggest Looking for a broader spectrum of disorders, looking for TMAs, for example. And then I'm going to ask you about genetics. Do you think there's a role for genetic testing which doesn't really need to be stat, but is there a role for it early on? And just to say it, you get it through Meijan, you can get it back in two days. So it becomes a real world test.
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B
Yeah, yeah. I think that in this patient, I would say when you're recognizing this HLH phenotype is evolving, the first thing that you really want to do is go all hands on deck looking for the driver, you know, and thinking of hematologic malignancies, new rheumatologic conditions, if still's disease even creeps onto the differential. Sending an IL18 I think is very important in differentiating that even in the adult world. And then of course, infections, which are usually not the major driver of the HLH but the trigger to tip the patient over the edge. There's some caveats to that. If you have disseminated TB or disseminated histo or acute ehrlichiosis, a tick borne infection, those will put you right into an HLH flare at times, but you could have a brewing malignancy that's on the HLH spectrum and you get bacteremic and you go full blast into the ICU with it. So looking for underlying drivers, extraordinarily important. And then using these other tests like soluble interleukin 2 receptor, I think of that as just a marker of T cell activation. You could have a small number of T cells making a ton of interferon gamma. So it doesn't give you as much of an acute readout as I think CXCL9 does. And you can have soluble IL2 receptors of a couple thousand in patients in the ICU with CXCL9s of 100,000 that could respond to gamma targeting HLH therapies, but maybe don't respond to T cell depleting therapies like etoposide massively would shift how you approach the patient. Whereas if they're brewing a little bit, you send the Soviet receptor and it's 80,000 and the CXL9 is 20,000. I would cool them off, but then have a much lower threshold to go to some of these T cell depleting therapies sooner rather than later as well. So I think that drastically changes your acute approach to the patient and always keeping your mind open for these different syndromes, as you mentioned, and atypical hus, these sort of fulminant hemolytic syndromes, especially things like in sickle cell patients that have these things that give you out of proportion elevated ferritins are certainly things focused on that erythroid level where you get like acute hemolytic crisis. Anyone with sickle cell can have ferritins through the roof. These atypical hus, autoimmune hemolytic syndromes that are becoming fulminant. Those patients look like HLH. We've sent CXCL9 in a decent chunk of those patients. They're usually not that elevated. They're usually less than a thousand, certainly less than a couple thousand. There's a question of could there be patients that have both? I think these are reasons that were things we're trying to figure out and which we'll have more data on in the future. But I really think that keeping that differential broad, I would call things like acute hemolytic crises. I would call those more as mimics. Things like ehrlichiosis or disseminated histo. That's very severe. I wouldn't think that as much of an HLH mimic. I think of that as a pathogen that activates that interferon gamma axis. If you could get rid of that pathogen quickly, you might be out of the woods. But if that pathogen has set off a positive feedback loop of T cell hyperactivation, you might still need to dampen down that access with gamma targeting therapies or even T cell targeting therapies.
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C
You'll probably talk more about this in just a minute. But that notion of sort of an HLH phenotype that maybe you don't really need to diagnose HLH, but the CxCL9 is really high. They're on the spectrum, they have the phenotype, and maybe even more than that, they're reaching towards. They're asking for, if you will, a certain therapy, a therapy that deals with this interferon gamma. I think it's a key notion and a slightly different way of thinking about hlh.
- [15:33]
B
Yeah, and I will point out, because there's a lot of hlh, we'll say skeptics or semantic disagreers in a number of different situations. So I am a little bit biased in how I call. I have a low threshold for calling things hlh because I'm trying to refer to this thing as a spectrum. But when I say spectrum, I think the further you get on the spectrum is more likely to be gamma T cell driven and less likely to be other innate immune pathways primarily driving it, irrespective of them meeting criteria. So I'm hoping we get into the world again. We're shifting away from diagnosing HLH in quotation marks. We're recognizing hlh and then we're starting to recognize these sub sort of endotypes within the HLH spectrum. One of which, which I think is the most severe based on some of our data we actually presented recently this year, is if the CxCL9 is high and the T cells are very activated, the mortality of these patients is bordering on 60, 70, 80% within the first 60 days. And these patients really need therapies that target that access sooner rather than later.
