Guillermo Garcia-Manero, MD, MD Anderson Cancer Center

I’d like to ask you a question about the multidisciplinary management of MDS [myelodysplastic syndrome]. What other members of the patient care team are involved, and what are their roles? For us at Cleveland Clinic, our core team includes some of the transfusion nurses and our pharmacists, who are part and parcel of the other issues in the drug-drug interactions. There are a number of people who are on our team who help care for patients. What is it like for you at The University of Texas MD Anderson Cancer Center in the management of your MDS patients?

 This is a fundamental question that we actually started on at the beginning of our conversation. Because our patients are older, they tend to have comorbidities. What we have learned through the work of many groups is that there might be some type of connection between these comorbidities and myelodysplastic syndrome. There might be a potential connection between heart disease and MDS and so forth, so this is being explored. This really emphasizes that we need to be able to provide multidisciplinary care.

I’m sure this is actually ordinary in a place like Cleveland Clinic, where you have not only top-notch leukemia doctors but also amazing cardiac care. We are a big cancer center, but this is a very important topic because this will probably translate into better outcomes. If we can integrate geriatric care for our very old patients or try to maximize the internal medicine needs of our patients, this is something we’ve been paying more attention to over the last couple of years. We used to disregard this, thinking that a diagnosis of MDS meant that we don’t have to worry much about your diabetes or high blood pressure. It turns out that it’s probably crucial. Having that kind of multidisciplinary care should be very important.

In our group, we are improving our integration of stem cell transplants. We’re starting to transplant older patients. Before, it was thought that if you were older than 50 years old, it was impossible. Then the threshold became 60. Now we’re starting to consider transplants in some patients over 70. Integrating the transplant team with the MDS leukemia team is really important. Earlier, you mentionedgenetic screening. Many of the centers have created leukemia programs where, for some patients with high-risk mutations, screening families is something that needs to be discussed.

It’s becoming a really complex multidisciplinary approach. From the typical group like you and me, you have nurses, physician assistants—the people who really provide the care. You also involve the transplant team, and in some cases, maybe hereditary clinics and geriatric internal medicine. This is really important. This kind of care is what will eventually translate into improved survival of our patients.

If it was in my family, this is what I would look for: clarity in terms of the diagnosis, a clinical trial that will help because we’re really far from curing a lot of our patients, and multidisciplinary care. Finally—I emphasized this at the beginning—the family support is critical. These are complex diseases. In older individuals, the conversation is difficult and having good family or friend support is really critical. Try to come to the clinic with another set of eyes and ears to help you and support you. I admire the families of our patients because without them, we would probably not be able to deliver a third of what we can. It’s critical to think about them as part of our team because they really are.

 What I hear you saying is recapitulated at our practice as well. The team is extensive. It’s first and foremost the patients and the caregivers around that patient at the home front who really help ensure that all the information needed to be communicated is being communicated directly from the physician team. That’s inclusive of the nursing support that’s helping give chemotherapy and transfusions but also the cardiac management, drug-drug interactions from pharmacists, and just making sure there aren’t issues with the medications. We spoke about the future for some patients, including therapies such as transplant or even clinical trials. It is really important to ask questions so that you have the answers. Pursue that. Don’t be shy about asking questions and advocating for yourself or your loved one. More than ever, we want to encourage the MDS community. We are receptive to answering those questions, and we want you to be engaged and involved in as deep a way as possible in the management of MDS.

I think that we’ve been fortunate at our home institution to have the incorporation of genetic counselors and also the incorporation of the bone marrow transplant teams. That helps us really support patients who are able to pursue those types of therapies and answers with regard to the underlying pathogenesis of MDS.

I’m grateful for the time we’ve had today to talk about the management of patients with MDS. We’ve covered a lot of ground in the last hour and a half, and I can’t underscore how fortunate we are as doctors. I want to echo the comments of Dr. Garcia-Manero. We learn a lot and are very privileged to help take care of patients with this diagnosis. We’re humbled by the grace that you all show us in sharing a difficult time. We learn from you all how to remain open. We’re just delighted to help at a time in your life where you can lean on physicians and caregivers to help you at a time where there is some uncertainty. But we do want to leave the message that we are incredibly hopeful and excited about the state of affairs with the treatment options for patients with MDS, as well as the future.

