Dr. Jacqueline Garcia discusses the use of hypomenthylating agents.
Leigh Clark: Hi, everyone. This is Podcast for Patients, with the Aplastic Anemia and MDS International Foundation. I'm Leigh Clark, Director of Patient Services, and I'll be moderating the podcast today. I'd like to give a special thanks to our corporate sponsors and our patients, families, and caregivers, for supporting the podcast series.
Today we are talking about treating MDS after hypomethylating failure, [00:00:30] with Dr. Jacqueline Garcia, who is an assistant professor of medicine at the Dana-Farber Cancer Institute and Harvard Medical School. Dr. Garcia specializes in treating patients with leukemia.
Welcome, Dr. Garcia. Thank you so much for joining us today.
Jacqueline Garc...: Hi. Thank you so much for having me.
Leigh Clark: Dr. Garcia, what are hypomethylating agents?
Jacqueline Garc...: That's a really good question. I think that we've all been struggling in the field to fully [00:01:00] understand what these are, but this is what the pre-clinical data has shown, and what we're still trying to fully understand. Um, hypomethylating agents, um, including azacitidine or decitabine... I like to call them cousin drugs, because chemically speaking, they're both very similar compounds. And they have a unique, uh, mechanism actually compared to traditional chemotherapies. I call these less intensive or gentle chemotherapies, because they are anti- [00:01:30] cancer.
But compared to the traditional cytotoxic chemotherapy, they are very different in how it works. In one hand, they can cause cytoreduction, meaning that they can reduce cancer cell burden. On another hand, at low doses or strategic doses for which these are already, uh, scheduled and how the doses are fixed per the FDA label, we know that they can offer activity at the methylation level. [00:02:00] Methylation means, you know, how genes are expressed and silenced.
So in the human body, We are made up of millions of cells. And similarly, in our blood compartment, our blood compartment is made up of millions of cells. And within each cell, in order for cells to function properly... Such as make blood, and carry oxygen, prevent bleeding, prevent infections. All of those wonderful functions in our blood cells have... is operated and determined [00:02:30] by the genes that are expressed within each cell.
And each gene, uh, within the cells is actually controlled by different properties at what's called the promoters, or the switches that turn genes on or off. And when genes are methylated, it essentially means that a gene can be silenced or turned off. It prevents potential functions from occurring. So when cancer cells occur, there has been, uh, pre-clinical evidence, or evidence [00:03:00] coming from the laboratory... Either from human or animals, uh, models, that suggest to us that there are certain genes that are silenced or not being normally expressed. And because of that, it leads to a series of events that result in the development of myelodysplastic syndromes, or leukemias, or abnormal cell development.
And so the idea is if you can apply a hypomethylating agent, which is a, an epigenetic therapy, we hope [00:03:30] to re-express these silenced genes. So one quick example, would be to think about tumor suppressor genes. These are genes within each cell that are literally supposed to prevent cancer cell or abnormal cell growth. If these genes are silenced, um, due to cancer development, then cancer will continue to progress. If there was a medication that could allow re-expression of these genes, such as a hypomethylating agent, that would potentially [00:04:00] change the underlying biology, or how the disease operates.
And so we use medications like azacitidine and decitabine, which are both FDA approved drugs for myelodysplastic syndrome, to not only reduce the burden of the MDS disease within the body, but in hopes that it could change the underlying biology of getting the cells to behave the way they are supposed to before they became a cancer cell. In order for events like this to happen, it takes a lot of time [00:04:30] for the disease and behavior to change.
Leigh Clark: Thank you, Dr. Garcia.
Why do hypomethalyating agents fail patients?
Jacqueline Garc...: So, hypomethylating agents has been our backbone, um, in the treatment of MDS primarily for a few reasons. One, um, there's clinical activity. Meaning it helps patients to feel better. It can help patients to improve their blood counts. And in some patients, not [00:05:00] the majority, it can help to achieve, achieve complete remissions or responses.
Um, unfortunately, these complete remissions or responses are not the same as cure. So we see hypomethylating agents as a way to prolong survival. As a way to induce remissions. As a way to delay leukemic transformation. And as a way to improve symptoms and laboratory blood counts for patients dealing with myelodysplastic [00:05:30] syndrome.