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C
So I'm going to ask you in just a second to talk more about your recent study and sort of the impact of CXC online on calling a subset of people with an HLH like phenotype for aggressive therapy. But just to take one step back, you talked earlier about getting the CXCL9 earlier in patients with a more smoldering course. Give a number that pops out. If they come back with a CXC online of Cross 2000 and they've got fatigue and malaise and maybe even occasional fevers, does that make you jump forward? How much you just follow, where's the number where you pull triggers?
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B
Absolutely. Great question. And the number does vary a little bit. But I do get these calls, not infrequently. Oh, I have this patient with the phenotype you described, fevers, they feel crappy. The CXCL9 is, it's super elevated. It's like 3,000. So 3,000 is certainly high. But I always joke with the residents, I don't get out of bed for an CXCL9 less than 10,000. I think as you get into the 10,000 range, you know, my ears perk up. But certainly, you know, even severe infections in the setting of cancers or stuff like that could probably get you in that range. I think one of the most important things we've shown in our data is the higher, the worse. So it's not just a. What's the cutoff? You know, I love a good cutoff as much as the next person. Oh, if it's high, you know, worried. And I think between 10 to 20,000 is a quote, unquote, pretty good cutoff on that spectrum. But really it's when you're getting someone 40,000, 50,000, 150,000, your heart rate needs to exponentially increase. As that goes up, because their mortality rate skyrockets as you reach those very high levels.
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C
Fantastic.
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B
Yeah.
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C
So I think at this point, if you could move forward and talk a bit about your recent study and sort of what we've learned, what you're teaching us about the impact of the CXCL9 on stratifying people.
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B
Yeah. And I think that, you know, I'm very excited to discuss this study because when all you do is see these patients and get these numbers every day, you know, we were recognizing these patterns, and we have great collaborators also a part of the study at Sloan Kettering and University of Pittsburgh and beyond that helped us put this multicenter cohort together. And we all recognize these patterns. But when we would try and talk to people about them, they'd be like, ah, where's the data? You know, there's a lot of skeptics out there, which is good. I like skeptics. But. But we're actually able to put some solid data together. And this was a cohort of no over 170 patients. Everyone sort of had the suspicion of a hyperinflammatory syndrome and had this very comprehensive workup that included a CXCL9 assay soluble IL2 receptor. They hadn't received any therapies for HLH yet. So they were a fairly naive HLH population. Of course, many of them had underlying malignancies and infections and autoimmune diseases that they were receiving therapy for. But it was a relatively uniform cohort in that it was very diverse, but uniform. From the HLH side of things, I will say one of the caveats in all of HLH is, you know, the time that you think about it does shift these things. And I think that's why having multiple centers, us, Sloan Kettering, Pitt people are always thinking about this at different times. So you cover a little bit of that spectrum of variability. And what we're able to show is of the patients that we put on the HLH spectrum, we defined that which some people don't like. But we didn't want you to have to meet the sort of full published criteria because you could meet the H score criteria, but also you could meet 4 of 8 of the HLH 2004 NK cell function. That's kind of out the door. No one really sends that anymore for a number of reasons. And soluble C25s I think, are very good. Most patients had those, but most patients didn't necessarily have bone marrow biopsies. Sometimes they're too sick to get them. So we made it a 4 of an 8 cutoff because we wanted to pick up the earlier HLH cases and maybe the borderline cases. And everyone had a CXCL9. And what we were able to show is in those patients that sort of met those softened HLH criteria, we'll call them HLH spectrum or interferon gamma hyperinflammatory spectrum cases, we found that the CXCL9 was actually, if you put all the clinical labs together and you run a prognostic analysis and say who's going to die? This admission, the only marker in this decision tree analysis that gets spit out was actually CXCL9. And this we found very intriguing. And when we sort of plotted the cutoff that the algorithm, again, I don't like cutoffs, but it fell between about 16,000. So between this 10 to 20,000 range and as you went above 16,000, the mortality for these patients was extraordinary. Within the first 60 days, 90 days, it was well over 50%. And I think that that put things into perspective. But we were also able to show, looking at CXCL9 as more of a continuous variable in chunks, 5,000, 10,000 increases, that for every increase in 10,000 of CXCL9, we, your 90 day mortality increased by up to your 90 day odds of death increased by about 6 or 7% for every 10,000 increase. Emphasizing again, if you're coming in at 100,000, intervention is needed. You know, now there's no waiting for things to mature. And if you're getting it back two weeks later, as you mentioned, unfortunately, which has happened to me just recently for a couple patients, you're getting it back post mortem.