 I would like to echo that to close, Hetty. It’s been an honor to spend this time with you. You’ve been a great colleague for so many years, so it’s nice to see you. I would also like to say that we are living through a transformative period of time. For many years, we had 2 or 3 drugs, so the best we could do was better diagnose this disease and try to do the best in our research. But now it’s starting to pay off, so I am optimistic.

This is a serious condition, but we’re going through a transformation, and things are moving fast. It’s thanks to the academic researchers, the families, and the patients who were part of all this. Luspatercept was one of the first things that happened in many years, but it shows how perseverance is going to help us achieve better therapeutics for our patients. Thank you, Hetty.

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A Multidisciplinary Team in Treating Myelodysplastic Syndromes

 I just want to acknowledge a lot of work that you’ve done in your career for patients with myelodysplastic syndrome [MDS] and ask you some questions about the lower doses that you’ve been investigating for patients with myelodysplastic syndrome. What has your experience been like? What might you share with the audience today about what your institution has done with regard to newer therapies for patients, whether it’s the lower-risk hypomethylating agent approach or novel therapies that we need to look for in the upcoming year or years?

 Thank you, Hetty. You’re too kind, because you’re part of this effort as much as I am. First, the message for the audience is that patients and their families need to be engaged. We talked earlier about how you need to be active with this disease. These are very complex disorders. Not to be critical, but many times, even hematologists may not be 100% on top of what’s happening or the latest. Medicine is getting very complex. Hetty and I treat two or three disorders. Beyond that, we probably don’t know much. So it’s really critical for the families and the patients to be engaged.

In my opinion, it’s really critical for families to ask these questions that we talked about earlier: “What is my risk? What are my chromosomes? What are my mutations?” You really need to ask the doctors and be aggressive in a positive way in terms of the therapy working, what is next, and if there’s a clinical trial close by that could help you. This is a big country, but we have big research centers all over that likely will have some degree of expertise or a clinical trial.

With regard to your specific question, we’re going through a transformation in our ability to treat patients with this disease. Maybe we can talk about high-risk disease someday. There are a lot of new doublets that are very effective. In low-risk disease, we’re seeing something that is eventually going to be very positive. You and I, through the MDS Clinical Research Consortium in the United States, work in these lower-risk trials and try to use the hypomethylating agents at a lower dose. That was an intuitive concept because we thought that lower doses could be effective and possibly less toxic. It turned out that, for some subset of patients with lower-risk disease, they can actually be beneficial.

We are also developing oral hypomethylating agents. Hypomethylating agents are given subcutaneously or through IV [intravenous] for three, five, or seven days a month. This gets tiring. The injections are short, but they take some time, and that may be a week of your month that goes away. So for many years, we’ve been working on oral hypomethylating agents. We now have two of these compounds that I think are going to help our patients very much, because they are oral and because they’re going to allow us to actually take a lower-intensity approach without coming in so many days during the month for the therapy. There is a revolution on treatments, and these treatments may be easier to receive and more patient-friendly. This is going to be a major breakthrough for our patients.

We believe that a lot of these are some type of combination where it’s not just one drug or the other. You may see combinations of all these compounds helping our patients and hopefully, at some point, transforming and improving their survival. Thank you for that, Hetty.

 Exciting things are to come in the upcoming years with regard to what therapies we might use in the up-front setting in ways that are different from the current state of affairs. Combination therapies are likely to emerge for patients with MDS, inclusive of some of the targets for the mutations on the blasts or the cancer cells themselves. They then allow for combinations with the backbones of therapy that we use. We have specific agents that are going to be targeting 

. Many of us in this space of MDS and AML [acute myeloid leukemia] are very excited about some of these 

 modulators that may be used in combination with hypomethylating-based therapy. Those studies are soon to emerge as well.

There are exciting things that are ongoing in the clinical trial space. There’s a lot of hope for the future for our patients with MDS, even with higher-risk MDS. It’s important, exciting, and at the forefront of research.

