ESH CML/MPN 2025 | The most promising therapeutic approaches currently being investigated for CMML

Yeah, so this is something I did discuss a little bit in the talk at the meeting. So there are quite a lot of interesting things happening. I think it’s worth mentioning, just looking to the future that there’s quite a lot of attention being given to this. For example, in the US, the Leukemia and Lymphoma Society has had a recent CMML special initiative. A very large donation has allowed them to fund a whole range of projects specifically to try and improve outcomes in CMML, two $5 million grants for two consortia to work on different projects, four standalone drug development project grants, money for a clinical trials network. So I think the future does look much brighter. 

Amongst the sort of most promising agents in development at the moment, one that I’d like to mention would be a drug called lenzilumab, so this is a monoclonal antibody that targets the GM-CSF receptor and you know this is something to which CMML cells have hypersensitivity, they seem to respond without the need for the ligand-receptor binding, and that probably drives some of the more proliferative subtypes of the disease – it seems to be associated more with RAS mutant cases and these are some of the ones that need treating and have the worst prognosis. This drug’s been around a while. It’s been used in a lot of patients. It’s very, very safe. It has barely any side effects. 

And in the CMML setting, it’s been through Phase I trials, showing some responses. And at ASH last year, an Australian study presented the first 23 patients, I think, with some really quite spectacular results. This was a single-arm study, it was a slightly bigger study than just the lenzilumab, there was another arm to it, but for the lenzilumab-treated patients who had RAS pathway mutations, they received lenzilumab alongside azacitidine, and there were some really impressive durable responses, and they also showed a reduction in the allelic burden of some of the mutations, something we don’t tend to see with azacitidine. And the results were really quite impressive. At ASH, they compared to historical cohorts of HMA-treated patients, that’s obviously open to interpretations of whether that’s a good thing to do or not, but the comparison was really very striking. The response rates and duration and survival significantly better with the addition of lenzilumab. So what’s needed there is direct randomized trials of the combination, and there are discussions about those taking place at the moment, so we’re quite interested, and there may be a trial of that coming to the UK soon. 

Another drug I’d like to mention is a monoclonal antibody that targets a protein called LILRB4. This is at the earlier stage of development. So this is a protein that’s expressed on antigen-presenting cells and is highly expressed on some CMML samples. And this monoclonal antibody, again, has been tested in Phase I studies and seems to be safe. And there are definite responses seen. And interestingly, the responses were very closely linked to the expression level of the protein. So if you have a lot of the protein, you respond better, which is a pretty good sign that this is an on-target effect. And there’s enough interest around this that the FDA have granted it orphan drug designation status in CMML, which doesn’t happen very often. So we’re quite interested in this drug, and there’s a Phase II ongoing in the US at the moment. No current plans for it to come to the UK. 

One other thing I might just mention in this is about JAK inhibitors. There’s a number of these. There have been trials of ruxolitinib in this disease. Those results have not been spectacular, although there are responders. There is interest, though, in some of the other JAK inhibitors. One that I would mentioned is perhaps pacritinib, which has some potential advantages in CMML, and there’s certainly interest in trying that drug in this disease. This is a JAK inhibitor that’s obviously licensed and used fairly widely in myelofibrosis but is notable for being safer in thrombocytopenia, which is helpful because a lot of CMML patients are thrombocytopenic, but more so it’s to do with the different tyrosine kinase targeting profile of that drug. It’s not just hitting JAK2. It also hits something called IRAK1, which we know is overexpressed in CMML. And it also hits CSF1R, which is the monocyte colony-stimulating factor receptor, again, with a potential role in driving some of the more proliferative CMML features. So we think that this could be an interesting drug in CMML. So these are reasonably advanced stages of development and could, or certainly will be coming to trial soon.

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