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C
I think that's most of it really for that article.
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B
If I could point out one other thing about the article. Great. One other thing I wanted to mention is, you know, we found very little variability in CXC09 across all the different drivers of HLH. So if we plot out all the different drivers of HLH, there's actually no significant difference between the CXCL9. Now when we did that for other key markers such as ferritin, you know, the highest ferritins are some of the highest ferritins, even though you see high ferritins in every cause. But the highest ferritins were in rheumatologic triggered patients and post stem cell transplant patients. Some of that probably artifactual from them getting a lot of blood transfusions. So those aren't necessarily the sickest patients with the worst mortality, but they have ferritins that are very high. And I think that's one of the reasons that ferritin is maybe not the best prognostic marker for HLH. One of the other findings that we found, soluble IL2 receptor much higher in malignancy driven HLH. That's been actually very well described by groups in Boston and others. Big variability in unknown cases or lymphoproliferative disease cases, but really minimal elevation in rheumatologic cases, infection cases, even some of the early onset presentations of very bad HLHs like EBV, HLH and genetic HLH. We found even smaller elevations in those despite very high CxCL9s, potentially meriting more treatment. So again, maybe it gives you an idea that if it's a very high soluble IL2 receptor, I think that portends to a worse long term prognosis, especially in the setting of a malignancy. That's been well shown with the OHI index and some of these other new things that Mike Jordan and Diesel Eff Lorenz have worked on. But is it as good of an acute dynamic marker when your patient's coming in sick? I don't know. I think the CXCL9 really has a role in that. And in fact, when we plotted OhI positive patients, we found that those with a CXL9 over 16,000 were much more likely to die in the first 30 days than those without it, even though their long term mortality, as has been shown in those studies at the two year mark is exceedingly high.
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C
Interesting. What about the impact of Drugs on the CXCL9? What if somebody's confused, thought it was maybe Still's disease, so they went ahead and gave him some steroids or whatever else, then they call and say, can I order a CXCL9 now, even though I've treated this patient?
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B
Yeah, fantastic question. And I think also one of the most interesting things of this study because that was asked by reviewers and we found that the patient presentation on more immunosuppression actually had higher CxCL9s. I think the reason for that is because one slowed their onset of the HLH. They were probably more dysregulated. All of these patients had underlying malignancies and other conditions, but their HLH I think was more severe. And I think that supports that. CXCL9 is actually a little bit less likely to be prone to changes based on underlying immune suppression. And I think that lends to Its specificity for the interferon gamma access. So if you're getting HLH and you're on immunosuppression one, you might be in more trouble because you're more dysregulated. And I think CXCL9 is still going to have no problem recognizing those patients. We did not find that association with ferritin and crp, which were no different or even maybe slightly lower in patients on more immunosuppression as you might affect. And, and the other point on top of that, sorry, I get too excited.
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C
Talking about this thing, this is utterly.
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B
Fantastic, was when you initiated more HLH directed therapies, which may be just steroids. And again, I'm not saying that a high CXL9 merits a specific therapy, but if it's over 16, 20,000 or higher, it certainly merits an escalation of therapy that targets the interferon gamma in subsense if they're not on steroids, tossing them on steroids is not a bad idea. Or giving them something, which I think we'll talk about later, that targets interferon gamma access a bit more. But if they were responding to therapy, those that survived with the high CXCL9s were much more likely to have a significant decrease at about 1 week to 10 days of follow up in the patients that had CXCL9 repeated. So it does seem to correlate with HLH disease activity. Those that did not have a significant drop in CXCL9 were much more likely to go on to die. And clearly they were either suboptimally treated or treated with things that didn't target the access involved, which was the interferon gamma axis.
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C
Fantastic. So you alluded to it later, has come what is your approach to managing these people? What is your sequencing of therapy? You've already sort of alluded to the CXCL9 is a way to modify maybe the acceleration of your therapy. But what should somebody be doing? You've got this guy. First you think it's HLH, then you're pretty darn sure. The silt tour, the CXCL9 are up. What are you going to give him?
