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SOHO 2021 | SOHO 2021 highlights: ‘Targeting p53 in MDS’
David Sallman, MD, of the Moffitt Cancer Center, Tampa, FL, shares the key information and perspectives from the presentation ‘Targeting p53 in MDS’. Approximately 80-85% of patients with myelodysplastic syndromes (MDS) are high-risk patients adversely affected by p53 with a severely short survival of 1 year, hence, it is extremely important to rapidly identify these patients through cytogenetic assessment among other methods. Dr Sallman further talks on the novel agents explored for this patient population such as eprenetapopt, an agent which demonstrated higher remission rates in a Phase III trial (NCT03745716) but failed to reach statistical significance This interview took place during the ninth annual meeting of the Society of Hematologic Oncology (SOHO 2021) congress.
Transcript
It’s being well-recognized that, clearly p53 has inferior outcomes. This is by really all cohorts, both in MDS and AML that we’re kind of focusing on MDS at this time. I think not only presence or absence of mutation, but now multiple groups have shown that the burden or the varied allele frequency of the mutation, really ties in tightly with the clinical trajectory of these patients...
It’s being well-recognized that, clearly p53 has inferior outcomes. This is by really all cohorts, both in MDS and AML that we’re kind of focusing on MDS at this time. I think not only presence or absence of mutation, but now multiple groups have shown that the burden or the varied allele frequency of the mutation, really ties in tightly with the clinical trajectory of these patients.
So basically a higher clonal burden and more inferior prognosis. Similarly, if you’re what’s called biallelic or have multi-hits and p53, which can be two somatic mutations, or sort of a mutation plus loss of heterozygosity with a hit on chromosome 17P. All of this is adverse. And really, if you look at very adverse p53, it’s probably about 80, 85 percent of all the patients. There’s a small subset. If you have a lower allele frequency, you’re not complex on cytogenetics, except those patients may have somewhat of a more indolent course, but really the vast majority are these very high risk patients with the survival of somewhere less than one year.
I think rapidly identifying the patients is important. We show some data, there’s kind of multiple ways to have a high clinical suspicion about a patient having p53. Because the NGS can take anywhere from two to four weeks, particularly in the community. So what to think about if a patient may have it. And so the couple of things to look at would be of course a history, if they have therapy related, past cancers. And then a couple new things that we’ve shown is that if you have actually an increase in ring sideroblasts, which most people think of in low risk MDS, but if you see it in the setting of excess blasts, actually about 70 to 80 percent of those patients in a multicenter cohort had p53 mutations. So I think that, along with having a complex cytogenetic and some of this can turn around based on FISH staining, which can happen in about 24 hours.
And then third, if you have an accumulation of sort of this misfolded p53 protein, this is just a standard p53 IHC. That’s a little bit older data, but can also sort of rapidly identify those patients. Moving forward, clearly novel therapy is critical. The concept that was most advanced was the APR-246 or eprenetapopt, which unfortunately in the phase three trial; although complete remission rates were higher, it did not reach statistical significance. I think the full data presentation; the whole communities started eagerly awaiting. Cause I think what’s the survival? What are subset analyses? Two phase two trials showing significant improvements, but unfortunately a then setback in the phase three study, although there is a second-generation inhibitor APR-548, that is entering clinical trial as we speak.
And then we kind of looked into other therapy. I think what is quite well-established now is, although HMA venetoclax has very high response rates across all subsets, even including p53. The quality of the response and the duration of the response and p53 is underwhelming.
So the true CR rate and the updated presentation from Dr. Wayne at ASCO and EHA was 16 percent. So very similar, if not lower than what the aza monotherapy control arm would be. And so I think then, at least by itself with HMA is inadequate, whether or not triplets change that I think is an interesting question.
One other exciting therapy would be the anti-CD47 therapy magrolimab, which is being evaluated, and all MDS. But has had particularly activity in p53 AML. So I think similarly, very interested to see what is going on in p53 and MDS, the subset of patients has been smaller, but I think what’s been most encouraging, at least in the AML data, is that not only are a high percentage of patients are responding, but they’re appearing more durable, not forever.
The median OS at ASH at 2020 was nearly 13 months, but that’s about double what we’ve been seeing across other AML studies. So I think looking at magrolimab HMA. And then I think in the future, all of these are going to have inadequate durations of response, I think versus what we would like in p53 wild-type patients. So I think we’re already starting to think about what optimal triplet, both in p53, MDS and AML may be able to further improve outcomes because we still have a long way to go.
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