If you consider one of the greatest unmet needs for response durability (ie, TP53-mutated AML), I think that the data from the VIALE-A trial are informative. In the whole group, survival was improved with the combination of azacitidine plus venetoclax compared with azacitidine alone. And in the analysis of the molecular subgroups, the combination of azacitidine plus venetoclax did produce a significantly higher incidence of composite complete remission than the control regimen. Among patients with TP53 mutations, the incidence of composite remission was 55.3% in the azacitidine-plus-venetoclax group and 0% in the control group. So, patients with TP53-mutated AML do respond to combination therapy, but, unfortunately, those responses are not durable and they do not translate to an improved overall survival.

It is important that we try to develop therapies that can impact patients with TP53-mutant disease and extend responses or, alternatively, actually target the TP53 mutation in a more effective way. Novel strategies, such as those that work through CD47, TIM-3, or, perhaps, compounds such as eprenetapopt, may be beneficial in patients with TP53 mutations, and those trials will hopefully demonstrate benefit as time goes on.

Outside of TP53 mutation, we hope to improve outcomes for another group of patients (ie, those who are in remission with low-level minimal residual disease [MRD]). There is simply less of a disease burden and more anticipation for effectiveness with an immune-based approach in this MRD-positive or early relapse–type setting, whether it is by targeting TIM-3, a monoclonal antibody, or something else. As we think about a total therapy approach, emerging agents might be used to transition from a standard therapy, they may be added to standard therapy, or they, perhaps, may be employed as part of an ongoing maintenance regimen or in an MRD-directed approach.

The prevention of relapse after allogeneic stem cell transplantation, the only potentially curative treatment for MDS, is one major focus. Even today, relapse is a significant post-transplant complication. In addition, we would like to learn how to optimize response durability in patients who are not undergoing transplant, which is a slightly different question because these individuals still have residual disease.

We are learning how the molecular disease burden may play a role in assessing the patient prior to transplant, and, as we develop more active therapies in MDS, it may become possible to optimize the patient’s molecular response prior to transplant, although this is still fairly experimental right now. In the study by Dillon et al, the presence of adverse genetic features before transplant was associated with worse outcomes in patients with MDS who had received reduced-intensity conditioning vs myeloablative conditioning. Additionally, some retrospective data suggest that reducing the TP53 variant allele frequency burden or clearing disease that has complex cytogenetics prior to transplant may be linked to improved post-transplant outcomes.

Another pursuit is to improve the duration of response for patients on azacitidine or decitabine who will not proceed to transplant. There, too, the need is great. It is quite a burden—almost like a job—to receive chemotherapy for 7 days each month and to also have to be seen in between treatments for transfusions.

So, how do we improve the quality of that time, and how can oral agents be best used? Are there agents that will emerge to prolong a response? With emerging agents, will the treatment paradigms be the same as those of sequential therapy, rotational therapy, or combination therapy? There are many research questions that are now starting to be asked with regard to the treatment of MDS, and the hope is that they will lead to a more nuanced approach to treatment, with different options for different types of patients.

Survival in MDS relates to the complete response rate and durability, and a durable complete response rate is what translates to a survival advantage. To improve outcomes, we must have agents that will either increase response rates or improve the durability of the responses that we already achieve with our current treatments. As noted by my colleagues, for patients who will proceed to transplant, we want to be thinking about newer strategies. This includes considering a maintenance therapy, particularly for those who are at higher risk of relapse post transplant. For patients who will not proceed to transplant, the average duration of response to hypomethylating agents is currently approximately 1 to 1.5 years, so there is a great need to improve upon that.

TP53-mutated MDS is one of the greatest areas of unmet need. These individuals may be sensitive to treatment initially, but they usually do not have durable responses. Patients with TP53-mutated MDS do very poorly with intensive AML-like induction regimens, and, while they do slightly better with hypomethylating agents, the median survival is short. So, this is a very "low bar" in terms of a treatment standard, and this underscores the importance of clinical trials.

One of the agents that appears promising in TP53-mutated high-risk MDS is sabatolimab, an immuno-myeloid therapy targeting TIM-3. Dr Brunner has been involved with the early phase trials, where data suggest that adding sabatolimab to hypomethylating agent therapy does add some durability. In the final analysis from the phase 1b study, durable responses were also observed in patients with adverse-risk mutations, including TP53 mutations in those with very high-risk and high-risk MDS.