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B
Yeah, so I think to back on the points that I mentioned, the higher it is, the worse it is and the more nervous you should get and the more aggressive you should be with initiating therapies. And when I say aggressive, I don't mean give them all a topicide because I think that we've come to the point where in these acute Settings where we have very high CxCL9s, we have more targeted drugs that have less toxicities, at least at the start. So good old steroids are always fine. A lot of these patients are already becoming refractory to steroids. Maybe they initially respond and then they get worse. That would be the most common thing that I see. Patients get. Steroids get a little bit better and then over the next week or two they get worse again. And the CXCL9 is still going up. And we have really good drugs now that target this interferon gamma axis. We have a monoclonal antibody that targets interferon gamma and mepalumab. We have downstream inhibitors of interferon gamma signaling like JAK inhibitors. The one we have the most experience with is ruxolitinib. And I would say that both of these medications I would dose based on how high the CXCL9 is and when we're getting to CXCL9s, 30, 40, 50,000 and above, giving 1mg per kg of imipalumab is probably not enough. I would start at 6 to 10. I believe the FDA label is currently for secondary HLH from macrophage activation syndrome or other causes. 6 mgs per kg is the recommended starting dose. Ruxolitinib, we always start at 20. Bid people get worried about the cytopenias. However, the cytopenias from the JAK inhibition themselves, in our experience, again, those kick in maybe two to three months later, certainly not within the first month of therapy. So I think being aggressive is extremely important with these non toxic therapies because again, the ultimate goal is not just treating the hlh. The only thing that treating the HLH buys you is keeping the patient alive so you can figure out what's causing the HLH and then subsequently treating that. Because the only way to really cure this or prevent it from coming back is to treat the underlying driver.
- [29:11]
C
So you said as the CXCL9 goes up, you begin to think somewhat differently. So talk a little bit about when somebody comes in, they have a CXCL9 of 30,000 and they're sick and they've already had steroids, or you give them steroids and they're not getting better right away, where do you go next? How do you stratify your decision making based on that? And then how often do you recheck the CXCL9 and then look to maybe change therapies down the road?
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B
Yeah, great question. So exactly the scenario you come in, patient comes in, they're relatively borderline stable. CXL9 is in the 30,000 fevers. We don't know what's going on. I think that some of this is a CCXL in the 30,000 on steroids already. I'm not going to waste a lot of time in initiating therapies. I think you have a couple options depending on what's available. If you know the underlying driver like this patient has, DLBCL is a lymphoma. They need their next line of treatment for the lymphoma. I still think cooling this patient off in some way actually has benefit. You know, we're starting to do that more often. We have good results. That data is still a little too fresh. But, you know, a dose of imipalumab and then go to chemo or something like that I think is reasonable. If you have no clue what's going on and you're just initiating your workup, pan scanning them, looking to get biopsies, sending your serological workup. I think in a patient that's not unstable, that you're not super worried about. Things like ruxolitinib work really well in steroid refractory patients. Starting those 20 bid, those patients always respond. The CXL9 is at that level. Everyone responds and they buy you time. Then you could complete the workup, look for the causes. And rexolitinib doesn't really interfere with biopsies in our experience. For more specific things, if you're worried about the patient being unstable whatsoever, or if the CXL9 is getting to the 60, 70,000, certainly if it's over 100,000. By far the fastest acting drug in this setting, in our experience has been imipalumab. Dosed at least at this sort of 6 mgs per kg mark. It's not easy to get. We're working on the data. This stuff is all in process, but it works immediately. You'll see patients the next day look remarkably better. We've had patients coming in with, I'll give you the one example. This patient's coming in with acute ehrlichiosis. He has no other cause. We actually didn't know he had ehrlichiosis through the door. But he was put on broad antibiotics including doxycycline through the door. No response whatsoever. On high dose steroids, no response whatsoever. He's on day plus 4 of his presentation. He's in the ICU, he's on two pressors, he's going downhill. His CXCL 9 is 120,000. We give him 10 mgs per kg of imipalumab. The next day he's off pressors and his lactate normalized. And the day after that he's out of the icu. So it really does work very fast in these very sick patients. And again, that case, it was kind of easy because we knew that we were getting rid of the trigger with the antibiotics. We still looked for other triggers. And anyone that gets that sick with a relatively, not a common infection, but a relatively common infection needs a deeper look for things beyond the infection that's causing it. You know, you mentioned genetics. This is a. Well, I'll finish up the case. So I think that in the acute setting of treatment, using these things to keep the patient alive, obviously we see a lot of patients that have refractory T cell lymphomas that look just like that. We give two to three big doses of imipalumab. All of their organ function gets better, kidneys get better, liver gets better, cytopenias usually improve a little bit. It's actually striking how much of these changes may just be because of pathologic interferon gamma production. And then they tolerate the chemotherapy for