ASH 2024 | Novel non-transplant treatment approaches for high-risk TP53-mutated myeloid disease

This was the most challenging presentation on therapy, novel approaches in TP53-mutated MDS or AML. This is like the highest unmet need in malignant hematology right now because with the standard chemotherapy or with hypomethylating agents, the median survival is only about six to seven months regardless of the regimen, high dose, low intensity, so all of them work the same. 

So I showed a few new things that we think could be promising. The first approach is actually using our institutional different schedule of decitabine called metronomic administration which is weekly, very low dose, one-tenth of the regular dose of decitabine given subcutaneously combined with the therapeutic dose of venetoclax. Again, both drugs are given the same day but only once a week. So because for TP53-mutated disease, I think chemotherapy just selects its clone due to chemoresistance. But this approach, in fact, results in a survival of around 10 to 11 months, which has been reproducible right now in 24 patients, so we continue enrollment. Obviously is not curable but it’s a better backbone than the standard chemotherapy 

Then I reviewed some things that are coming out not yet and perhaps in clinical trial there was abstract from this ASH from Dr. Shruti Bhatt’s lab that showed that the resistance of these patients is due to high expression of inhibitor of apoptosis proteins called survivin and that’s why the tumors are unable to mount the cell death. So in preclinical models inhibiting this pathway led to the sensitization to venetoclax and chemotherapy. Again, this is preclinical work, but it looks promising. 

I also reviewed the efforts to reactivate the mutant p53 and make it work like wild type. So one agent that we have had going through all the way through phase three APR-246 unfortunately failed to meet primary endpoint and the pivotal phase three studies. But right now there are two other drugs that are being tested the first one is in fact arsenic trioxide that’s been used for acute promyelocytic leukemia, it works in a subset of mutations not and all across the board however the clinical trials are ongoing in China. And the second is a new one that works for only one mutation, Y220C. It’s again a reactivator that binds to that mutation and makes the mutant protein bind to the DNA and induce transcription. 

And so finally, I talked about immune therapies and the fact that the T-cells are deficient and that there is a work here presented by Michael Andreas group that T-cells also carry mutations and therefore they’re exhausted. So there is a huge suppressed microenvironment, which is perhaps why the immunotherapies have not really worked for the subset. But again, the preclinical studies for one mutation have identified the peptide HLA-2 complex that was presented on the cell surface and making the bispecific antibodies against that led to the activation of T-cells and the clearance of tumors. 

So I think some of these new approaches are needed for TP53-mutated disease, which still remains such a huge challenge therapeutically. And we all should be thinking of putting patients on clinical trials to find out what’s next steps.

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