Treatment Options for MDS (Myelodysplastic Syndromes) with Dr. Rory Shallis - 2022

Dr. Rory Shallis discusses a variety of current treatments for MDS, or 

Transcript

Hi, everyone. This is Podcast For Patients with the and MDS International Foundation. And I'm Alice Houk, senior director of patient and professional services. Our podcast series is brought to you thanks to generous support from patients, families and caregivers like you, and our corporate sponsors. Thanks to everyone for supporting this series. Today, we're talking about advances in treating MDS, with Dr. Rory Shallis, Assistant Professor in the section of Hematology, [00:00:30] Department of Internal Medicine at Yale University School of Medicine, and Yale Cancer Center and Smilow Cancer Hospital. Welcome, Dr. Shallis.
Rory Shallis:    Thank you so much for the opportunity, it's a pleasure.
Alice Houk:    We'll start off with a basic question, and what is MDS?
Rory Shallis:    That's a great question, and it's, uh, unfortunately it's, it's not too simple. But, um, I can try. So MDS, it stands for the , [00:01:00] a collection of diseases that, uh, arise out of a, a biological disturbance just to kinda use a vague term. Um, but a disturbance, a- among the hemapoietic, uh, or blood cell making cells or compartments, specifically the parent-like cells within the that, uh, accumulate over time, and this translates into abnormalities in the blood cells they make, in both quality and quantity, uh, the latter really manifesting [00:01:30] as low blood counts, one of the more common presenting signs of MDS. 
    Um, the disturbance that puts these cells on the path to becoming MDS initiating, uh, i- is multi-clonal or multi-step process, um, and subject to really a, a wide array o- of variables, genetic, uh, and what we call epigenetic. Uh, but also, we're learning the importance of the sequence, i- in which they occur. It's for, for this reason that it is in fact a collection, with a diagnosis of MDS really being [00:02:00] biologically, uh, genetically what we call phenotypically, uh, distinct from person to person. So, um, but, um, there are areas of, of overlap, as it relates to these issues that allows us to at least attempt to study them, uh, to hopefully lead to improvements in management.
Alice Houk:    And what are the current treatment options for both low risk MDS and high risk MDS? And perhaps you can explain the difference between those as you, uh, discuss the treatment options.
Rory Shallis:    [00:02:30] Sure. It's a great question, and you really bring up one of the, you know, the classic dichotomies, um, that we really have to kind of a- assign o- o- or basket, when it comes to, you know, as we just talked about, each diagnosis is somewhat unique between patient to patient. Um, but in formulating a treatment plan, we first attempt to predict how the disease is likely to behave inherently, and of course, down the road with certain treatment that, uh, may or may not be offered to the patient. Uh, we can estimate this by using tools, uh, that incorporate [00:03:00] a collection of information, uh, the types and depths of low blood counts, the number of bone marrow , certain what we call chromosomal abnormalities that can inform the prognosis and really individualize the treatment approach. 
    Newer tools, um, well, one in particular incorporates molecular or mutational data, um, which we've known for, for some time, to impact the behavior of certain forms of MDS. So, um, you mentioned lower risk disease or higher risk disease, or what risk are we talking about? It's mostly the risk of it really [00:03:30] progressing to, uh, what we generally regard as being a very, very, you know, bad or aggressive form of MDS, known as or AML. Um, there are patients that have predicted lower risk disease, uh, which we can sometimes just watch if the blood counts aren't that low, and there are no disease related problems. Uh, some patients even with low-risk disease, uh, do have low blood counts that require consideration for some type of therapy that can perhaps improve it. This is typically , and we have effective, uh, medication, [00:04:00] such as those that increase the body's production of, uh, , which is the, uh, the that stimulates production. 
    Uh, the chance, uh, of good effect differs between patients, based on a number of factors, um, which I guess we don't really have to get into. Higher risk disease, um, is different, uh, in its behavior and, you know, by the same token, its approach, uh, our goal is to actually put pressure on the disease itself, and not just address the problems with which it comes or, or the causes. High risk disease must be [00:04:30] really met at the frontlines is what I often tell patients, uh, as if, you know, uh, unchecked we are accepting a higher risk of, of the disease eventually progressing to AML, like we talked about. Which is essentially just an aggressive form of MDS. It's different, but you know, just for the sake of simplicity.
    Um, so for high-risk disease, you know, for quite some time, the frontline therapeutic standard has been the administration of what we call the hypomethylating agents, or HMAs, they go by several other names as well, um, the two classic ones are , and . [00:05:00] Um, although the rates of remission with these agents are, are relatively low, they have been shown, uh, in both real world study analyses and randomized control trials, um, which is really one of the gold standards, uh, to improve our overall survival. Um, without any differences appreciated between these two agents, being azacitidine, or decitabine. 
