EHA 2025 | The influence of clone size on treatment decisions and disease progression in MPNs

So thinking about clone size for MPN is really topical. We had a great debate at EHA, Spain versus Holland, a bit like a football match. And what was very interesting was almost 75% of the room felt that clone size did matter. And I think that’s definitely, you know, strong in our thinking in MPN at the present time. Probably there’s more data for JAK2 than for the other mutant clones. And therefore, it’s important as we kind of lift the lid and think about that as a concept we have to think okay JAK2 right fine what thresholds so if we’re making a treatment decision generally we’re increasingly thinking that a threshold of 50 percent or above might be important but does it matter if the clone goes from 10 to 30 percent, don’t know the answer to that. Then trickling down and thinking about our next common mutation CALR there is evidence that a higher VAF for CALR is associated with greater risk of progression. But as for JAK2, there’s no clear evidence that intervening early with treatment yet, although of course there’s hugely exciting data presented at EHA about CALR targeted therapies, is important. We do know that some therapies will also drop the CALR mutation, but we don’t have the same degree of evidence as we had from the MAJIC study and other studies about JAK2. And then we have to think about MPL. These mutations are less common. And as we saw from a lovely abstract presented by Stefan Kochmeder on behalf of many of us in the ELN, these patients with those mutations do badly. And we don’t know much about clone size there. And then just to add the other layer of complexity, there are the non-driver mutations. And this is particularly so for patients with advanced disease. Does it matter if there’s a bigger clone in a patient with, you know, more advanced ET or PV or myelofibrosis? So, yes, it matters, but the devil is really in the detail. And increasingly, we need to be able to kind of colour those in. I would say one of the most striking pieces of evidence that would make everyone say a resounding yes is the recently published data in the New England Journal of Medicine showing that if you clear your driver mutation within 30 days of a stem cell transplant, your progression and disease-free survival is better. But that data also shows us that transplant isn’t a perfect therapy for patients because patients still do relapse and they still do die of transplant. So we do need to look at other therapies.

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