Review Series on Hemophagocytic Lymphohistiocytosis (HLH)

Summary

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Blood Podcast: Review Series on Hemophagocytic Lymphohistiocytosis (HLH)

Date: May 21, 2026
Host: American Society of Hematology
Guests: Dr. Helen Heslop (host), Dr. Nancy Berliner, Dr. Joanne Su, Dr. Carl Allen, Dr. Bethany Verkamp

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Episode Overview

In this bonus episode, the Blood Podcast discusses recent advances in the understanding, diagnosis, and treatment of Hemophagocytic Lymphohistiocytosis (HLH). Dr. Helen Heslop interviews experts Dr. Nancy Berliner and Dr. Joanne Su (adult HLH specialists), and Dr. Carl Allen and Dr. Bethany Verkamp (pediatric HLH specialists), drawing from two recent Blood review articles on adult and pediatric HLH. The conversation delves into evolving diagnostics, underlying biology, clinical challenges, and the expanding landscape of therapies for both adults and children with HLH.

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Key Discussion Points and Insights

1. Defining HLH: A Syndrome, Not a Single Disease

• Bethany Verkamp (Pediatrics):
  • HLH is “best to think of as a syndrome. It's not one specific disease or one specific etiology. … It's easier to think of it as shock than it is of one specific diagnosis.” (00:45)
• Pathogenesis centers on immune dysregulation, with T-cell hyperactivation and excessive cytokine release (notably interferon gamma).
• Quote:

  “If someone's in shock, what is causing it? And the same for if someone presents with HLH, what is causing it?” – Dr. Bethany Verkamp (00:57)

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2. Adult vs Pediatric HLH: Is the Division Useful?

Adult HLH: Distinctive Characteristics and Challenges

• Joanne Su:
  • Adult HLH is usually triggered by factors like cancer, infection, or autoimmune disease—not typically by inherited genetic mutations seen in children.
  • “A key distinction from pediatric HLH is that there is usually no family history or identifiable homozygous or compound heterozygous alterations… For me, it’s humbling how much of the pathophysiology is not yet completely understood…” (02:09)
• Nancy Berliner:
  • Adult HLH is more heterogeneous and harder to characterize than pediatric HLH.
  • Diagnostic criteria borrowed from pediatric protocols are “fairly nonspecific in adults.”
  • The fixation on strict diagnosis (e.g., with elevated ferritin) is being replaced by a focus on immune and cytokine profiling, which should guide therapy.
• Quote:

  “90% of the patients in the ICU...have a ferritin over 2000. They don't all have HLH.” – Dr. Nancy Berliner (04:14)

  • The debate now centers on whether cytotoxic therapy is necessary in adults, as the disease presentation and biology are highly variable.

Pediatric HLH: More Clear-Cut, but Overlap Exists

• Bethany Verkamp:
  • There is more frequent genetic/familial HLH in pediatric practice, but overlap with acquired forms exists.
  • Critical to always “find the etiology” and not treat all HLH cases the same, even in children.
• Carl Allen:
  • Highlights that HLH is fundamentally about “too much inflammation” due to immune activation.
  • Differences between pediatric and adult HLH come down to host developmental stage and typical triggers (inherited mutations vs. acquired diseases).
• Quote:

  “If any of us got Ebola, we’d probably meet clinical criteria for HLH and maybe could benefit from a little bit of immune suppression.” – Dr. Carl Allen (06:37)

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3. Diagnostics: From Criteria to Cytokine Profiling

• Diagnostic challenges have evolved as understanding of HLH biology has improved.
• Current focus is on identifying immune status, cytokine signatures, and specific triggers rather than relying only on legacy criteria.
• Both pediatric and adult specialists agree: The etiology and pathophysiology must guide management.

