Activity Transcript

Paneez Khoury, MD, MHSc, FAAAAI: Hello, I'm Dr Paneez Khoury, Program Director and Allergist Immunologist with a clinical and research interest in eosinophilic disorders in Bethesda, Maryland. Welcome to the segment titled 'Understanding Hypereosinophilic Syndrome and Its Treatment'.

Princess Ogbogu, MD, FAAAAI: Hello, I'm Dr Princess Ogbogu, Chief of the Division of Pediatric Allergy, Immunology, and Rheumatology at University Hospitals Rainbow Babies & Children's Hospital in Cleveland, Ohio.

Dr Khoury: Hypereosinophilic syndrome (HES) consists of a group of disorders characterized by abnormal accumulation of eosinophils in the blood or peripheral tissues that is not due to other secondary causes of eosinophilia. The clinical manifestations of HES are quite broad with a wide range of presenting symptoms, disease manifestations, and prognosis. In today's discussion, we will review the pathophysiology of HES, the role eosinophils play in HES, and how we treat the different subtypes of HES.

Dr Ogbogu: Let's start with a brief review of the pathophysiology of HES. Dr Khoury, can you tell us a little bit more about eosinophils in general?

Dr Khoury: Eosinophils are white blood cells involved in a number of different roles in both health and disease. They play a role in innate and adaptive immune responses and have regulatory functions. There are certain cytokines that play a role in eosinophil growth and development, for example, IL-3, IL-5, and GM-CSF. When you have activated eosinophils, they can contribute to disease through direct cytotoxic effects as well as recruitment and activation of other inflammatory cells. As a consequence, eosinophils in the blood or accumulation in the tissues, can have very negative consequences by causing inflammation in organs such as the lungs, the heart, the nervous system, or the GI tract.

Now that we've talked about what an eosinophil is and how they develop, Dr Ogbogu, why don't you tell us about how to distinguish between hypereosinophilia and HES?

Dr Ogbogu: Hypereosinophilia is defined as a blood eosinophil count of greater than 1500/mm³, so this is an absolute eosinophil count, on at least 2 occasions at least one month apart or blood eosinophilia with evidence of prominent tissue eosinophilia that's associated with symptoms. There are many causes of hypereosinophilia. This can include parasitic disease, allergy, asthma, drug hypersensitivity, connective tissue disorders, neoplasms, among others, but HES, really, is a diagnosis of exclusion. It means that you've excluded secondary causes, and this is really important because it affects or impacts the way that we approach treatment.

After we've excluded these secondary causes of hypereosinophilia and have determined that a patient has HES, Dr Khoury, what's your general approach to treatment?

Dr Khoury: The approach to treatment really depends on a number of factors, including the severity of the clinical manifestations, what organ systems might be involved, as well as the subtype of HES, which we'll talk about in a little bit. It also depends on the degree of peripheral eosinophilia and the potential role that these eosinophils are having in disease pathogenesis.

In cases where really urgent intervention is needed due to markedly high eosinophils or, for example, end-organ damage, we often employ glucocorticoid therapy as first-line. We sometimes give ivermectin if there's potential exposure to Strongyloides to prevent glucocorticoid-induced hyperinfection syndrome, and there are other non-pharmacological approaches such as hematopoietic stem cell transplantation in select cases.

Dr Ogbogu, can you describe the subtypes of HES to our audience, what are those subtypes, and why is it important to know about these?

Dr Ogbogu: The general subtypes include myeloid variant, lymphoid variant. We talk about overlap conditions, and these can include eosinophilic granulomatosis with polyangiitis or the eosinophilic GI disorders, and idiopathic HES. Now, it's important to note that there are rare families that have an autosomal dominant form of eosinophilia, and so there can be familial HES, as well.

When we start with myeloid HES... Let's talk about what points us towards that diagnosis. In the blood, we look for elevated serum tryptase levels, elevated serum B12 levels. We see other abnormalities such as cytopenias or thrombocytosis or elevated LDH levels, and then we can also see molecular abnormalities such as fusions and platelet-derived growth factor receptor alpha (PDGFR-α), PDGFR-beta (PDGFR-β), JAK2, FGFR1, and others. We also see dysplastic eosinophils in myeloid precursors in peripheral smear. On clinical exam, we can see hepatosplenomegaly. These are features that would really kind of push us to obtain a bone marrow biopsy and aspirate. On the bone marrow biopsy, you can see a hypercellular marrow, dysplastic eosinophils, sometimes increased mast cells and blasts.

Dr Khoury: That's really great. I was wondering if you could walk us through your approach to treatment of myeloid HES?