    We now have a, an oral formulation of decitabine which is approved, um, in this setting as well, and certainly, uh, an oral, you know, once a day pill [00:05:30] in cyclic fashion is, is attractive to many patients, and providers for that matter, too. Um, some patients with high risk disease, and a blast percentage bordering on that defining AML receive, in many cases, AML-like intensive therapy, with the eventual goal for all of these patients, namely high risk patients, if they're able and it's feasible, they have a suitable donor, to undergo what we call an allogeneic hematopoietic stem cell transplant, which is the only curative therapy of which we know today. So that was a, you know, a higher level summary of what could [00:06:00] really be an hour, uh, long lecture. 
Alice Houk:    Yes, it's a lot to, to cover in a short period of time. I think this is helpful though for patients just trying to learn the options, and for family and friends who are trying to understand what their loved one may being going through. Uh, with the, the transplantation, uh, as an option, years ago that the, uh, there used to be a cutoff just based on the age of the patient. But we understand that's been changing in recent years, [00:06:30] can you talk a little bit about that?
Rory Shallis:    Yes, it's changing. And, and we think for good reason. Uh, age is really an imperfect surrogate for, you know, candidacy. Whether it's, you know, we could define this in different ways or in euphemisms, oh, appropriateness or eligibility for, uh, what is a non-trivial procedure. Transplant is a procedure that does carry a risk, and these are risks that are accepted, you know, by patients that are 25-year-old marathon runners. [00:07:00] Um, however, um, this somewhat arbitrary age 60 or greater or less than, for that matter, cutoff, um, is getting a bit more, uh, blurry. At least, the border's getting a bit more blurry, just because we know some patients who are younger, for instance, that just can't accept the risks of transplant, whether it's because of a end organ reserve that's just a bit more frail. 
    Um, but there are also, quote, older patients than age 60 for that matter that, uh, we do think are, are quite fit. Uh, and [00:07:30] thus, quote, eligible, end quote, to undergo, uh, this procedure, which as we discussed, is the only curative therapy. So, um, the risk benefit calculation, depending on one's goals and clinical situation might, might be favorable, uh, in this case, even for patients that are 70, 75 years old for instance. Um, the, the reason why this is becoming a, a bit more dynamic over the years is that we now have newer transplant techniques. Uh, a, a wider availability of donor selection, I'd say better, better [00:08:00] . 
    And then more recently, uh, we do have some data to suggest that even older patients, quote, unquote, um, can get through transplant, uh, you know, reasonably safely, um, and derive some benefit. Now, and that, it might not mean that we're curing all these patients, but at least from a disease directed therapy standpoint, it is moving, uh, the goalpost a bit further, um, and this is, of course, a, a benefit to, to many, many patients.
Alice Houk:    Yes. thank you for elaborating on that. I think that helps, uh, patients [00:08:30] understand that the options are expanding in that regard. And are there any new treatments on the horizon. And as you're talking about those also, if you could, uh, talk about the, uh, potential to participate in a for patients, and why that's an important consideration for them.
Rory Shallis:    Sure. new treatments on the horizon, yes, and, and thank goodness. Um, because of the, the shared pathobiologies we call it, between MDS, famously high-risk disease, and as we just [00:09:00] discussed, AML. Um, there has been a fortunate and ongoing effort to extend the advancements in AML therapy over the last five years or so, um, and it has been sort of a golden age, uh, to the MDS space, with some minor considerations regarding, you know, e- either dosing or administration schedule. 
    Uh, the one on the horizon that holds quite some promise is the use of, uh, what we call the Bcl-2 inhibitor, , which, um, in combination with the hypomethylating agent, uh, combination approved for the treatment, uh, of AML, among patients [00:09:30] that were, um, inappropriate to receive intensive therapy. This combination improved survival, in comparison to azacitidine monotherapy, um, in AML and, and has been a game changer for many patients. So why not see if it changes the game for patients with MDS? Interim data suggests that the addition of venetoclax can achieve responses among these patients who are, uh, being failed by azacitidine, which is, you know, one of a, you know, two if not three if you wanna include the oral, uh, HMA. Um, but these aren't perhaps [00:10:00] perfect responses, but maybe just enough to finally proceed to transplant. 
    Uh, the addition for venetoclax to frontline azacitidine is also being studied, uh, and some data suggest responses to be, uh, a bit quicker and deeper, um, when indirectly compared to the current standard of, you know, as we discussed, single agent hypomethylating agent. Much attention is being paid to an ongoing, uh, randomized phase three trial, which is comparing azacitidine alone, the current quote, unquote standard to azacitidine and venetoclax, and it's gonna use [00:10:30] overall survival as its primary end point. Then we'll, of course, hopefully render a conclusion soon, and it could be practicing changing. 
    So, um, this is one example of why are, are certainly encouraged in every setting, whether it's frontline setting if it's appropriately designed, um, and perhaps, uh, with a bit more critical knee deep, what we call the relapse/refractory setting where, you know, there aren't, I'd say as many true game changers. So clinical trial is certainly something that should be sought out and encouraged whether you're being treated [00:11:00] in the community, or certainly at an academic setting, this should be, um, you know, one of several options presented. 