The hypomethylating agents, um, with all of these wonderful clinical benefits, can also be, uh, provided as inpatient and importantly, outpatient. It can be also delivered to younger and importantly, older patients... And they make up the majority of MDS patients. Suggesting that it is a tolerable regimen. Um, and one of the newer things that has happened the last few years, is we've now had the availability of an oral formulation, [00:06:00] which has helped to increase feasibility and accessibility to patients that might otherwise not be tied to a clinic for frequent infusions, and so forth.
So hypomethylating agents are a foundation of MDS therapy for many reasons, from it being, uh, logistically easy to administer, um, tolerable and clinically active. But hypomethylating agents are limited in its ability to eradicate the origin of MDS, or the leukemic stem cell, [00:06:30] that essentially repopulates the bone marrow with the MDS disease.
Um, so hypomethylating agents are active, but are not active enough to lead to durable responses for the majority of patients. When the patients, uh, that achieve complete remission, which is unfortunately a minority... When they do achieve a complete remission, those are the ones that can enjoy the benefits of hypomethylating agents on the order of years, um, as opposed to months.
[00:07:00] And so we have been looking for therapies that can either replace hypomethylating agents or be added to hypomethylating agents, to deepen responses. Make them more durable, but yet still be safe and easy to deliver in an older patient population, that is predominantly outpatient and in the community.
So our hypomethylating agents have been a necessary medication for us, um, but we recognize its limitations. And it serves as a really [00:07:30] good backbone, uh, for future and current investigational therapies. Meaning we are hoping to add to hypomethylating agents, given how effective they have been. Knowing we can probably, based on how these drugs work, try to leverage its activity by partnering it with a potentially more active drug.
And so currently in the, uh, investigational arena, meaning what's happening in clinical trials, we have been combining many new drugs with [00:08:00] hypomethylating agents. From oral therapies that target the cell death pathway, or anti-apoptotic pathways... Such as the venetoclax, which has in combination with hypomethlyating agents, resulted in an approval for frontline treatment of acute myeloid leukemia in patients ineligible for intensive chemo. We hope to translate similar safety and efficacy in patients with higher-risk myelodysplastic syndrome.
There has also been combinations with, [00:08:30] uh, immunotherapies, such as CD47, checkpoint blockade. Uh, which is a pro-phagocytic, uh, signal on the surface of tumor cells that we hope to increase expression of, to allow targeting with this novel checkpoint inhibitor. That has been, uh, safe and active in the preliminary setting in patients with higher-risk MDS.
There are additional therapies that are underway. So we're looking at ways to leverage [00:09:00] hypomethylating agents, hoping that we can work with a drug that is easy to tolerate, increase responses, increase durability of clinical activity, and importantly, change or disease modify what happens to MDS... Such that we can actually lead to treatments that provide long-term, durable remissions, or prevention of leukemic transformation.
Leigh Clark: Thank you. [00:09:30] what are the options for patients after these treatments fail?
Jacqueline Garc...: Well this is where we really struggle in myelodysplastic syndrome, because quite frankly we don't have any. A few of the options that are not necessarily options for everybody, because it depends on age, comorbidities... And comorbidities meaning, what other medical ailments are patients experiencing? Um, and molecular mutations in cytogenetics, meaning [00:10:00] what are the features of a patient's underlying blood cancer that make it sensitive or resistant to treatments?
And in that setting, we don't have many drugs that are approved for the treatment of patients after hypomethylating agents. Some of the potential options include going to transplantation, providing intensive chemotherapy... That includes a prolonged hospitalization and [00:10:30] notable side effect rate. Swapping from one cousin to the other, meaning going from azacitidine to decitabine or decitabine to azacitidine, with the hopes of a switch that might lead to prolongation of benefit. And off label use, potentially, of other drugs that are currently available in acute myeloid leukemia. Because sometimes that's the only option we have.
In addition to the above, we [00:11:00] offer palliative care, supportive care, transfusions, growth factor support. But in the end what will really be most important for when the initial first line therapy does not work for patients with MDS, is to really look towards clinical trials. Because we need novel therapies to provide new ways to get rid of bad disease.
And so currently there has been many therapies that are in clinical trial investigation, that have demonstrated initial promise, and [00:11:30] safety, and efficacy... That have made it to the phase three or randomized setting. With the hopes of at least one or more of these options becoming approved in the coming, uh, years.
So at the end right now, we make decisions on what options a patient might receive after the point of patients no longer deriving benefit from hypomethylating agents, based on what our goals [00:12:00] are for the patient. We think about, is the patient able to be bridged to a curative plan, which would have to include transplantation? Are they transplant candidates? Or because of age or comorbidities, meaning other medical ailments... Are they too frail and sick to undergo such an intensive plan?
