EHA 2025 | The advent of targeted therapy in MPNs: CALR and other targets

So I think this is such an exciting time in MPN at the moment because we have, you know, the opportunity to see the first data now coming from the mutant CALR-targeted antibody and I’ve personally been so excited to be able to offer patients that treatment and to see the results presented by John Mascarenhas at EHA in the late-breaking abstract session. And what we presented in that session was data from over 40 patients with ET treated with this antibody actually in two studies because the dosing in North America was different from the rest of the world. And the rest of the world, we went much faster and treated patients up to 2,500 milligrams, whereas the increments in North America were slower, as mandated by the FDA. 

What was very striking from this data is, one, that platelet control happened very quickly within two cycles. So what the patients receive is an infusion that lasts an hour. They have it every two weeks. And the platelets were generally normalizing within two cycles. These are patients who failed at least one therapy. They were allowed concomitant, either anagrelide or hydroxyurea, but for most patients, they have stopped that, including my own patients. The infusion is very well tolerated with, you know, very, very few grade three or above adverse events. Lipase increase, which we don’t really understand, but wasn’t associated with any pancreatitis or liver abnormalities, etc., and we need to dig a bit more into why that actually happens but we do see sometimes lipase abnormalities for example with JAK inhibitor therapy. And also beautiful data so if the listeners have the chance to watch that online take a look or take a look at the post-EHA webinar that we’ve got recorded with VJHemOnc coming up we’ll have John present that and discuss the results, but what we saw was also rapid reduction in the CALR VAF. So clone size reducing, but also mutant megakaryocytes, beautifully stained bone marrow showing mutant CALR on the surface. And then after 24 weeks, that these mutated megakaryocytes were reduced, but also really importantly, that normal megakaryocytes were increasing. And we also showed some data with regard to that as well in terms of progenitors. So clinical efficacy well tolerated and then the beautiful biological data coming along underneath, I think it’s so important and really great to see.

There’ll be more data presented at this ASH. There are MF patients also being treated with that, there are MF patients being treated with the Janssen T-cell engager antibody, hopefully we’ll see some data with regard to that, and they also treated ET patients. And then there was just sticking to the topic of CALR. Of course, there’s the CAR T-cell developed by Alex Rampotas from the UK, and presented at EHA by Beth Psaila, the T-cell engaging CALR bispecific antibody from Incyte. So these agents will all be really important to use for patients and varying potency, of course, and it’s important to remember that we know that patients especially with myelofibrosis don’t have very intact immune systems so we may well need something a little bit more potent and something that can penetrate the fibrotic marrow. 

And then a word on other targeted therapies such as those targeting the V617F mutated JAK2 and the pseudokinase domain of JAK2 also we should expect to see some data. We haven’t seen any clinical data with these agents yet. They’re all agents and potentially could offer a lot of benefits for patients, especially avoiding off-target harms potentially, such as skin cancer, which we do unfortunately see with current JAK inhibitors, but also perhaps offering more potent effects on the clone. So super exciting. Looking forward to discussing in more detail in our post-EHA webinar, but also seeing the data unfurling later on.

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