    Other treatments on the horizon, uh, are mostly being, I'd say studied in combination with hypomethylating agents, including, I mean, just to name a few, the anti-CD47 agent, Magrolimab, or other targeted therapies like the IDH inhibitors, or enasidenib, or enasidenib. Uh, monotherapies, uh, in their relapse/refractory setting might also hold promise such as, um, the IRAK-4 inhibitor, CA, uh, 4948. [00:11:30] Or you could even say the ever-expanding armamentarium of cellular therapies. Each targeting different aspects of MDS biology. And of course, all these are, are really being exclusively studied in a clinical trial setting. So you're really getting that access to novel and for potentially game changing medications is, um, we think, uh, you know, a benefit to patients, but of course the, the larger field as a whole.
Alice Houk:    And when patients [00:12:00] do participate in a clinical trial, an important thing to reiterate is that, uh, they get at least the standard of care that they would be getting even if they were not in a trial. But, from then it varies based on the trial and, and they get, uh, wonderful guidance and care throughout the whole process, uh, because, uh, one fallacy that we try to address is that, uh, uh, a clinical trial is not [00:12:30] necessarily the last resort, or, y- you know that it, it is a viable treatment option for patients, if they are considered eligible.
Rory Shallis:    Yes. This is an important distinction to make. And I, I would agree with you that this is a conversation that comes up, or a misconception that comes up, uh, quite often in the clinic. Um, now I, I would probably just clarify with one, with one comment. There are some trials that, you know, are using, uh, agents, or attempting to study agents that [00:13:00] really are, in many cases, sort of, you know, a, a close to last resort and we have to think more outside the box. And a patient's already been failed by either our tried and trues or our, you know, all of our meaningfully effective therapies, and disease is still quite stubborn. 
    So we have to, you know, try to outsmart it. And this might mean using an agent for which we really don't know, uh, what to expect with regards efficacy and to a certain extent, you know, side effect profile. Uh, and those are trials which, you know, we [00:13:30] do think still, have a, a favorable risk benefit calculation for the individual. But, uh, more so to your point, there are, uh, many more, I'd say frontline or maybe early salvage trials that, yes, have to have what are, what are known as a reference standard. 
    In the frontline setting, uh, as we just discussed, it's going to be a, a backbone using a hypomethylating agent, just so as, as you said, the patient is not being deprived of a, a, standard of care, you know, [00:14:00] uh, being effective therapy. Without that then, yes, patients would be cheated out of, uh, of therapy that they would also, uh, that they would otherwise get if they were not on the trial. So that is, I, I would agree, that is a key distinction and, you know, uh, we really hope that this, this stigma can hopefully be, be mitigated over time.
Alice Houk:    Yes, thank you for that clarification. And, uh, and finally, are, other than the treatments that you've discussed, are there other advances happening in MDS, related to perhaps a diagnosis or [00:14:30], patients, how their therapy can be targeted. You mentioned that in discussing the treatments. And, uh, are there any advances like that, like that, that are impacting diagnosis and treatment, and a really management of MDS?
Rory Shallis:    Yes, 100%. And this is a, this is another important question, you're asking great questions. Um, advancing the understanding of MDS biology and what brings it about or allows it to hang around even after exposure to fairly affective therapy i- is [00:15:00] critical to moving the field forward and identifying really newer therapeutic targets, mechanisms of resistance that may predict a patient who is more likely to respond to a particular therapy, or conversely, which patients are unlikely to respond, and in reality may just be exposed to all the side effects without, without much benefit. 
    Um, improvements in the diagnosis, uh, and estimating prognosis, which informs treatment, uh, will advance the field forward as well. So whether it's, you know, the ongoing effort to understand what we call CHIP or CCUS, we don't have to go through what those abbreviations mean. [00:15:30] Uh, but in brief, clonal states that have not yet, or may not ever really manifest with actionable quote, disease, end quote. Uh, or among patients with a, a bona fide di- disease state, the recent progress in softening that border between the diagnosis of MDS and AML, UM, we think we'll end up truly helping more individuals. 
    And just kind of to harken back to our last discussion that, yes, this will probably allow more patients with quote, unquote, MDS, to get therapies that were otherwise previously restricted to, you know, AML trials, and in some cases, [00:16:00] vice, versa. Um, there are more advances, but let's probably just say lastly the development, uh, and wider availability of next generation technologies to, to dig deeper and, and better identify, um, maybe actionable targets, as we talked about, but also the smallest, really, what we call foci 00:16:17] disease, that we call quote, measurable residual disease, end quote, um, the use of which, if properly understood, which is an important caveat, uh, might change management decisions and, and hopefully impact patient outcomes.
Alice Houk:    [00:16:30] Very good. Well, we'll end on that hopeful note of some new things on the horizon, and the treatment options available, many more than there used to be, but of course, we always want to see more and improved outcomes. So, uh, thank you so much, uh, Dr. Shallis for sharing your time and expertise with all of us today.
Rory Shallis:    Thank you for the invitation.
Alice Houk:    You can find out more about disease on our website at www.aamds.org, by following us on Facebook, Instagram, and Twitter, or by calling our helpline at 800- [00:17:00] 747-2820. Thank you for listening.

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