EHA 2025 | Clinical characteristics & survival of a large international cohort of patients with MPL-mutant ET

Dear ladies and gentlemen, dear colleagues, thanks for selecting our abstract on the clinical characteristics and the survival data on 312 patients with a rare disease. It’s a subentity of essential thrombocythemia with those patients having MPL mutations or TPO receptor mutations. And the fact that you cannot really read what is on the slide, highlights the fact that in these rare diseases we need to collaborate amongst each other. So this is a large collaborative international study fostered by the European Leukemia Net. These are my disclosures. 

So myeloproliferative neoplasms, or MPNs, are chronic blood diseases characterized by too many cells in the blood or bone marrow and by enlargement of the spleen. And one of the classic MPNs is essential thrombocythemia, or ET, leading to an increase in platelets in the blood. Patients may suffer from symptoms including chronic fatigue, chronic itching, headaches, and concentration problems or pain. And the life expectancy can be compromised by complications such as severe bleeding or thromboembolism, meaning they could have thrombosis, heart attacks, or stroke, even at a young age, or progression to secondary fibrosis of the bone marrow, which we term myelofibrosis, or even acute leukemia. 

Genetically, ET is characterized by acquired mutations in the genes encoding either JAK2 or calreticulin or, as said, the thrombopoietin receptor MPL. And this is what this talk is about. However, while considerable scientific knowledge exists on ET cohorts with the more frequent mutations, JAK2 or CALR, much less is known about the group of patients with ET and MPL mutations. They comprise roughly 3% to 5% of all ET cases. So there’s a high unmet medical need to study the outcomes of a large cohort of these patients. 

And so the aims of the study were to describe the current management of patients with MPL-mutant ET in a large international cohort. And for this, we used retrospective clinical data from 312 patients with ET who harbor an MPL mutation. And these data were collected in 37 international centers from nine European countries and Australia. And descriptive statistics were performed. 

So here you can see that the median age of disease in these patients was 59 years, with an expected female predominance of 69%, as has been described for ET before. And the median follow-up is six years, but it ranged from 1 to 32 years, so really long follow-up. The different mutations you can see here are as follows. So the most frequent one is the W515L mutation with 58% of patients and then followed by the W515K mutation and other mutations. And the mean platelet count at diagnosis was, the median platelet count was 740, meaning this is elevated and was in keeping with the diagnosis of ET. There are thrombosis scores that assess the risk of thrombosis in these patients and about half of these patients had a low risk and about half of patients had an intermediate or high risk score. 20% of these patients had already had a thrombosis and 3% had already had a severe bleeding. And you can see some of the treatments these patients have received. And also here you can see that 3% of these patients have eventually progressed to acute myeloid leukemia, and 21% had progressed to myelofibrosis. 

So what were the results? There were no survival differences between these MPL mutants, as you can see on the right. In the overall cohort, median survival was quite favorable with a 10 and 20 year survival of 86 and 72 percent. However, reduced survival was significantly associated in the overall cohort with an intermediate or high IPSET thrombosis score or a history of thrombosis or major bleeding at diagnosis, but also with platelet counts at diagnosis above the median, and this was not known for other cohorts of ET patients. And interestingly, reduced survival was also associated with a higher grade of fibrosis, but not with failure to achieve hematologic remission, which is currently the mainstay of assessing treatment response. Thrombosis-free survival for thrombosis, for the first thrombosis, was not different among the patients with the different MPL mutants. And when assessing baseline parameters in the three MPL mutant cohorts, there were interestingly significant differences in the number of platelets at diagnosis as well as the pattern of previous arterial versus venous thrombosis pointing towards differences in biology between these three cohorts. 

So in conclusion, this is the largest study so far of MPL-mutant ET patients documented in an international collaborative retrospective study fostered by the ELN. Overall was generally favorable, but we did identify risk factors at diagnosis which were associated with reduced survival. And also, even though the overall survival was not different in the three groups with the different mutants, differences in baseline parameters included platelets and the history of arterial versus venous thrombosis, which should be analyzed in the future. 

So in conclusion, we describe novel biologic and clinical characteristics of patients with ET, with MPL-mutant disease, opening up new avenues for research and also providing new evidence for recommendations on the clinical management of these patients. With this, I would like to close and thank all contributors and their teams for their documentation of the data and scientific discussions, all patients for supporting this research, and ELN for providing the framework that fosters such international collaborations, which are necessary in rare diseases. Thank you very much.

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