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4. Treatment Strategies: Shifting Paradigms in Adults and Children

Adult HLH: Moving Beyond Pediatric Protocols

• Nancy Berliner:
  • Early adult HLH treatment copied pediatric protocols; now, more nuanced.
  • Many adults with HLH-like syndromes do not benefit from cytotoxic therapy.
  • Growing use of steroids and ruxolitinib (JAK2 inhibitor) before cytotoxic agents.
  • “…we will do cytokine profiling on patients and choose the therapy to tailor it… whether that’s anti-interferon gamma or anti-IL1 or anti-IL23 or whatever is driving the disease.” (09:05)
• Joanne Su:
  • Excited about research into specific inflammatory pathways.
  • Emphasizes increasingly sophisticated profiling of cytokines and chemokines (e.g., interferon gamma, TNF alpha, IL-18, CXCL9) for both diagnostics and future targeted therapies.
  • Quote:

    “The tide truly has shifted from the HLH 94 protocol… over an expanded repertoire of anti-inflammatory agents that target dysregulated cytokine release.” (09:58)

Pediatric HLH: Innovation on a Proven Foundation

• Bethany Verkamp:
  • Dexamethasone and etoposide (from HLH94/2004 protocols) “are very useful and effective.”
  • The field is exploring how to safely combine or sequence new agents (e.g., emapalumab, biologics) to minimize toxicity and improve outcomes.
  • Major challenge: Designing studies that can determine best frontline and combination therapies, given HLH’s diverse etiologies.
• Carl Allen:
  • Therapy goals: Quickly control inflammation and prevent death from acute episodes.
  • Etoposide is highly effective but leads to cytopenias; steroids are effective but have long-term side effects.
  • Central issue: Deciding between medical management and need for hematopoietic cell transplant (BMT/HCT).
  • New biologics (e.g., anti-interferon gamma agents) are increasingly used.
  • Quote:

    “How do you control the inflammation upfront? ... How do you titrate the amount of immune suppression needed to safely get to [transplant]?” – Dr. Carl Allen (13:05)

  • Stresses critical role of consortia and prospective trials (“embarrassment of riches” of new drugs)—need to systematically define the best treatment approaches.

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5. Outlook: Personalized and Precise Therapies

• All speakers cite rapid advancement in actionable biology, diagnostics, and tailored therapies.
• Move towards individualized, precision medicine for HLH, with deeper profiling of immune status and customized combination treatments for both children and adults.

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Notable Quotes and Memorable Moments

• Dr. Bethany Verkamp (00:57):

  “If someone's in shock, what is causing it? And the same for if someone presents with HLH, what is causing it?”

• Dr. Nancy Berliner (04:14):

  “90% of the patients in the ICU...have a ferritin over 2000. They don't all have HLH.”

• Dr. Carl Allen (06:37):

  “If any of us got Ebola, we'd probably meet clinical criteria for HLH and maybe could benefit from a little bit of immune suppression.”

• Dr. Joanne Su (09:58):

  “The tide truly has shifted from the HLH 94 protocol... over an expanded repertoire of anti-inflammatory agents that target dysregulated cytokine release.”

• Dr. Carl Allen (13:05):

  “How do you control the inflammation upfront? ... How do you titrate the amount of immune suppression needed to safely get to [transplant]?”

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Important Segment Timestamps

• Defining HLH and its pathophysiology: 00:45–01:23
• Adult HLH: Distinctions and diagnostic challenges: 02:09–05:05
• Pediatric HLH: Overlaps, genetic forms, and etiology: 05:21–07:47
• Evolving diagnostic approaches: 07:47–08:09
• Adult HLH treatment approaches (moving past cytotoxics): 08:09–11:15
• Pediatric HLH treatment innovation (new immune modulating agents): 11:35–15:31
• Conclusions and future directions: 15:31–16:00

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Conclusion

This episode highlights the complexity and evolving landscape of HLH in both adults and children. The panel emphasizes the importance of understanding underlying immune dysregulation, the need to identify specific triggers and pathophysiology, and the rapid shift towards individualized diagnostic and therapeutic approaches. Both review articles discussed in the podcast are recommended for deeper exploration of these themes.