Possible Treatment Options for Myelodysplastic Syndromes

 I really appreciate your comments and you encouraging patients to enroll in clinical trials, because the clinical trials really lead to new drugs being FDA approved, like with luspatercept, and it’s very exciting. Can you share with me what your experience with luspatercept has been? When might you consider increasing the dose?As you’ve managed patients with this new drug, has there been a cut-off time due to a lack of response? What toxicities should patients be aware of with luspatercept?

 This drug is an injectable compound that you give every 3 weeks. The audience needs to realize that these ESAs [erythropoietin-stimulating agents] have been with us for 25 years or so—almost since I was a student. They’re basically imprinted in the practice of doctors. It’s not that they are good drugs or bad drugs or that we don’t know to use them. They are actually very important compounds that help a lot of our patients. But eventually, they either stop working or they do not work, and we know when that’s going to happen. Right now, luspatercept is used when these ESAs don’t work or with some patients for whom we can predict.

We’ve learned a number of things. Because it’s a new drug, we’re phasing in to what I’m about to say. We know that luspatercept works better in patients that have fewer transfusions. That’s why it’s so important for the physicians to realize that, at some point, you need to transition from a traditional ESA to luspatercept. I am not at all advocating to stop the ESA if it’s working to go for this other new drug. But we know that if the patient becomes transfusion dependent and is not responding to the ESA, we should probably consider transitioning earlier because that’s when you have a greater chance of response to this new compound.

Similar to the ESAs, based on algorithm, you could increase the dose that is based on the weight of the patient if you don’t see a response. This is described very well in the drug insert. If you don’t see an improvement in transfusions after a few weeks, you may ask the doctor if the dose should be increased.

These are not chemotherapies, so they don’t have the kind of toxicity that everybody associates with that kind of treatment, but luspatercept can have some side effects. In particular, I have seen in my practice that sometimes the patients may experience fatigue. This is important because the whole goal of the treatment is to improve the hemoglobin, improve quality of life, and have more energy. Unfortunately, some of our patients sometimes complain of feeling a little fatigued with this compound. It’s critical with this disease, and any other disease, that you describe the expectations up front every time you introduce a new drug, so you won’t have poor adherence or misunderstanding in terms of what the compound will do. I don’t think any fatalities have been reported from this drug. But fatigue is something I have seen in my patients. I don’t know about your experience, Hetty.

 So far, it’s been pretty well tolerated. You’re also struggling to come up with some heavy toxicity, and I think that’s teaching us that people tend to be tolerating it well. I do think it matters to escalate the therapy as you go through, and if the therapy isn’t helping patients, to be mindful of stopping it at those same time points that we talked about with ESA-based therapy. The every-three-week administration is nice for patients, although many of them, if they’re transfusion requiring, need to come and have their counts checked anyway. But from that standpoint, the administration is pretty straightforward for patients and the toxicities are pretty well managed.

 It’s a simple injection. You are right, the three weeks doesn’t mean that they may not require some checking in between, unfortunately.

Luspatercept in the Treatment of Myelodysplastic Syndromes

As we’ve talked about, the things we’re focusing on have been supportive measures to help decrease transfusion requirements, but ESA [erythropoiesis-stimulating agents]–based therapies are really not addressing the underlying disease. You smartly started with hypomethylating therapies and other agents in the high-risk category, where we try to modulate the disease rather than just treat a cytopenia. If I’m not mistaken, that’s what you were probably alluding to.

 You brought up a very important point: These bone marrows change in time. The blasts, chromosomes, and mutations can all change, so it’s crucial for the patients and audience to realize that, through the course of this disease, you may need to repeat a bone marrow test in addition to all the tests we were talking about earlier to know exactly where you are.

Hetty, you were talking about a new compound and new therapies for second-line treatment of anemia in patients with MDS [myelodysplastic syndromes]. You were saying that this was the first drug approved after 14 or 15 years. The study that led to that approval was called the MEDALIST trial. Perhaps you can teach us about the study and what we found.