refractory T cell lymphoma or refractory B cell lymphoma much better when they're not having a creatinine of 3 and an AST alt in the 400s. So I think that in these very sick patients, you know, a couple doses of these non toxic interferon gamma targeting therapies may do a lot more good, even in the complex malignancy patients. And there's actually a study in Israel that's opening up that's looking at imipalumab for these hyper inflammatory HLH malignancy patients when they come in. And we're talking about studies that are in progress here as well of trying to make that happen. So lots of exciting things on that front. Can I say one thing on whole genome sequencing? Of course. I think that's what you're going to ask reading your mind. I think that this is my NIH bias and everyone tells me NIH is not the real world to some extent, but a lot of patients we get are from the real world and we do whole genome sequencing. Everybody. That may be not practical yet in the real world, but it probably will be soon. And you know, panels are getting better and better and you're coming back quicker and quicker. But I would say there's a lot of patients in the world that have lymphoma, there's a lot of patients that have autoimmune disease, there's a lot of patients that have infections, and there's a lot of patients that have other weird presentations. And less than 1% of each of them gets HLH. So I think that even finding an underlying trigger or cause is not always the only answer. I think that genetics has a lot to teach us on this front. A lot of it we don't know yet, but hopefully we'll get better in the future with AI and better computational techniques to figure out what these variant changes mean. But I will say my sort of strong recommendation is patients with an unknown cause of hlh. And we have a series coming out on this very soon of over 30 patients that they had unknown etiology of HLH. They're all adults presenting in adulthood. If you look at the literature, the published literature says over 95% of cases of primary genetic HLH present before the age of 3 years and close to 99 present before the age of 10, 12, 13. Well I1 I think that's just definitely not true because we never look. We do a lot of retrospective studies looking in adults and you know, retrospective studies are only as good as the cohort that exists where the samples were dropped. So in these prospective cohorts where we're doing this on everyone, we've found in the last couple years alone 10 to 20 cases. And we ain't sampling the whole country. You know, this is our multi center cohort. I think we're vastly under diagnosing genetic HLH in adults. And I think this needs to be built into pipelines. Again, not in the acute setting, you can always cool them down, but gamma targeting therapies and other things and then you send the genetics, when they come back, you figure out more what to do in the long term.
- [35:41]
C
Great. And just to say Najan doesn't do whole genome sequencing, we do do targeted next gen sequencing looking at all the known HLH genes as well as a lot of the other hyper inflammatory genes, including inborn errors of both somatic and genetic, inborn errors of immunity which can contribute to this kind of stuff. And we get those all out with about a two day turnaround. So again, unlike the whole genome which can take a while outside of the niaid, we can get these things back in real time. You talked about the dosing of imipalumab. Six is the dose that's recommended, 10 is where you would go. What about more? Are there levels of CxO9 or responses that would make you think maybe more is better if you can get your hands on it.
- [36:25]
B
Yeah, yeah, I think imipalumab specifically to talk about that. It's a very unique drug in that its clearance is driven by the amount of interferon gamma present. So as soon as it binds to interferon gamma, it's essentially one stop shop. It binds and then it's cleared immediately. So probably the right thing to do is correlating the dose with a reliable marker of interferon gamma activity, which I think CXCL9 buys us in our retrospective cohorts, which is pushing 100 patients now that we've treated in the ones that we've dosed the imipalumab by the CXL9 and we do similar for ruxolitinib, of course too, is much better associated with good responses. So if the 609 is 30,000, do you need to give six? Probably not. Is six going to hurt them also? Probably not. You probably don't need to give 10. But as you're approaching 50, 60,000. And if you're over 100,000, I think if you can only get six, give six and then give another six the next day because the half life is going to change. And this is where we screwed this up in the beginning when we weren't checking CXCL9s or we didn't know how to interpret them, we were always starting at 1mg per kig, which was the initial FDA label. If your CxCL9 is 100,000, I always make this joke with the resident. If your CXC9 is over 100,000, like the imipalumab doesn't make it out of your antecubital fossa because it runs into the all the gamma there that it binds to, and it binds to it all. The patient feels better for 10 minutes and then you know, it's gone. So giving bigger doses in the setting of These very high CXCL9s is, I think, mandatory. This will keep the patient alive. This is not a cure. This is when you start running into things that work this good, this quick. Sometimes people say, oh, this patient was in the icu, they're on the floor, you know, they look like they're discharged stable. If you didn't get rid of the driver once it wears off, they're going to be right back in the icu. And we've actually had that before with patients in the ICU two days later at the imipalumab Getting ready for discharge, the imipalumab wears off, back in the icu and like, all right, so let's figure out the driver. So lots of things to think about in these patients, which is why it's so hard. But I think we're learning a lot now and how to use these key markers to stratify these patients. And they do predict treatment response and help with dosing, which really makes them invaluable.