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Transcript

[A]

Welcome to this week's bonus episode of Blood Podcast, your source for innovative ideas and cutting edge information. In this episode, Associate Editor Dr. Helen Hislop interviews two authors who specialize in HLH, Dr. Nancy Berliner and Dr. Joanne Su, and she discusses pediatric HLH with Dr. Carl Allen and Dr. Bethany Verkamp.

[B]

Helen I'm Helen Heslop. I'm one of the deputy editors of Blood, and I'm delighted to welcome you to a podcast associated with a review series on hemophagocytic lymphohistiocytosis, and I'm first going to ask one of our authors to define this syndrome.

[C]

Bethany Verkamp thank you, Helen hlh I think, is best to think of as a syndrome. It's not one specific disease or one specific etiology. I think it really is best defined as a specific process of immune and that dysregulation is driven by T cell hyperactivation and subsequent interferon, gamma and other cytokine secretion. I think the key there is that it's easier to think of it as shock than it is of one specific diagnosis. So if someone's in shock, what is causing it? And the same for if someone presents with hlh, what is causing it.

[B]

Thanks, Bethany. We felt it was timely for a review on this topic since there's been increased understanding of the genet mutations and the other environmental triggers that predispose to this condition. There's been a lot of new information about biology and simultaneously developments in new therapeutics for this disease. We decided to have two review articles, one on adult and one on pediatric hlh, and I'm going to start by introducing our two adult authors, Nancy Belinda and Joanne Thieu, and ask them what they consider adult characteristics of HLH to be, if they think this is a good division of the topic and how they think about biology.

[D]

Joanne in general, how we think about adult HLH is certainly involves sustained immune activation from defective clearance of cells targeted by the immune system. But one of the unique things in adult HLH is that the cases we see are frequently precipitated by triggers such as cancer infection, autoimmune diseases, or rheumatologic conditions. Importantly, a key distinction from pediatric HLH is that there is usually no family history or identifiable homozygous or compound heterozygous alterations that are traditionally seen in primary hlh. For me, it certainly is quite humbling how much of the pathophysiology is not yet completely understood, particularly in the various contexts that we see in adult cases.

[B]

Nancy, would you like to add your thoughts?

[E]

I agree with that. Joanne has covered most of the really important parts. But I also think that we have come to recognize that the adult forms of HLH are much more heterogeneous and much more difficult to characterize than the pediatric patients. And as a result, for years, we diagnosed adult HLH using the criteria that were used to exclude patients in a pediatric protocol that was used to develop a therapeutic approach to pediatric hlh. And it turns out that it's fairly nonspecific in adults. And so we have come to recognize that there are clearly some patients with adult HLH who fulfill all the criteria of pediatric HLH and behave similarly to them. But a huge number of them are really difficult to pin down. I have come from having started out trying to persuade people to think of hlh, because in adults, no one ever thought about the diagnosis. Then there was a phase where whenever anyone had a ferritin over 2000, they would call and say, is this HLH? And 90% of the patients in the ICU, in the hospital have a ferretin over 2000. They don't all have HLH. And now I think I've come around to thinking that because it's so varied, that really what's important is an assessment of the immune status of the patient, but also the cytokine profile. Therapy really needs to evolve to tailor itself to that, rather than hanging your hat on whether you say this is hlh. And basically, I think the obsession with deciding yes or no about HLH in adults is whether or not you need to give cytotoxic therapy. And I think it's become a much more difficult decision than it used to be.

[B]

So I'd now like to introduce the authors of the Pediatric review, Carl Allen and Bethany Vacamp, and ask you the same question about whether you think this is a good split between adult and pediatrics and how you approach new patients. Maybe start with Bethany.

[C]

Thank you, Helen. I think this is a good way to split it. I think it's tough because there is still a lot of overlap. So in pediatrics, it is more frequent to be genetic or familial HLH compared to the adult world. But I think kind of similar to Nancy, one of the big problems is the ones that aren't a genetic hlh. We have the same issue as adults as what is causing it, what is driving it, and do you need to treat it? I Think overall in pediatrics, it's sometimes harder to remind people that you must find the etiology. And so I think that's our main issue. But then when it is genetic hlh, I think it's a little more straightforward for the pediatric side.