 Earlier, you talked a little about this new agent, luspatercept, that was FDA approved. This agent is what we call a ligand trap. It works to inhibit the TGF-beta superfamily, which allows for the maturation of the red blood cell or the erythrocyte. This is a very special drug. In the first study, the PACE-MDS study, there were low or intermediate-1 MDS patients who were no longer responsive to this ESA-based therapy. We found that those patients were more likely to respond to luspatercept if they had the presence of ring sideroblasts or an 

 mutation. In the PACE study, they found that about 70% of patients with ring sideroblasts had an erythroid hematologic improvement, and about 40% of patients had transfusion independence with regard to red blood cell transfusions. The same numbers, in general, held true whether those patients had the presence of ring sideroblasts or an 

We became very interested in patients who had ring sideroblasts or 

 mutations. That led to the MEDALIST study, which was a phase 3 study looking at these lower-risk MDS patients with the presence of ring sideroblasts. They found that about 40% of patients in the luspatercept arm achieved transfusion independence, and about 50% of patients in the luspatercept arm achieved erythroid hematologic improvement. Of those patients who were treated with luspatercept and had a nice response, about 93% harbor this 

 mutation. The promising transfusion independence rates and the promising improvements in the erythroid line with regard to hematologic improvement led to the FDA approval of luspatercept for this specific patient population.

Patients who were enrolled in this MEDALIST study had previously received ESA-based therapy and were no longer responding to it, along with patients who were not likely to respond to ESA-based therapy. The question has become whether we can give luspatercept to patients in the up-front setting prior to them even receiving an ESA-based therapy. That led to the COMMANDS study, which we were alluding to earlier, to further answer that question.

 That was excellent. This study was transformative for us in the field for multiple reasons. We had not been able to approve a drug in 14 or 15 years, and that’s not because we were not working. We were working extremely hard. A lot of laboratories learned about the research, the mutations, and the biology of this disease. People like you and me did a lot of clinical trials to find better treatments. The reality is that the FDA had a very strict threshold for showing treatment that improved survival, which was difficult because of the heterogeneity of this disease. Eventually, they agreed that other things were also important, like the reduction in transfusions in the MEDALIST trial. That was a breakthrough moment to me because the authorities, the FDA, started looking at other aspects of this disease. Thanks to that, I believe we’re going to see many other agents approved for our patients. It’s important to realize how important it is to participate in a clinical trial.

I totally agree with you about luspatercept. It’s a drug that was approved for this specific type of MDS for all the reasons you were saying, but I believe it should have a broader role with this condition. The COMMANDS trial that you were mentioning is critical. This is a study for patients with earlier-stage disease, where the doctor is probably going to use an ESA. If someone is listening who is going through this transition, please ask your doctor about the COMMANDS trial. We need to get this data out because we strongly believe that drugs like luspatercept work even better if we use them early in the course of the disease. With the MEDALIST trial, we saw that patients who had fewer transfusions—let’s say less than four—had a much higher rate of transfusion independency and that the duration of those responses was significantly longer.

We see that this drug could be combined with multiple other compounds because the toxicity profile is quite acceptable. It’s a biological agent as you were describing, so we see trials combining it with lenalidomide, with growth factors, and even with these low forms of chemotherapy that we call the hypomethylating agents. So we were very excited about the approval of this compound. We were also very excited that results of this trial were published as the No. 1 poster in our annual hematology meeting and then published in the 

, which is the top journal in medicine. That was a major thing for a small field that doesn’t usually get this kind of notoriety. It was a combined collective effort from many hospitals all over the world, so it was beautiful to see and has been a major breakthrough for our patients.

Understanding the MEDALIST Trial

 Hetty, let me ask you a question if you don’t mind. Now that we’re talking about the incorporation of these agents, how do you measure the response? How long do you wait for the therapy to show any evidence of activity?

 For the ESA [erythropoiesis-stimulating agent]-based therapy, we’ll typically keep our patients on ESA therapy for about eight to 12 weeks. I tend to favor closer to 12 weeks to make sure we’re giving people a fair shot at staying on this therapy before we evaluate for a decrease in the number of transfusions that our patients are requiring, or an increase in their hemoglobin by 1.5 g/dL. Those are things that we look at to measure our patients having an improvement in their hemoglobin criteria with these agents, and if they are, we then can continue them on these therapies.

