Managing Outcomes of Patients With TP53-Mutant AML and MDS

At the 2022 Transplantation & Cellular Therapy Meetings, Melhem Solh, MD, presented data on a group of patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) with TP53 who had the who underwent an allogeneic hematopoietic stem cell transplant for this indication.

Research was performed by investigators at the Blood Marrow Transplant Program at Northside Hospital in Atlanta, GA, to examine the post-transplant outcomes of patients with AML and MDS who have a TP53 mutation. Previous data have shown this patient population has poor outcomes, respond poorly to chemotherapy, and often relapse quickly.

A total of 30 patients with a median age of 55.5 years were evaluated. A total of 47% of patients had haploidentical transplants, 30% were match-related donors, and 23% were match-unrelated donors. Several end points were examined, including overall survival (OS), relapse and non-relapse mortality, and disease-free survival (DFS).

Overall, findings of the study demonstrated that match-related donors were inferior to other groups of donors, and approximately a third of patients with TP53 mutations could be saved by getting a transplant, according to Solh. Additionally, the 3-year OS outcome for these patients was 29%, and having deletion 17p (del[17p]) did not negatively impact the OS outcome.

While ongoing trials are currently examining various hypomethylating agents plus venetoclax (Venclexta) for patients with high-risk disease, which this group would fall into, further studies are needed to properly understand and care for these patients.

In an interview with Targeted Oncology^TM, Solh, who is the medical director for the Cellular Therapy Program at Northside Hospital, discussed how the post-transplantation outcomes for patients with MDS and AML with the TP53gene mutation has changed.

Targeted Oncology: Can you discuss your presentation on the post-transplant outcomes of patients with TP53-Mutant AML and MDS?

Solh: I presented on behalf of our group, the Blood Marrow Transplant Program at Northside Hospital, on the outcomes of patients with AML and MDS who have a TP53 gene mutation. To be more specific, we looked at the post-transplant outcomes of those patients. In this presentation, we looked at a group of patients who have AML [or] high-risk MDS who underwent an allogeneic transplant in our program for this indication. We looked at several end points, including OS, DFS, relapse and non-relapse mortality.

The reason we're doing this is because patients who have TP53, which is a tumor suppressor gene on chromosome 17, tend to have very poor outcomes. If you look at patients with AML and MDS, their outcomes are usually very low and 1-year survival is very low. Even with transplant, historically, it's been reported to be less than 30%. Now, at this day and age, the improvement in attachment outcomes is newer medications that we can use to help get patients in deeper remission before transplant. That question [is], can we save some of these patients by taking them to an allogeneic transplant?

What were the methods of the study?

As far as the methods go, we had a total of 30 patients who got transplanted at our program between 2014 and 2020. As far as TP53 detection, we do use next-generation sequencing on all our [patients with] acute leukemia who come to our program. We're unique in a sense because we do both acute leukemia treatment and transplant. We do have these patients from the time of diagnosis. We collected all the data from our database, and we did a statistical analysis for the univariate and multivariate analysis.

Could you discuss the findings of your study?

As I mentioned, certifications were incorporated in this analysis. The median age was 55 years, and the range was anywhere from 26 to 74 years of age, split half between male and female, and the diagnosis was about 60% AML, 40%, between MDS, chronic myeloid leukemia, and there were a few cases of del(17p). We're a program where we tend to prioritize haploidentical over other alternative donors.

Because of that, our population had 47% haploidentical transplants, 30% match-related, and 23% match-unrelated donors. Peripheral blood stem cells were a main source of graphed at 87%. When we look at the disease risk, most of these patients who had high and very high disease or escape route, so 77% were in the high or very high-risk group. There were 47% myeloablative, 23% nonmyeloablative, and 30% reduced in intensity. As I mentioned, these patients were transplanted between 2014 and 2020. The median follow-up was 29 months for these patients.

Now as we move into the outcomes for this patient population, 1-year OS was 62%, DFS was 42%, relapse rate was 51%, and the post-relapse survival was 19%. I looked at the specific subgroups of patients who haveTP53 mutation and del(17p). The numbers were similar with OS and DFS at [73% and 53%, respectively at 1 year, and that goes down to 27% at 3 years [for DFS]. The main reason for transplant failure was relapse and the TP53 alone or the TP53 plus del(17p).

We looked at factors associated with outcomes and responses; we really didn't see much. This is a small study that's already set for a patient so we may not have much power to detect any variability. But when you look at OS, the DRI was a main factor and picking [out] patients who did worse vs patients who did better. For DFS, it was the same story that disease risk was the main contributor to this. For relapse, we noticed 1 interesting finding, that patients who are better matched-sibling donors did poorly compared to patients who get either an unrelated-match donor or a haploidentical donor. Again, at relapse, the higher disease risk was correlated with a higher relapse. There was no difference in outcomes if patients have del(17p) or if they did not have del(17p).

To sum up our findings, what we found out is you can still save about a third of patients with TP53 mutations by taking them to a transplant. We saw that the 3-year outcome was about 30% to 35%, and having a del(17p) in this group of patients did not impact the outcomes. Our finding of a match-sibling donor being inferior to other groups of donors is interesting and worth looking into on a bigger study set, like a registry study, to see if this carries on can potentially be a factor in choosing donors for this group of patients.

How has the standard of care for these patients changed over the past decade?

This has been a very challenging population of patients because we know they've done poorly with chemotherapy; they tend to be refracted or have very quick relapses. If a patient has TP53, del(17p) AML, they are not eligible for transplant for one reason or the other, they are not going to do well now, even with transplant. They still don't do too well, compared to other subtypes of AML. The question is, using the drugs we have available now to put them in a deeper remission before transplant, would that translate into a better outcome?

Now, unfortunately, we didn't have the amount of deep data on those patients in our analysis because some of them go back 6, 7 years ago, before we're able to collect that type of data. That would be one question to ask: Do you really need to get as deep of a response to help improve with the transplant matter at that point? In this specific subgroup, we know it matters in general to get somebody minimal residual disease negative.

The other thing is using post-transplant maintenance service. There’s a tendency to put patients on a hypomethylating agent. There are studies going on to do a hypomethylating [agent] plus venetoclax for high-risk patients, which I'd imagine this group would fall into. The answer is, would that make a difference in their outcomes? Well, we have to wait for the study to decide.

What are you most excited about for the future of this space?

With this specific population of patients, definitely the newer leukemia therapies that we have going on, another study for bispecifics, the natural killer cell treatment, and the chimeric antigen receptor T-cell therapy. It will be very interesting to see how we incorporate these types of therapy into transplant, pre or post, to help improve the outcome of this patient.

What do you recommend community oncologists treating patients with TP53-mutated AML or MDS keep in mind?

It is very important with acute leukemias to be in touch with a tertiary center from the time of diagnosis, because with acute leukemia, getting these patients into donor typing and donor search and getting them to transplant in a timely fashion is very important. I can't stress that enough. Especially with a TP53 del(17p), admission might be short, and you don't want to be delaying that. A quick referral to a transplant center is definitely helpful. To be sure that you are sending the markers of acute leukemia, as you're checking the chromosomes [and] next-generation sequencing to have all that data available at time of diagnosis, because that will help the transplant center makes the best decisions and how to proceed with those patients.

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Presented at: 2022 Transplantation & Cellular Therapy Meetings; April 23-26, 2022; Salt Lake City, UT.