Advancements in AML & MDS: Genetic Sequencing & Immune Therapies | David Swoboda, MD | ASCO 2023

One of the things that I'm really excited about that we're doing at Tampa General is specifically utilizing our tissue biorepository for research purposes. And one of the things that we're doing there, you know, right now in AML, we primarily are looking at the genetics with targeted base sequencing. And so at Tampa General, working with different companies, one of the things that we're looking at is broadening that and doing whole exome, whole transcriptome sequencing. So really, not just looking at a set amount of mutations that are in AML or MDS, but looking at all the potential possibilities for mutations. And this will allow us to not only have mutational features that we know currently, but also to have additional mutations that then we can detect and potentially use for therapeutic reasons in the future. Outside of the tissue biorepository, you know, another thing that I'm doing is partnering with the NIH and the NCI. And there what we're doing is we're looking at in MDS how the immune system affects the micro environment for MDS and do specific mutations in MDS influence the way the immune system interacts. You know, the other things that we're doing at Tampa General is we're bringing on a couple novel clinical trials. You know, one of them is looking at a really interesting pathway that I think a lot of leukemia doctors are exploring, which is the macrophage checkpoint pathway. And so currently, when you think about immune therapy and how it's being utilized in cancer, primarily we're looking at T cell based therapy and what we call checkpoint inhibitors, you know, are primarily focused on T cells. So there's been a big push to look at other immune cells in cancer and specifically in AML, one of the areas that we've seen that has promises macrophages. And so what we're actually doing is basically turning off a switch that down regulates macrophages and allow the macrophages to basically eat cancer cells. And so there's a lot of different ways that we're, you know, manipulating the checkpoints that do this. You know, there's, you know, a drug sort of in the late stages now in a phase three clinical trial called McGrollamab. McGrollamab is just one of the drugs that, you know, targets this pathway with, you know, there are several other drugs that are coming up the pipeline, you know, hoping to potentially improve on side effects or efficacy. And so, you know, one of the trials that we have is a, you know, a new type of macrophage inhibitor in combination with Vitae's Venetoclax, which is a standard therapy for elderly patients in AML and seeing, you know, are we able to continue to push the boundaries of what we're able to do with macrophages. The other clinical trial that we have at Tampa General that, you know, is of interest is looking at BCL2. And similar to what, you know, I sort of spoke about with macrophages, you know, BCL2 is another pathway that is being utilized across different cancer types. And that's with Venetoclax primarily. There's, so in AML, you know, the FDA approved for elderly unfit patients, Vidaeza plus Venetoclax. And you know, that has been the backbone now for really all of our, you know, elderly unfit patients, but possibly the backbone for potentially all patients with acute leukemia. And so another clinical trial that Tampa General is, you know, interested in and participating in is looking at a second generation BCL2 inhibitor and seeing if again we can sort of improve on what we're able to do with Venetoclax, be, you know, more selective for BCL2, potentially improve efficacy and side effects as well. When it comes to ASCO, you know, I think the things that I'm most excited about are some of the new therapies in MDS. You know, for a very long time, you know, we, you know, we had only a couple options for patients with myelodysplastic syndrome, especially low risk patients, transfusion dependence where we primarily use a red blood cell simulating agent as our mainstay frontline option. So at ASCO, you know, there's now two phase three trials with novel agents that are hopefully going to either add to or potentially improve on what we're able to offer in that low risk space. And so I think a lot of people are excited to see what those phase three results look like today. And hopefully that will lead to FDA approvals that will improve the care for patients overall. You have, you know, red blood cell stimulating agents, you know, with Rithropoietin agents, ARINES and Procrit. But ultimately, once you get past that point, you know, we basically have immune modulatory agents like lenalidomide that, you know, really work well in certain subsets of MDS, but not as well in other subsets. And you know, Lusbatercept is one of the drugs that, you know, a lot of people are really excited about. Currently, it has an approval, you know, in patients that, you know, don't respond to ESAs in the front line setting and is approved specifically for a subset of patients that have an SF3B1 mutation or RINX sideroblasts. But the big question, and I think the big, you know, exciting theme here is, you know, can we start to use Lusbatercept in all of our patients? Is it potentially better than what we're doing with standard of care ESAs? And, you know, because the nice thing is Lusbatercept is really well tolerated, pretty minimal side effects. And overall, you know, I think a really good drug that patients, you know, seem to benefit from. And so if we can start to push the boundaries, because you've got to think about being an MDS patient, you know, especially a low risk MDS patient, you know, their biggest, you know, decrease in quality of life is just this continued going to the doctor, getting transfusions, you know, even if in the best offices, you're still going to spend, you know, four to six hours every time you're getting a blood transfusion. If you're having to do that, you know, once a week, twice a week, it's a lot of, you know, lost time. And if we're able to get better drugs, like potentially Lusbatercept moving forward, you know, I think it's really going to improve the quality of life for a lot of patients.