- [38:39]
C
Just you've said that a couple times, but just to pin you down even a little bit more on that, it does predict response. So whether someone were to argue with me that really the CXCL9 of 80,000, 60,000 doesn't say that they have HLH, but it does say that they have elevated interferon gamma related disease. But most importantly for the clinician, it does correlate with the response to imipalumab and to Bruxolitinib.
- [39:04]
B
Yep, yeah, exactly. That's been our experience. I'm thinking hard of who I've given these drugs to that had a high CXL9 that didn't respond. And the only patients that didn't respond were the ones that I didn't give enough to. So there's lots of questions in the what happens afterwards phase, how long do you give it? What do you do? You know, how does it change the dynamic of treating the underlying disease? We're learning about those things. It may make it better. We need to prove that. And then the other realm that you're sort of potentially bringing up here is what about not HLH patients with CXL9s of 70,000 or 20,000 or, you know, these mild elevated things, would they respond to these therapies? And what is that list of patients? I will say we are trying to parse that out. We do see, you know, NIAID here we have this large service which is effectively an immunodeficiency and immune dysregulation inpatient service with weird genetic diseases, GATA2, CTLA4, haploin deficiency, all these things. Patients with a high CXL9 in the 10 to 20,000 range without HLH, we certainly do see. And they are usually patients that get treated because they have a T cell hyperactivation problem. It's not necessarily systemic giving them hlh. Maybe it's tissue related and maybe they need some T cell gamma targeting therapies at lower doses or for longer durations. We don't know. Many people here are studying that too, but they've all responded pretty well, to interferon gamma targeting therapy. So is this only a marker of hlh? It's probably a reliable marker in a, in a broader spectrum. We just need to learn more about it.
- [40:41]
C
All right, super. Along the way, you alluded to the fact that you need to figure out what the underlying driver is. So you give somebody imipalumab, you're continuing to look for that underlying driver. Sometimes it's easy, sometimes not so easy to sort that out. What do you do to keep them going? I assume you don't keep giving them a palumab. At some point you back off.
- [40:58]
B
Yeah. And these cases are by far the hardest. The ones that you can't figure out what the driver is. Lymphoma and malignancy HLH patients, they're terrible. They have high mortalities. But at least I know a little bit about what to give them. You know, the treatment for their lymphoma. So, you know, cooling them off and giving that makes it not easy, but at least somewhat the decision making straightforward. The patients where you don't know the cause, you're still looking, they have these weird lymphoproliferation. You can't characterize it even on genetic sequencing. You get a bunch of variants that you don't know what they mean. I do rely on in that setting. You could suppress the gamma with imipalumab, but it doesn't do anything to the T cells. And we've run into this problem before in some of these patients where they felt absolutely fantastic on the imipalumab. They got completely better, but it doesn't touch the T cells. And then you could fall of them over time on imipalumab. And the soluble IL2 receptor goes from 2,000 to 10,000 to 30,000. And then the imipalumab dose is increasing to 100,000. And then they're in the ICU and they've got a lymphoproliferative disease. Some of them look like these large granular lymphocytic lymphomas that are T cell driven. And in those settings you got to give them something that at least slows the T cell proliferation. Ruxolitinib has worked absolutely fantastic. It slows T cell proliferation. You have other options. It's like a batacept could target it, lots of other JAK inhibitors. But you do need to impair T cells in a lot of these unknown cases. And then maybe you need to kill some T cells too. And giving patients some low doses of Etophoside, if your end organs are functioning, atoposide works are really good at killing activated T cells and you know, 7550 migs per meter squared here or there. You don't have to give the eight weeks couple doses, four doses we've done before and we've had great response in killing T cells and that usually again fixes them. But then if you still don't know the underlying driver, it just comes back and then we get into talking about aloe transplants and stuff like that.