Dr Ogbogu: When we think about the PDGFR positive myeloid neoplasms, imatinib is really the treatment of choice, plus or minus corticosteroids. Imatinib is FDA approved for HES, and the majority of patients with PDGFR abnormalities will respond to this or another TKI. Imatinib's generally well-tolerated, but side effects could include peripheral edema, cytopenias with initiation, and some GI side effects.

Now, for those patients without PDGFR abnormalities or those found to have other molecular variants, you can consider a TKI, and that may include imatinib as well. Now, Dr Khoury, can you tell us a little bit about lymphoid-variant HES? What do we look for, and what kind of treatment options do we have?

Dr Khoury: I'm happy to. Lymphoid HES is defined by the presence of populations of phenotypically abnormal or clonal T-cell populations. Those cells secrete eosinophil-promoting cytokines such as IL-5, IL-13, or IL-4. To diagnose it, you can really look for these immunophenotypically abnormal lymphocytes or clonal T-cell populations using a T-cell receptor gene rearrangement test. In the blood, you can sometimes see things like an elevated IgE, or clinically, you have a variety of skin and soft tissue manifestations, including exanthematous changes, urticaria, angioedema, and sometimes, lymphadenopathy.

Dr Ogbogu: Great. Well, can you tell us a little bit about how you approach treatment for this lymphoid variant HES?

Dr Khoury: Of course. A mainstay of treatment has really been glucocorticoids for a number of years. Glucocorticoids have been used in all subtypes of HES owing to the fast onset of action. The main exception to this is, as you mentioned, myeloid HES with known molecular defects. Sometimes, we do give steroids as an adjunct, but it's not really the main treatment.

The other therapies that have been used include things like interferon. Interferon has been used off-label for both lymphoid and myeloid variants historically and also sometimes in idiopathic HES. The unfortunate thing is that can be associated with significant side effects or toxicity, including flu-like symptoms, myalgia with initiation, myelosuppression, and autoantibody formation. It can be associated with fatigue or neuropsychiatric side effects, including cognitive, affects memory, and it does require close monitoring, and the risk benefit profile and alternatives should be considered prior to initiation.

The other therapy that we sometimes use is hydroxyurea. It is generally well-tolerated except for at higher doses where hematologic side effects such as macrocytosis, anemia, or thrombocytopenia may occur. It can also be associated with GI side effects. We don't often use hydroxyurea as initial monotherapy, but it is often used in conjunction with other therapies.

Sometimes, standard therapies that we've discussed don't work. Dr Ogbogu, when do you reach for immunosuppressive agents?

Dr Ogbogu: When a patient develops toxicity or they become refractory to standard therapies, this is where you really want to consider using immunosuppressive agents. Some examples of these can include mycophenolate, methotrexate, cyclosporine, but really, each of these have their own individual side effects and adverse effect profile, so this really requires shared decision-making with the patient before implementing these therapies.

But really, the good news is, is that we have more targeted therapies that are either now approved or on the horizon for HES, and so anti-IL-5 monoclonal antibody, or mepolizumab specifically, was recently approved for HES. This is generally well-tolerated, has minor side effects, can be glucocorticoid-sparing, and importantly, it's used for the non-myeloid forms of HES. We have other targeted therapies that are on the horizon, and so these include other anti-IL-5 monoclonal antibodies, anti-IL-5 receptor agents that are in clinical trials such as benralizumab and reslizumab, and there are other targeted therapies that are in development for other eosinophil-associated diseases that in the future might actually be helpful for HES, as well.

Dr Khoury, what would you do if a patient presents without myeloid or lymphoid-variant HES, especially one who presents with a really high initial absolute eosinophil count?

Dr Khoury: That's a really good question. I think one of the things that we want to just make sure that they really don't have is lymphoid HES, particularly, because there can be other things that we would be concerned about. For example, patients with lymphoid HES can go on to progress to lymphoma, and the types of lymphoma are really varied...but you want to make sure that the patient doesn't have really enlarged lymph nodes that you'd want to evaluate with a PET scan or actually do a biopsy of. Similarly, I think you would probably have some concerns about ensuring that the patient doesn't have a myeloid HES.

What are the things that you worry about when someone presents with a really high eosinophil count and you're not certain that they don't have myeloid HES?

Dr Ogbogu: Well, with myeloid HES, you really want to make sure that you've ruled that out, again, looking at that serum tryptase, looking at vitamin B12 levels, getting a bone marrow biopsy, and looking for those features that we talked about before because this can be a really deadly one if you don't rule it out. These patients can have really life-threatening side effects and end-organ manifestations like neurologic disease, cardiovascular disease, especially endomyocardial fibrosis, so this is one that you really want to pick up. But once you determined, as you've said, that they don't have lymphoid features and they don't have myeloid features, then you're really left with possible idiopathic HES, which is what we see a lot of. That's the most common variant.

