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ESH CML/MPN 2025 | The prognostic and therapeutic implications of TP53 expression in CMML
Daniel Wiseman, MBBS, PhD, University of Manchester, Manchester, UK, provides insight into the prognostic and therapeutic implications of TP53 expression in chronic myelomonocytic leukemia (CMML). Dr Wiseman notes that agents acting as a p53 activator have shown synergy with azacitidine in CMML samples, suggesting a potential therapeutic approach for CMML patients with low TP53 expression. This interview took place at the European School of Haematology (ESH) 4th How to Diagnose and Treat: CML/MPN meeting in Vienna, Austria.
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Transcript
So, I mean, this was a small study that we published quite recently last year, which is one of the curious things about CMML, particularly for a disease like this, particularly prominent in the elderly, is how rare p53 mutations are. It’s the most common mutation across all of cancer, and yet you hardly ever see it in CMML. Nobody really knows why.
So the first thing we did was we looked at a large cohort of patients...
So, I mean, this was a small study that we published quite recently last year, which is one of the curious things about CMML, particularly for a disease like this, particularly prominent in the elderly, is how rare p53 mutations are. It’s the most common mutation across all of cancer, and yet you hardly ever see it in CMML. Nobody really knows why.
So the first thing we did was we looked at a large cohort of patients. We gathered 650 nearly, I think 648, CMML patients from across the northwest, for which we have good clinical correlated data and outcome data, and we confirmed that was the case. Less than 2% of the patients actually had a TP53 mutation, which is much lower than you’d find in, for example, MDS or AML, or indeed, myelofibrosis, when it goes bad, very often accrues a TP53 mutation. It’s not the case. So that was interesting.
But then we had RNA sequencing data on a lot of these patients. And we identified that there’s about 15% of CMML patients who seem to have unusually low TP53 expression. We don’t know why, but they were quite different from the rest of the CMML patients and they had a worse prognosis. So it would appear that in this disease, the expression is more relevant, certainly to a greater number of patients, than mutations.
And importantly, we showed ex vivo, so in the lab, we haven’t taken it to patients yet, but there is a drug that targets both MDM2 and MDMX and basically functions as a p53 activator. These drugs have been tested in early-phase trials in AML and MDS, and we showed that there was synergy with azacitidine in CMML samples in the lab, and it did seem to correlate and be a greater effect in those in this lower-expressing subgroup.
So again, just with the goal of trying to personalize therapy for CMML patients, you know, we don’t have very many therapies at the moment, but what we would like to be able to do is try to find newer therapies, but then target them to the right subgroups of patients, and this could be another approach, and that might be relevant to a meaningful proportion of CMML patients. It needs to be tested in trials, though.
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