- [42:58]
C
All right, fantastic. Any thoughts to close this up about the future studies you'd like to see? Studies that you know are going on that we don't know about?
- [43:07]
B
Yeah, I think that this is an ultra exciting time to be in this hyper inflammatory HLH base. I would even refer to myself more as hlh. We see tons of HLH of all different types, but we're really getting a good handle on the interferon gamma driven T cell hyperactivation cases. And CXCL9 has been instrumental in recognizing that extremely severe phenotype. We didn't even touch on the patients with mildly elevated 69 or just a couple thousand, or maybe it's just 200, but they're still dying in the ICU with unrelenting fevers. That's a whole new cohort that we can study and start to study and try to parse out. So that's extremely exciting in the T cell driven side of things. I think really flushing out the data of using these drugs like imipalumab and ruxolitinib, which there's a lot of great people around the country that we're working with to help do that is going to be instrumental drugs that target and kill T cells that aren't toxic. I said atoposide is good, but it does have a toxicity profile. And again it does kill all T cells. And in ebv hlh, you'd like to just kill the super activated ones. There is newer drugs on the horizon. There's a phase 2B trial where opening is a site for called ELA026. Not FDA approved yet, but is this really unique drug that targets SIRP proteins which are expressed on activated T cells, both probably T cells and also myeloid cells. So maybe it's an even better double whammy to clear out some of these pathologically activated cells. I think that's going to be extremely exciting and there's lots coming even further down the pipeline. Those are the ones I can think of. But I think it's a whole new world. I think we're carving out one very clear phenotype with an extraordinarily high mortality that we may be able to have a significant clinical impact on improving those patients and at least the acute term. I think this is exciting, interesting way to think about this. You know, this is a population of patients that almost universally died. 50, 60, 70% of them died within 60 days. They're all going to live. Now, if we do this correctly, if we show that drugs like imipalumab and stuff work well, what happens to them after the 60 days that they're now alive? And I think that's a whole new population to study that we need to follow in longitudinal prospective studies with unknown drivers or with malignancy drivers. An exciting time. There's lots to do and we're going to keep working on it. And we are happy to have as many collaborators who can help us figure this out that want to work on it.
- [45:38]
C
Fantastic. So unless you have final things you wanted to say, I think this has been simply unbelievable. It's hard not to catch some of your enthusiasm for this field, but I think it's all justified. This is really kind of. It's amazing. I assume if people have questions, you'd be happy to have them contact you. Do you want to give them some kind of contact information? Obviously, Dr. Joseph Rocco at the NIAID, easy to find online.
- [46:04]
B
But yeah, it's pretty easy to find because as part of our natural history trial, I'm definitely one of the contacts. My email's there. It's. When you work with the government, you're not hard to get a hold of, so people can definitely reach out. Always happy to discuss cases, to care for patients, to enroll patients. I'm here and happy to talk. As you probably realized, I'll talk about this all day, anytime, so.
- [46:27]
C
And had useful information with every word that came out. It was fantastic. So for all of you who are listening, thank you once again. This is Blood, Sweat and Smears from Matrion Diagnostics. We look forward to seeing you again at the next podcast. You may want to listen to this one two or three times. There was quite a bit of material in there.
- [46:42]
B
Thanks so much now.
- [46:43]
C
Thank you.
- [46:45]
A
That's it for us here at Blood, Sweat and Smears, a podcast produced by Macheon Diagnostics, your reference lab and CRO specializing in thrombosis, hemostasis and rare disease. Thank you for listening and if you have a question or comment or there's a topic you'd like Dr. Lewis to speak to. Please send us an email to blood sweatandsmearsacheondiagnostics.com that's M A C H A O N diagnostics.com you can follow Matrion at Twitter ationdx. Be sure to subscribe to Stay in the Know Share this podcast with clinicians you think might appreciate it, and we hope you'll join us next time here at Blood, Sweat and Smears.