All right, thank you for having me. So as described, we're going to talk about HLH, or macrophage activation syndrome, in the context of cellular therapy-related toxicity today. I currently work at UPMC. I have no financial disclosures. Maybe if I'm lucky, one day I will. Here are our learning objectives. So we're going to talk about the signs and symptoms of HLH after cellular therapy. And in my opinion, this likely represents just advanced CRS that you've heard about in earlier talks. And we'll talk a little bit about treatment algorithms, understanding that the evidence is not robust. And I can't say this with confidence, but your institution may vary slightly in how they recommend your treatment. So I learned things in terms of pattern recognition and associating it with a case. So we're going to go through a recent patient that I had with what I think was HLH. So this is a 55-year-old with a history of lymphoplasmicytic lymphoma, Waldenstrom's macroglobulinemia, which if you will think back to the first presentation, you'll say that's not an approved indication for CAR-T. And you would be right. This patient was not responding to any line of therapy, so an appeal was made to his insurance company, and they approved the use of CAR-T. So he was given Yezcarta with flu-side lymphodepletion. His initial course was complicated by cytokine release syndrome and neurotoxicity that I'm going to show you on the next slide. And then on around day seven post-infusion, the team starts to note the ferritin levels are increasing along with triglycerides, the liver function tests are going up, they're developing a low fibrinogen level, and their encephalopathy is worsening. So on the next one, we're going to go through the timeline. So on the x-axis, you'll see days post-infusion with day one being the first. On the y-axis is the scale, which differs based on what lab parameter we're looking at, but we had to put them all on one. So what you'll note is the green and red are the triglycerides and the ferritin and LDH that start to rise dramatically around one weekend. So going through the course, on this first event, the patient developed cytokine release syndrome grade two, fever, hypotension. They are started on tocilizumab, like you heard about in the first presentation. Pretty standard. Later, they become encephalopathic, they develop grade two neurotoxicity and are started on steroids with dexamethasone, 10 milligrams every six hours. Also pretty standard. Here is where the patient has worsening encephalopathy and lab parameter changes that are making the team nervous, including myself. And we are assuming that the patient might be developing HLH, and we'll talk about why. And they're started on pulse dose steroids for this worsening toxicity. And then later, anakinra. And then down here is when the soluble IL-2 receptor returned. But as you may know, it depends on your institution, but ours doesn't come back for several weeks after you send it. So unfortunately, this resulted afterwards, but it was sent and was dramatically elevated. Now on the next slide, I'm going to show you the ferritin level because it's off the chart. And you'll see around day seven is when this rises to greater than 15,000. And I can't tell you how high it was because our assay doesn't go that high. This is on tocilizumab, steroids, and anakinra. And eventually, you see it start to fall. But it took a very long time. And so this is one thing I'd point out to put in your little memory bank, that if you see the ferritin and the CRP decoupling, meaning the CRP is dramatically decreasing on treatment and the ferritin continues to rise along with LDH and triglycerides, you sort of have to have a spidey sense about it. But it should put your antennas up that something's wrong, that maybe they need further immune augmentation with the therapies we're going to talk about. So that's the first part of the case. We'll come back and conclude that a little bit later. Next, we're going to talk about epidemiology of HLH after cellular therapies. It really depends on what study you read. But in some of the prelim readings, around 3% in adult studies have this high-grade toxicity. In the pediatric studies, it's much different. And I think it's just far more common in pediatrics in general. But as much as a third in pediatric and young adults, depending on what product you're looking at. Some risk factors that don't matter for intensivists include low NK cells, high CD3, and high IL-18. But it could matter for hematologists and people who are collecting the cells and trying to select the right ones. This can matter. Also in these studies, high-grade CRS was a risk factor for development. But I would argue that this really, to me, is just really high-grade CRS and ICANNs progressing. And that's what I said just there. In research studies, median onset was 14 days after infusion. I'll tell you in practice, I get much more nervous when things are used off-label or if it's a trial patient. If things are unexplored, then I have noticed that those patients get far greater toxicity much earlier in their course. But median onset, roughly two weeks. Also the diagnostic criteria are somewhat blurry. So H-score and HLH-2004 are not really validated in this population. However, in a survey of intensivists, many institutions still use these because that's what we have and we extrapolate. Also IL-2 receptor, NK function, CXCL9, all can be helpful, but I would argue are not really clinically actionable. For this patient, that result didn't come back for a few weeks. Bone marrow biopsy can be helpful, but again, takes time. And if they're in your ICU intubated on vasopressors, that is precious time you don't have. So a treatment algorithm. Again, you have to have your spidey senses up for this diagnosis. I always say remember the basics. So if they come in with ACAR-T toxicity, don't forget the basics of critical care. Ruling out an infectious process is extremely important. Many of these patients do get septic shock and it looks almost exactly the same. And then most of these patients up to this point have already gotten the routine therapies for CRS and ICANNs. They've already received tocilizumab or siltuximab, depending on your institution preference. They've already gotten steroids. You can consider IVIG early on, but I would say I've rarely used that at our institution. I'd be happy to see what the panelists use at their own institution. If they're no better in 24 to 48 hours, ferritin's still rising, LDH and triglycerides still rising. They are encephalopathic on vasopressors. My go-to has been anakinra. That's what I have my most experience with, as Dr. Rain Brown alluded to on the first presentation. There is a newer drug called imipalumab, which I didn't include here. It's a monoclonal antibody against interferon gamma. I used that for the first time last week, so I didn't add it in here. But know that's also in your tool bag. I'm never prescribing these by myself, obviously. Call your nearest pharmacist, grab your nearest cellular therapy doctor, ask for help. But I start thinking about these quickly if they are not improving on the usual therapies. I would say stay away from this right box. Most people in this room don't even have chemoprivileges, I would imagine. But keep in mind that etoposide will probably obliterate the CAR-T cells completely. So this is an oncologist's decision and not mine as an intensivist. But know that it is a potential treatment if refractory to everything else and you're trying to save the patient's life. But it has dramatic implications for their cancer prognosis. So outcomes in this disease are really not well studied, as you might imagine. But at least in the case reports and series, you read up to 80% mortality. And I would say that tracks with my own experience with this entity. And oftentimes, it's not the toxicity itself, per se. We get patients through toxicity pretty well, if you read some of our CAR-ICU collaborative research. It's problems with the results or the sequelae of critical illness that end up killing them or progression of their disease afterwards if they can't have cancer-directed therapy and relapse. But it is a very fatal disease. So this patient's conclusion. He survived intubation, mechanical ventilation. He was extubated on day 10, had ongoing poor mental status, encephalopathy. The inflammatory markers did improve, remained on dexamethasone 10q6, and I believe got three days of anikenra. Unfortunately, as I said, they succumbed to something else. So on day 22, post-infusion, he had an aspiration event, had cardiac arrest, and we were unable to get ROSC. And so he died as a sequelae of his critical illness. So my takeaways. I think the current diagnostic criteria are pretty limited. It's a nebulous diagnosis. You really have to have a high clinical suspicion. I think it really is just high-grade cytokine release syndrome. Pulse-dose steroids and anikenra and IL-6 therapies are all things that I use on a regular basis when we have these patients. You could think about imipalumab, but you definitely need oncologic help. And I think that really speaks to what we've said thus far, is multidisciplinary care is important here. You can't do this alone. These patients are incredibly sick. There are no treatment guidelines really developed for CAR T-associated HLH, not yet. And the outcomes, unfortunately, remain pretty poor. There are some references.

HLH

CAR-T therapy

cytokine release syndrome

encephalopathy

treatment options