Impact of Chemotherapy, Radiation in Patients Who Develop Acute Myeloid Leukemia, Myelodysplastic Syndrome
In this podcast, Pinkal Desai, MD, discusses the impact of previous chemotherapy and/or radiation exposure in patients who go on to develop acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS), including the risk of adverse biology, and the rate of survival compared with people with AML or MDS who did not receive previous chemotherapy and/or radiation. Dr Desai also presented on this topic at the American Society of Hematology’s 2023 annual meeting in San Diego, CA.
Additional Resources:
Desai P, Abaza Y, Carraway H, et al. Molecular and cytogenetic characteristics of acute myeloid leukemia and myelodysplastic syndrome in patients exposed to chemotherapy and/or radiation. Paper presented at: American Society of Hematology's Annual Meeting & Exposition; December 9-12, 2023. Accessed December 21, 2023. https://ash.confex.com/ash/2023/webprogram/Paper190478.html
For more coverage of ASH 2023, visit the newsroom.
TRANSCRIPTION:
Pinkal Desai, MD: I am Dr Pinkal Desai. I am an associate professor of medicine at Weill Cornell Medical College and the Clinical Director of Molecular Aging at the Institute of Precision Medicine at Cornell.
We were very excited to present this work. What we looked at is approximately 350 patients who had either leukemia or MDS-diagnosed and they had a previous history of some other cancer that was not a myeloid cancer. If they had some solid tumors or lymphoma, myeloma, and then went on to develop leukemia or MDS and there was a mix of what kind of exposures they had. What we wanted to understand is how do these exposures, do these exposures matter when you then get leukemia and MDS. We always consider therapy-related leukemias and MDS as a joint category of therapy-related myeloid neoplasms and those generally have poor survival. We wanted to test whether as a group they have poor survival or is it related to the kind of exposure they had before. We had about 64% of patients who were exposed to chemotherapy, about 20% that were only exposed to radiation, and another 15% that had no exposure to either chemo or radiation because they just got surgery and hormonal therapy and things like that. We were able to compare across these categories and found some really interesting results.
The first thing we found was that with radiation exposure alone, there was no increased risk of adverse biology at the time of presentation of leukemia or MDS, and the survival of patients who were exposed to radiation before was very similar to those who didn't have any treatments suggesting that radiation alone may not be enough to give this designation of therapy-related myeloid neoplasms. On the contrary, we did find that chemotherapy exposure was associated with a higher risk for having these adverse biological characteristics and also age-adjusted worse survival compared to people who did not get chemotherapy. That was interesting.
The second thing we found was that we compared all of these different kinds of chemotherapy exposures in the past for their solid tumors and then the kind of disease they got when they were eventually diagnosed with AML or MDS or therapy-related myeloid neoplasm. We found that having platinum chemotherapy, it's a class of chemotherapy, the platinums, were associated with the highest risk of adverse disease biology and a higher risk of having TP53 mutations when they were eventually diagnosed. This is unique because there are a lot of datasets and a lot known about therapy-related myeloid neoplasm, but there's not a lot of data on this previous exposure and linking it to what kind of disease they get when they do get leukemia, so that was interesting.
The third thing we looked at was survival. What do these patients, how do these patients behave in terms of their disease survival once they get the leukemia and MDS? We found that for people who present with adverse chromosomal type, there was no difference in survival whether they had chemo exposure or not. But if on presentation they had non-adverse cytogenetics, most commonly the intermediate cytogenetics, that's where chemotherapy exposure in the past mattered and there was inferior survival within the same biological group, but with chemotherapy patients survived less or had an inferior survival compared to those who did not get chemotherapy exposure.
We also found similarly, blast counted diagnosis was important. We always say higher blast count may be relevant, but for therapy-related myeloid neoplasms, we found that that's true. A high blast count at diagnosis of more than 10% was only relevant when it was in the non-adverse cytogenetics. Again, in the high group adverse cytogenetics, there was no real difference if you presented with less than 10% blast versus more than 10% blast. The last thing, which was also interesting and important, when we tried to characterize the TP53 mutations and see do they impact what is the subgroup where this is important, and we found that TP53 by itself is not giving any worse survival in people who have adverse cytogenetics. Where TP 53 is relevant and as a predictor of worse survival are the ones that have intermediate-risk cytogenetics.
This is an important concept as well because many times we think about TP53 biology and which TP53 patients should be enrolled in TP53-directed therapies or clinical trials, and maybe that's the group, the non-adverse, because if you have adverse karyotype, the TP53 is not adding anything extra. But in groups of people that have non-adverse cytogenetics, that's where it seemed to actually impact inferior survival. That was an important observation in our dataset as well.
First of all, as I had mentioned earlier, therapy-related diseases confer an inferior prognosis. We need to know what is the definition of therapy-relatedness. When patients come to us and they do have a previous history of cancer, they're always interested in understanding what my previous cancer therapy would impact. What impact would that have on the current cancer or leukemia or MDS? So understanding their survival patterns and their disease biology pattern is important.
Second, our finding that platinum exposure leads to a higher TP53 mutation is important because a lot of patients now, when they are diagnosed with solid tumors, are getting sequencing in their blood as part of their tumor genomic analysis. We are finding some of these pre-malignant mutations in these patients and that question comes up all the time. If you find a mutation and they're about to get chemotherapy, which will increase the risk of leukemia in the future, patients tend to ask, what is this? Is this important?
This is going to give us information that if this happened, and if somebody is actually diagnosed with, for example, a TP53 mutation in the blood at the time of say they have lung cancer and they're about to get platinum, this is important because this might actually increase their risk of leukemia down the line, and these conversations need to happen. It's about time. These conversations need to happen with patients to say, "Okay, what is the risk versus benefit of using certain chemotherapies versus not?" These conversations, as genomics grows more and more, these conversations will happen more and more, but we need concrete data to be able to say, "Okay, this mutation is important, this chemotherapy makes it worse, but other chemotherapies don't," and until we don't have this data, we cannot advise how our solid tumor oncologists should be talking to their patients when they actually see it.
What we are looking for next now is understanding treatment patterns within these subgroups. We looked up till the point of they get the disease and how they do, but we're now collecting and analyzing information on if different treatments of leukemia or MDS, if that has an impact on determining the outcome of these patients depending on what kind of exposure they've had in the past. That has never been looked at, and we're looking to do that on the current dataset, as well as expanding it to a larger dataset.