And thus, our focus s- should really be on palliation. Keeping leukemic transformation as far away as possible, improving [00:12:30] blood counts, reducing infectious complications, helping patients to feel better given transfusion burden.
So we think about strategy. You know, transplant versus no transplant. And then we think about, is there a clinical trial that could potentially help the patient? And then next we think about, is this patient able to undergo intensive chemotherapy or not? Um, and that really allows us to think about what to do next. Understanding that our options truly at this time are limited, if we cannot, [00:13:00] uh, offer our patient a clinical trial.
So we really emphasize referrals or consideration for tertiary cancer care centers when possible. So that way we can continue to offer, and move the field forward. Because our patients are fortunately living longer. Um, surviving initial cancers.
Um, and we are starting to see the benefits of people living longer age. But now patients are developing other, uh, issues, including myelodysplastic [00:13:30] syndrome. So our, field is changing, uh, with the patient population. Meaning that we're trying to find therapies that are tolerable, efficacious, and impactful, understanding that we need more than one option available.
Leigh Clark: And what is the future of MDS treatments?
Jacqueline Garc...: That's a really great question. I think that we have been really excited in the last, uh, couple years, based on some of the [00:14:00] preliminary phase one data coming from the combination, uh, regimen that have been tested in the high-risk MDS setting... Um, that has been combined with hypomethylating agents from venetoclax, um, magrolimab, uh, sabatolimab, um, and other agents. There has been some really encouraging activity to suggest to us that we may be getting a new standard of care option for patients if these phase three trials are able to demonstrate [00:14:30] benefit.
So I think the future of MDS treatments may include doublet, or combination therapy. If we're able to confirm and have one of these regimens cross the finish line, one might argue that there could be a role for testing triplet therapies. Meaning providing three drugs to patients to try to deepen responses to try to bridge patients to transplantation, um, and prevent, uh, leukemic transformation.
Transplantation remains the cornerstone of [00:15:00] MDS therapy, as it remains the only known curative option. And so our goal is to get patients that are age appropriate and have, um, the ability to undergo transplantation, to get to a tertiary care center as soon as possible to be considered and set up for a transplant. And in the meantime, develop these doublet and triplet, uh, therapies.
I also think that there is a role for, um, genetically stratifying patients, uh, with mild dysplastic syndrome. Uh, molecular mutations [00:15:30] have become really important for us to understand how and why MDS develops. These diseases are heterogenous, meaning that they result from a series of events, often not just one event. And thus we have to be mindful and thoughtful about ways to target mutations.
And there have been very encouraging, uh, drugs out there, including drugs that target the splicing mutation genes, which make up half the patients with MDS. Um, including, uh, inhibitors that directly target [00:16:00] those complexes, IRAK-4 inhibitors. And so there are a lot of new mechanisms that I'm keeping my eye on in the future.
There are also immunotherapies, uh, that we need to pay attention to. So in addition to bone marrow transplantation, which has been again, the cornerstone and only curative option available, we have been looking towards other agents that provide immunotherapies. Some examples include CD123, um, immune targets that are conjugated [00:16:30] with toxins. Uh, one example is a drug called tagraxofusp, where there is some preliminary activity and early stage clinical trials.
There are also CD123 bispecific immunotherapies that show encouraging activity in the refractory relapse setting. Um, and in addition I had mentioned the Tim-3 and CD47 checkpoint inhibitors, which represent novel ways to leverage the [00:17:00] immune system to eradicate tumor cells.
So I think that the future of MDS, uh, treatments looks very promising. We have more data than ever before on preliminary clinical activity in the early phase settings. We are now incorporating, uh, molecular mutations into stratifying patients appropriating to trials.
So I am hopeful that we are making progress, and that we will have new therapies in the coming years. And I think certainly, there has been a huge emphasis in clinical investigation [00:17:30] to try to be thoughtful about how to put patients on to these, uh, clinical trials.
Leigh Clark: Thank you so much, Dr. Garcia, for sharing your time and your expertise with us today. And talking about this very important topic for all MDS patients, to understand better about what are hypomethylating agents, um, and what their options are should those treatments, uh, not work for them. So thank you again, for spending your time with us today.
If you'd like to find [00:18:00] out more about bone marrow failure diseases, please visit our website at aamds.org. You can reach out to us at any time through our Facebook page, or give us a call on our helpline, at 800-747-2820. This concludes our podcast. Thank you.