[B]

Carl, I'm going to ask you the same question.

[F]

I think Bethany covered that really well. And I think we can be lumpers or splitters. Right. In hematology. And I think one way to maybe oversimplify or lump HLH is just thinking of patients who have too much inflammation.

[E]

Right.

[F]

And it's a situation where the immune activation has pathologic consequences. Right. And I think Mike Jordan, our colleague in the original How I treat HLH 15 years ago and now in this recent Pediatric article, I think summarize it nicely, where we look at the different diagnostic criteria for HLH and indicate how those either reflect excessive immune activation or some kind of pathologic consequences. And so I think if you see a patient who's got highly elevated ferritin, highly elevated CXCL 9 other biomarkers reflecting this extreme immune activation, I think, as both Bethany and our adult colleagues indicated, the question is trying to figure out why that is. And I think the developmental stage of the host, if you use that word, and the immune challenges they encounter, I think account for some of the big differences between pediatric and adult, where inherited disorders of immune dysregulation play a much bigger role in children, where adults will acquire cancer, histoplasmosis, other kinds of infections that could trigger an immune activation. If any of us got Ebola, we'd probably meet clinical criteria for HLH and maybe could benefit from a little bit of immune suppression. And so I think from that generalized point saying, well, this is an issue of too much inflammation. It's our job to figure out what are the specific host factors, what are the specific triggers, and then try to use the tools that we have to create an appropriate response where we decrease inflammation while not putting the patient at risk for infections and complications from therapy.

[B]

So I think you've all outlined how the diagnostics challenges have evolved over the years as you've got more knowledge about biology. I think it's also true that there are different treatment options now, too. So I'm going to go back to Nancy and Joanne and ask what sort of treatments they use for HLH and what influences their decisions on different therapies.

[E]

The first case of HLH I ever saw, I looked up in PubMed to find out about treating adult HLH and there were zero articles on adult HLH. So by definition treatment of HLH in adults evolved from adopting pediatric protocols for treatment unless the patient had lupus or rheumatoid arthritis, in which case they tended to just respond to steroids and perhaps some other anti inflammatory agents. Almost all the other patients got steroids and adopticide. Now I think it's become somewhat more nuanced as people have come to recognize that there are forms of HLH like syndromes that are associated with hyperinflammation which do not obviously have an immune problem that requires cytotoxic therapy. And now that we see similar syndromes in people who've gotten CAR T cells, we obviously don't want to kill off their T cells because you kill their CAR T cells and then you lose the benefit of having put the patient through that. I think things have evolved toward considering using anti cytotoxic therapy. And I foresee that in adults eventually that is what will be done is that we will do cytokine profiling on patients and choose the therapy to tailor it to whether or not they should get anti interferon Gamma or Anti IL1 or Anti IL23 or whatever is driving the disease. And I think that it's become much more common for us to give steroids and ruxolitinib a JAK2 inhibitor since that blocks all of the candidate cytokines virtually before we consider giving cytotoxin therapy.

[B]

Joanne wants to add something here that

[D]

is a wonderful overview and insight into this. And even as a clinical fellow, what I've noticed is that the tide truly has shifted from the HLH 94 protocol that Dr. Berliner described with etobicide and steroids over an expanded repertoire of anti inflammatory agents that target dysregulated cytokine release. Certainly ruxolitinib has JAK1 or 2 inhibitor has really risen to the forefront is one that we're really interested in. But what I'm most excited about in terms of research into the future is even more detailed mapping of inflammatory pathways. Truly we can dissect the inflammasome to better understand what are the immunologic signatures of HLH, including what Dr. Berliner mentioned about profiling the cytokines and chemokines. Of course we know the most common ones are for example interferon gamma, there's TNF alpha, but there's more and more interest, for example in IL18 and CXCL9. As a young trainee, I'm incredibly excited for these future cytokines that we're yet we're exploring more on for not only for diagnostic purposes but with an eye towards therapeutics with specific targeting of these inflammatory pathways.

