EBMT 2025 | Managing Erdheim-Chester disease: the efficacy of MEK inhibitors in this rare disease

So one of my other areas of research is histiocytic disorders. I’ve been fortunate enough to work within the histiocytic working group at Mayo Clinic with one of my mentors, Dr Ronald Go. And we have coalesced with the University of Alabama at Birmingham and we work with our combined Mayo UAB histiocytosis working group to try and get a little bit more of a handle and a little bit of additional research in this rare disease. 

In general, histiocytic disorders are rare as a group. They represent clonal malignancies that were previously thought to be more inflammatory because we hadn’t found specific recurring mutations in the populations. They are different flavors amongst the different subtypes but in general I tend to think of them as patients that have a lot of inflammation. They are characterized by macrophage proliferation in a multi-system fashion that can lead to fibrosis, can lead to multiple organ decrement associated with where those macrophages are infiltrating. 

Specifically, Erdheim-Chester disease is the most common histiocytic disorder in adults outside of LCH, Langerhans cell histiocytosis, which has a couple of variants. But Erdheim-Chester is the one that we tend to think of more as kind of like the systemic involvement that can sometimes be a little bit more towards the aggressive end even though there can be a very valid spectrum and these are all just very broad generalizations. Following over the past decade it was identified that a good amount of patients with Erdheim-Chester had recurring mutations in the MAP kinase pathway, particularly the MAP kinase ERK pathway. First it was BRAF V600E for which fortunately our colleagues in the melanoma world had already developed BRAF V600E specific inhibitors. Those were the first drugs that were used, specifically vemurafenib more often than not. 

However, as we learned more about this, we identified that a number of patients in whom BRAF V600E was not identified had other sorts of MAP kinase mutations. And so, as of a couple of years ago, I believe I might be mistaken with the dates, but cobimetinib, a MEK inhibitor, was accepted and was FDA approved for use amongst patients with histiocytic neoplasms regardless of their mutational status. 

We recently had the possibility, because of our center being a major referral center in the US, of assessing our own data pertaining patients that received MEK inhibitors as first-line therapy or second subsequent therapies for Erdheim-Chester. And while we were able to see that we definitely saw extremely good responses in our cohort, we were also able to identify that there were a number of patients that did not achieve that response. Responses are still not universal. And upon attempting to identify what was the cause of that, we were able to see that MAP kinase mutational status was one of the key factors. So, amongst the three patients that were not MAP kinase-mutated, or did not have mutation in the MAP kinase pathway that did not respond, two of them had an identified CSF1R mutation that initially was considered a variant of uncertain significance, and then ultimately was considered pathogenic, were initiated on CSF1R inhibitor, pexidartinib, that fortunately our colleagues in the sarcoma world developed for another disease, and actually had a tremendous response to their therapy. And in another case, we did have another patient with a FLT3 translocation that also responded to directed therapy towards that driver mutation. So in this setting, we are seeing more and more that therapy can be individualized and NGS and genetic studies for our patients kind of in a first come first serve basis could certainly impact their long-term outcomes.

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