Then you really have to talk about the treatment. You need to decide when and how to treat. One thing that's really important is how they present. If a patient presents with a really high absolute eosinophil count, they need to be treated immediately. A lot of these therapies that we've talked about may take some time to start working; however, there may not be a lot of time, especially when end-organ manifestations are looming, so we recommend using high dose corticosteroids. If there is any chance that Strongyloides might be involved, you use ivermectin along with it, and you really want to prevent end-organ manifestation. That gives a little bit more time as you get some of these other therapies implemented in these patients with idiopathic HES.

Dr Khoury, one thing we didn't talk about so far, but we've mentioned it earlier, is overlap HES. Can you tell me a little bit more about that and how you approach it?

Dr Khoury: Overlap HES really defines known or defined conditions such as eosinophilic GI disorders or eosinophilic granulomatosis with polyangiitis that also presents with peripheral eosinophilia. Sometimes it's hard to distinguish these conditions from HES because they also have elevated eosinophil counts.

In general, those patients we approach very similarly. All the things that we talked about earlier, ensuring those patients don't have a lymphoid or a myeloid presentation with the testing that we discussed is important. There have been some case reports of patients who had PDGFR mutations with primary GI presentation at the outset. I think those things are very important, but then once you've ruled those things out and you think this is really an overlap HES and there are no other disease manifestations beyond the intestines, for example, eosinophilic GI diseases (EGIDs), you would then approach those patients with more of a targeted therapy or topical therapy for the gut, and potentially other therapies that are in development for eosinophilic GI diseases.

For EGPA, there is an approved therapy such as mepolizumab for EGPA as well as potentially other things in the pipeline, so really defining those conditions and ensuring that those are the right patients to treat with a biologic therapy is helpful, and also, as we mentioned, making sure that there's no myeloid or lymphoid HES.

What about you? How do you approach those patients?

Dr Ogbogu: I approach them really similarly. I think that once someone has an elevated eosinophil count, you really have to do your due diligence in the workup. This is an important take-home point to remember that even if they had a more single organ involvement, if they have an elevated peripheral eosinophil count, they can get a lot of those end-organ manifestations that we talked about like neurologic and cardiac, and so it's really important to still do the work up, make sure that you're not missing anything, and make sure that you are controlling the eosinophil count. I wholeheartedly agree, that's the same way that I approach it.

Dr Khoury: I guess if we have a couple more minutes, maybe we can talk about how you follow patients along. That's one of the most common questions I get -- "how often do you have to monitor these patients and what do you have to track over time?" Sometimes, these are iterative diagnoses. What are your thoughts on that?

Dr Ogbogu: That's a good question. The first thing is following them clinically. Some patients, especially those patients that have skin symptoms, might be really affected. Following them clinically...clinical clues can tell you how well they are doing. I do follow the peripheral eosinophil counts. In certain cases, you might still follow other markers like their troponin levels, etc. In patients that have predominantly GI disease, they may require endoscopy and colonoscopy with biopsies over time just to make sure that their disease is well-controlled, especially because we know that clinical symptoms do not always correlate with endoscopic findings, especially with patients with GI disease.

I think if I start seeing some major changes like cytopenias, then I might reconsider getting another bone marrow biopsy and making sure that they haven't developed a neoplasm. If I start seeing lymphadenopathy again, you would be looking at biopsies, and making sure that things don't change. The biggest key here is knowing the patient well, following their symptoms, following some of these labs that we've talked about and the few biomarkers that we know that might predict how a patient may do, and then following up on any clinical abnormalities to make sure that there's no transformation there.

Dr Khoury: There's some really good key takeaways from this discussion, the most important of which is that you need to make a correct diagnosis of HES and also figuring out the right HES subtype. In my opinion, this is especially important as making a myeloid diagnosis will ultimately change the treatment approach as you would want to select a TKI.

Dr Ogbogu, can you give us any parting words?

Dr Ogbogu: I completely agree with that. It's really important to understand the treatment options. We know that glucocorticoids play a key role in the treatment of HES, at least for the non-myeloid variant; however, they're associated with a lot of side effects and an adverse effect profile. What's really exciting is that now we have newer targeted therapies that are either now approved or on the horizon that can really make a difference for patients with these diseases.

Dr Khoury: I agree. Thank you for this really great discussion.

Dr Ogbogu: Thank you.

Dr Khoury: We'd like to thank the audience for participating in this activity. Please continue on to answer the questions that follow, and complete the evaluation.

This is a verbatim transcript and has not been copyedited.