[B]

So I'd now like to move to the pediatricians who have historically had studies that have justified the treatment for HLH and have also led some of the newer studies with agents that are immune modulating or anti cytokine. So. So Bethany, maybe I could ask you how pediatric treatment of HLH has changed over the last few years.

[C]

Clearly the dexamethasone and etoposide are very useful and effective in this and the HLH 94 and 2004 studies really moved the field forward and how we treat. But like we've mentioned, we have so many new tools in the toolbox now. But the question is how do you do a study to compare them and know which one is really the best frontline and what combination is the best use for each case? And you add on the complexity of the different types of HLH that you can see the different etiologies driving it that really makes it tough to study. I think the HLH94 protocol is clearly useful. But now that we have these extra things, can you add in something like imipalumab earlier to one improvement pre BMT outcomes but also to kind of minimize the side effects that you get from a long course of dexamethasone or this very frequent etoposide. So I think that's the way that the field is moving is how do we use these agents together to one rapidly get control of the disease but also to spare side effects as much as we can.

[F]

Kyle, I think Bethany really outlined that nicely. I think again big picture that the challenge is having this extreme immune activation and and there's a couple goals of therapy. The first is to have the patient not die from that acute episode. And I think it's incredibly important to get control of that inflammation. And HLH94, I can't quickly do the math, but it's a protocol that's been around for a few decades. Right. And I think the reason it stood the test of time is because, you know, etoposide is actually an incredible rheumatology drug. It seems to have specific activity against cytotoxic T cells. At least Mike Jordan's mice suggest this to be the case. And so it's fantastic drug. Initially the challenge is after, you know, two or three weeks of etoposide, you start to get cytopenias that become problematic. And then of course steroids work very well, but that have these long term effects. And so I think the challenge is how do you control the inflammation upfront? And then you have to try to decide is this somebody who needs to get a new immune system, do they need to go to bone marrow transplant or hematopo aquatic cell transplant? And then how do you titrate the amount of immune suppression needed to safely get to that point? Or if this is someone who just had a really bad case of mono, right. Figure out this is somebody that you can just decrease the immune suppression and they'll be fine. So I think to start off, etoposide and dexamethasone remain sort of our go to drugs, although the pace at which you get to that point may depend if it's someone who's slowly getting sick or someone who shows up in the icu. So that the pace and the escalation of immune suppression really depends on the individual patients. And Bethany outlined really nicely in the review article some thoughts about how to approach that. But then how do you manage the patient long term? It takes two or three months for most patients to get to transplant and it's not ideal to be on steroids and etoposide for that amount of time. I think some of these new agents are really playing a critical role. It's becoming, I think, increasingly clear that interferon gamma is really central to hlh. A lot of the other cytokines, I think, also contribute to some of the immune pathology, but they're really, I think, more in the downstream blast radius of really activated interferon gamma. And so I think figuring out how to use various agents that block interferon gamma are increasingly being incorporated into therapy. And I think we also have to give credit to our colleagues who started the Histiocyte Society decided to create prospective trials for hlh. It's not an easy thing to do, but I think it's increasingly important so that we can really figure out what works best. I think now we have this embarrassment of riches of so many different drugs. How do we figure out the best ones to use in which situations? Thinking about consortia, models of characterizing patients and trying different drugs and different approaches in a systematic prospective fashion will help us figure out this best approaches moving forward.

[B]

Thank you very much. I'd like to thank all the speakers for giving insights into how biology learnings and new therapies are really providing new options for diagnosing and treating hlh. And I think allowing more precise, individualized therapeutic strategies for this disease when it occurs in children and adults. And you can learn much more about this by reading the two excellent complementary reviews.

[A]

Thank you for listening to this bonus episode of the Blood podcast. To read these articles, visit bloodjournal.org this episode is copyrighted by the American Society of Hematology.