EHA 2026 | Key clinical outcomes for evaluating treatment success in myelofibrosis

That’s, I think, is the bottom point. I have to say that if we consider a single patient with myelofibrosis, and of course, a reduction of spleen and symptoms are mandatory, because we know today that reduction of symptoms imply a better quality of life of the patients that still continue to be the prime end point of our treatment. And also a reduction of this pain has important implication in terms of advantage of overall survival. And we have the demonstration now with ruxolitinib, the COMFORT study, and also demonstration in the SENTRY study, that is the Phase III in JAK inhibitor naive patient receiving ruxolitinib plus selinexor. But of course, this is the basis. So achieving spleen reduction is important for the patient. And, you know, sometimes we see patients who achieve a very nice reduction of symptomatology, and some of these patients achieve also a reduction of the VAF of genes, and other times there is a stability of progress on the genes. So the question is, okay, reduction of the spleen, okay, reduction of symptomatology, but to change the disease of the patient, to transform the disease, we need to reduce the clones. And so basically, we have some information that, of course, the driver genetic abnormalities have additional genetics that are important for the survival of the patient. But we have also information that reduced clones are relevant. For instance, we have evidence that reducing the clone of JAK2 more than 20% in the second-line setting with navitoclax and ruxolitinib, we can achieve a better PFS. We have evidence that reducing the clones with imetelstat, for instance, may have implications in terms of reduction of the spleen, symptomatology improvement, and a general reduction of myelofibrosis. So there are some correlations among mutation variation and clinical benefit. One among all, of course, is the reduction of the VAF of CALR, the new antibody against CALR mutated, are absolutely in line with this important association. Then there is also evidence that the cytokines are relevant, and we have now evidence that they modify the pro-inflammatory cytokines. They have an implication in terms of association with the spleen volume reduction. We have this data from pelabresib study, from selinexor study, from imetelstat study, and those with nuvisertib. So there is a signal that modifying and modulating the cytokines, we can have an advantage in terms of spleen reduction, symptom control, and also some very, very, very preliminary effect on overall survival. And then also bone marrow fibrosis, it’s more unclear the role of reduction of bone marrow fibrosis versus overall survival. We have an important paper that compares BMF reduction with ruxolitinib and momelotinib. Overall, the paper by Stephen Oh said that there is no effect on survival if you reduce grade one or more myelofibrosis. So this is the thing to investigate, in my view. But we have evidence that some of the compounds, some of the new combination can reduce bone marrow fibrosis very early. So within the first 24 weeks of treatment. And the last point is blast cell. We know that blast cells are very dangerous because blast cells more than 5% means a higher risk of evolution into overt acute leukemia. There is a clear association with reduced survival. Consider that the survival of those patients with blast cells, it will be 5 and 10, maybe around two years, and more than 10, so from 10 to 20, maybe, of around one year. So this is the population of patients with a really high risk of evolution. And today we know that with the JAK inhibitor, we collect a high number of patients with drugs. So there is basically no significant reduction in the evolution from chronic phase to accelerated blast phase. So we need to have drugs that are able to maintain a low-level blast cell and also to reduce the number of blast cells in the peripheral blood or the bone marrow as well.

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