MRD Monitoring Post-Transplant Predicts Survival in TP53-Mutant MDS/AML

David Sallman, MD

A clinical trial evaluating duplex TP53 minimal residual disease (MRD) monitoring in patients with TP53-mutant myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) post-allogeneic stem cell transplantation (allo-HSCT) found that MRD negativity after 12 cycles of maintenance therapy with eprenetapopt (APR-246) and azacitidine strongly predicted better relapse-free survival (RFS), event-free survival (EFS), and overall survival (OS).

Patients who achieved MRD negativity had a median OS of 33.9 months compared with 20.4 months for those who remained MRD-positive.

Presented at the 2024 American Society of Hematology Annual Meeting and Exposition, the study highlighted the potential of MRD testing to predict patient outcomes and guide treatment decisions in this patient population. Many patients remained MRD-positive both before and after allo-HSCT, reinforcing the need for novel pre- and post-transplant strategies to reduce relapse.

These findings suggest that incorporating MRD testing into treatment plans could help personalize therapy, potentially improving long-term survival for patients with TP53-mutant MDS and AML.

David Sallman, MD, Moffitt Cancer Center, discussed the trial's impact and the future role of MRD monitoring in treatment strategies for TP53-mutant MDS and AML.

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Targeted Oncology: Can you discuss the study design and objectives?

We had a clinical trial actually published in [The Journal of Clinical Oncology], which was a maintenance clinical trial of azacitidine with eprenetapopt following stem cell transplantation. The results showed quite impressive outcomes, potentially supporting the development of a future phase 3 study.

One big question was, could the analysis of TP53 MRD by deep sequencing, in this case, by duplex technology, further and better predict outcomes? [Currently,] there is very little data known in the transplant world about the impact of TP53 MRD.

For our study, we collected bone marrow samples at multiple time points: before transplantation, after transplantation but prior to initiating therapy, and at standard disease assessment intervals—namely at day 100, 6 months, and 12 months. Using these samples, we evaluated the role of TP53 MRD in predicting whether patients would experience relapse within the context of this maintenance trial.

Can you elaborate on the rationale behind using eprenetapopt and azacitidine together in this patient population?

TP53-mutant patients represent, really, the molecular subset with the poorest of outcomes across myelodysplastic syndromes and acute myeloid leukemia, plastic syndrome and acute myeloid leukemia. Long-term survival in these patients is only about 20%, regardless of age or fitness. This has sparked some debate about whether these patients should undergo stem cell transplantation. I believe they should, although there are cases where borderline performance status may raise legitimate questions about proceeding with the procedure.

Novel strategies to reduce relapse risk in this group are urgently needed. Eprenetapopt is a first-in-class TP53 reactivator that has shown significant benefit when combined with azacitidine in several phase 1/2 clinical trials. Unfortunately, a pivotal phase 3 trial, while demonstrating improved complete remission rates, did not meet statistical significance. We're still awaiting the formal presentation and publication of these data.

[Given these challenges], we conducted a maintenance trial using a slightly reduced dose from earlier studies but maintaining the same combination of eprenetapopt and azacitidine. This time, the focus was on using the regimen as a post-transplant maintenance strategy rather than as an initial treatment to improve patient outcomes.

What were the main findings from this abstract?

I think there are several key findings from this study. First, monitoring TP53 brings up several intriguing points. For example, all patients were positive for TP53 mutations pre-transplant, with a moderately high variant allele frequency (above 5%). This finding highlights the need for novel pre-transplant therapies to achieve deeper molecular remissions, which may help improve outcomes.

Post-stem cell transplant, the majority of patients remained MRD-positive. Over half had MRD levels above our defined threshold of 0.1%, and more than 80% of patients had some detectable disease, even if below that threshold. This led us to explore whether TP53 MRD could predict relapse. Generally, patients who were MRD-positive had a much higher likelihood of relapse, with clonal expansion often observed at the time of relapse.

We also evaluated whether achieving MRD negativity improved outcomes. Across the board, MRD negativity was associated with better overall survival, relapse-free survival, and event-free survival. While some of these findings were trends due to the small cohort size (14 patients with serial samples), the results were consistent.

We further examined optimal time points, as patients received maintenance therapy for 12 cycles. Those who were MRD-negative at the end of treatment had significantly better outcomes. Notably, four patients were completely negative for TP53 clones, even below the MRD detection threshold. Of these, three remained relapse-free and appeared effectively cured. Among the MRD-negative patients who relapsed, one had a late relapse (over 30 months post-transplant) and one had extramedullary relapse potentially involving a clonal escape mechanism unrelated to TP53.

In totality, these findings validate for the first time that TP53 MRD monitoring, at least in the context of this combination therapy, significantly predicts outcomes. More importantly, this underscores the need to incorporate TP53 MRD tracking into future investigational efforts for this patient population.

Based on the findings, how could MRD monitoring influence post-transplant treatment decisions?

We are all looking for novel strategies to improve outcomes. One important step is incorporating TP53 MRD monitoring as a standard assay, at least in investigational studies. This could help predict how therapies are leading to responses or lack thereof.

Additionally, we are exploring other potential strategies, such as early tapering of immunosuppression or possibly using donor lymphocyte infusions. We're considering a multi-institutional collaboration, potentially led by a group in the UK, to explore these approaches. A valuable asset to incorporate into that type of study would be TP53 MRD monitoring.

Looking ahead, the goal for maintenance strategies would be to identify patients who are truly TP53 MRD-negative, as they may not need ongoing therapy. On the other hand, patients who remain MRD-positive have an almost universal relapse rate, and this information could help guide the duration of treatment.

In the current trial, patients were required to stop maintenance therapy at 12 months. However, two of these patients relapsed within 1 to 3 months post-treatment, and their MRD remained detectable. If I had been able to use MRD data in the trial, I likely would have continued maintenance therapy for these patients, potentially helping to prolong their remission.

Overall, what would your key takeaways for a community oncology audience be?

Key takeaways from this study include the increasing personalization of treatment based on molecular subsets, even within the MRD space. Certain MRD analyses may be more predictive in different settings. For example, flow cytometry may not be as effective in this patient population, while TP53 MRD detected through deep sequencing—whether by duplex or error-corrected sequencing—may offer better predictive value.

Another important takeaway is that MRD monitoring will play an increasingly central role throughout patient management, particularly in the post-stem cell transplant and maintenance phases. This could help guide treatment decisions. For example, in the field of FLT3 inhibitors, it's been clearly shown that MRD-positive patients have a significant survival advantage compared to those who are MRD-negative and do not require additional treatment.

Moving forward, we will likely see the wider adoption of various MRD techniques to guide therapy more effectively.

REFERENCE:

Sallman D, McLemore AF, Komrokji RS, et al. Measurable residual disease monitoring by duplex sequencing for TP53 in the post allogeneic stem cell transplantation study with eprenetapopt (APR-246) + azacitidine strongly predicts outcomes. Blood. 2024;144(suppl 1):1046. doi:10.1182/blood-2024-204996