MDS updates from iwMDS-iwMPN 2024 | Approaching TP53-mutated MDS and secondary AML

David Sallman:

Hi, I’m David Sallman from Moffitt Cancer Center, and here joining me is Coleman Lindsley from Dana-Farber and Thomas Cluzeau from Nice. Just finished an exciting session, really describing or looking at the molecular subgroup with really the poorest outcomes, and a lot of this was focused around P53 mutant patients, although we got into the other adverse risk.

Maybe starting with you, Coleman, I think sometimes when we say adverse, we think one size fits all. Is that the case or should we really be looking P53 separate secondary type mutations? How do you think about prognostic risk, and are we sometimes lumping patients too much together? Then maybe, Thomas, how do you think about treating those patients, maybe P53 versus not?

Coleman Lindsley:

That’s a great question and I think we can collectively agree, I think, that P53 represents a distinct type of adverse risk. That’s not only with what their outcomes are in the absence of transplant or treatment, but after treatments themselves and their refractoriness or sensitivity.

In the recently published IPSS-M, it has very high predictive value for progression to leukemia in the setting of HMA or observation in that very high risk group. But that group of very high risk patients seems to be different when it comes to allo transplant.

When we move to AML, I think somewhat similar, and maybe Thomas can talk about this. Secondary AML coming after MDS is adverse risk. P53 is adverse risk and some karyotype abnormalities are adverse risk, but they have different biological characteristics that may be relevant for treatment.

Thomas Cluzeau:

Yeah, so I totally agree. I think there is two parts. There is patients with adverse risk with TP53 and today we have nothing to propose. Intensive chemo or not intensive chemo is the same result for these patients who or without allo stem cell transplantation, unfortunately.

But for the other secondary AML not mutated for TP53, we could obtain a great high level of complete remission, maybe deep CR, and we could undergo to allo stem cell transplantation and we could obtain good results.

To my mind, I think the problem with TP53 is that we have only retrospective data from studies. This is only subgroup analysis, so there is not really a study focused on TP53. Recently, you did a clinical trial specifically for TP53, but now we have to work together to focus specifically on this setting and maybe to find something better for thess patients.

David Sallman:

Yeah, I think one clear consensus from the group, from the panelists, from the room is that this is a singular disease, particularly if you talk about P53 mutant MDS/AML, sort of an multi-hit state. I still think that the definition is, again, there’s slight differences, but I think in general, if they are multi-hit, complex karyotype, excess blast, by and large, this is relatively a singular group with uniform poor outcomes.

I think we move to a hot topic and a big question in the field, including in academic centers, is should or should these patients not go to transplant? I think with outcomes and reimbursement rates in the US, this has created even a bigger challenge, maybe from a logistic perspective. What’s the answer, Coleman? Should these patients go to transplant? I think you have really nice data to support more of a definitive answer, but I think summarizing that would be nice.

Coleman Lindsley:

I think it’s really important to separate should they go to transplant from can transplant benefit patients, highlighting the complexity of decision making. I think in terms of the data, retrospective data has suggested that there are very poor absolute outcomes in P53 MDS, meaning patients with a P53 mutation going into transplant have a low probability of long-term survival.

What we sought to do in a biologically randomized study was to quantify the benefit of transplant and determine whether it was there. What we showed was that transplant in this prospectively biologically randomized setting, we showed that transplant can benefit patients with P53 and that there are no variables that we could identify that could help prioritize particular groups of patients or deprioritize them.

Really what it raises is the imperative for that doctor-patient discussion about priorities, quality of life and things like that, and so can it benefit? Yes. Should everyone go to transplant? Patient specific.

David Sallman:

I think it’s good. I think your trial, again, this is really standard of care therapy approaches showing that benefit. I’d say in the novel setting, that’s really what we’ve seen with APR-246, with multiple other trials in general, that patient group that can get to transplant. Again, there’s all these other factors is the group that has long-term survival. I think a major hope is how can we improve it. I think again, with just routine standard of care, we’re stuck with somewhere around this 20%, 25% long-term survival, both in US studies and actually a similar EBMT study that was published.

Maybe Thomas, what are your approaches to think about improving how these patients? We know it can give them benefit from what Coleman really discussed, but I think all of us say it’s not enough, we need to make it better. What should your approaches be? Can you think of things standard? How do you think about maintenance, DLI, pro GvL strategies, and maybe trials to help address those questions?

Thomas Cluzeau:

Yeah, so I guess if these patients should go to transplant, yes, but not with the strategy we have today. Because today we have no treatment, so we have to improve each part of the therapeutic strategy. Before the transplant, maybe during the transplant, as you show the RIC conditioning is better than the MAC, so maybe it’s something we have to do specifically for this kind of patient.

We have to discuss also after the transplant. Maybe for these patients, there is a challenge after the transplant, so usually the transplant is the last treatment for the patient. But now I think for this high risk of relapse patient, we need to discuss, maybe azacitidine alone, maybe azacitidine plus venetoclax. Maybe azacitidine plus DLI, azacitidine plus venetoclax plus DLI. Azacitidine plus eprenetapopt, like your team did in Moffitt.

There is some option and I guess we can’t discuss only induction, transplant or maintenance after transplant. We need to discuss everything together and maybe to find the best therapeutic strategy, but the complete therapeutic strategy for this patient.

David Sallman:

We had Andrew Wei in our session and I think he summarized that. Unfortunately right now, we don’t really have anything that exciting in this space. I think although cellular therapy has been very challenged in myeloid malignancies, I mean this might be an interesting group to think about not in treating overt relapse. But when we know we have a very clear benchmark, could we think about early trials, prophylactic or peri-transplant CAR-T to improve this high risk group with again, either a CAR-T or some sort of other cellular therapy.

I think the appetite internationally to try and improve this group in these prospective trials would be good, and again, potentially allogeneic and some other strategies. When you have that P53 potentially at its lowest level that it’s going to be at, I think there’s interesting data also how these stem cells are exhausted and other things and challenges with engraftment.

But I think maybe the clear message that we had in the room is that we should study this group as a singular entity, and again, as you nicely summarized, strategies before, during and after. Then ideally really pioneers like Coleman as far as doing the right translational studies at the right time to help answer those questions when we have unclear or challenging clinical trial data to interpret. But I thought it was a really nice session and discussion. But thanks for joining us.