It is important because patients can end up on these therapies for a very long time, not benefiting from them, and then they’re incurring toxicity without having benefit. Equally important with knowing when to start a therapy is when to stop if it’s not helping your patients. That’s one piece of information that patients and caregivers should be aware of. It’s OK to ask, “Should I still be on this therapy? Is it helping me?” And if it is, then of course, we want to keep you on it. But if it isn’t, then we need to move to the next option in terms of therapies.

 Can you describe the threshold for transfusion of red blood cells and how you do that? Also, what is the impact of these transfusions or therapies in terms of the quality of life? Can you go over the toxicity a little bit? What are the levels of hemoglobin for transfusion? This is something that is very obvious to us, but that’s the first question my patients ask. Talk a little bit about quality of life and toxicities.

 We alluded to the goals of therapy for patients with MDS [myelodysplastic syndromes] and as you mentioned, many of our patients are older. If they have comorbidities, some patients can’t consider curative therapy with a bone marrow transplant, and we find ourselves in an area where our goals of care are to improve quality of life and delay progression of disease. In that setting, many of my patients tend to be symptomatic in terms of increased fatigue, increased shortness of breath, and decreased ability to do the activities that bring them joy. With a hemoglobin level less than 8.0 g/dL, people are typically symptomatic with increased shortness of breath with exertion, going to the store, or doing other activities around the house, such as gardening, and spending time with family. For many of our patients, if the hemoglobin level is less than 8.0 g/dL, we offer transfusion of packed red blood cells.

In this time of COVID-19 [coronavirus disease 2019], we’ve had to restrict the amount of transfusions for some patients. Sometimes that threshold has gone down to as low as less than 7.0 rather than less than 8.0 g/dL. Some of my older patients with comorbidities, such as COPD [chronic obstructive pulmonary disease], heart failure, or CHF [congestive heart failure], have needed transfusions sooner—so with a hemoglobin of less than 8.5 g/dL. Having patients who are symptomatic can change that parameter, and many of our patients know when that is. But we try to standardize our practice across our enterprise here at the Cleveland Clinic, and having a hemoglobin level of less than 8.0 g/dL is where we typically land for offering transfusion support.

With regard to platelets, we try not to give patients platelets because of the development of antibodies. We want them to have platelets that are useful if they are, in fact, having bleeding. If they’re symptomatic with bleeding events, then often we will offer platelet transfusion support, and it can be incredibly scary as you talked about. The risk of bleeding for patients with low platelets remains a challenge, but we try not to offer transfusions just to fix a number.

In patients with issues with neutropenia, where patients can be neutropenic but not have frequent infections, we don’t tend to do too much to boost that neutrophil count with G-CSF [granulocyte colony-stimulating factor]. If they’re not having active infections, you have to treat the patient, not the number. I always come back to talking with my patient about how they’re feeling, what’s going on, and if the trajectory of their quality of life has changed in any way to dictate how we’re moving forward.

 Something that I see in my practice is the patient may not be benefiting any more from the ESA, yet they continue on therapy. Of course, in general, these drugs are not very toxic, although they have financial toxicity that I don’t know if patients or doctors realize. But I will see patients who for many months have been on this therapy when they really fail. Sometimes the doctors are already using some other treatments but they continue with the ESA. Can you tell us a little bit about failure—specifically of these ESAs—and when you would consider a second-line type of compound, such as luspatercept, for these patients?

 These agents, ESAs, can fail patients. It’s really the agents that we’re using that can no longer add benefit to patients. If patients have been on these ESA-based therapies for four months and they’re still transfusion dependent, there can be toxicities from ESA-based therapy, including hypertension and even fluid retention. For some of those toxicities, it is important for patients to be aware of them.

I have had a number of patients who have been on ESA-based therapy and they’re not benefiting from them. They’re still transfusion-dependent, just as much as they were before they started the therapy. At that point, it’s important to address that they’ve been on these therapies, at times increasing the dose of that ESA, and they’ve been on that increased dose of ESA-based therapy for some time, and their transfusion dependence has not gone down. In fact, for some patients, it goes up. In those scenarios, it’s very reasonable to stop ESA-based therapy. For some of those patients, you just need to give them a break. Even if we don’t have everything perfectly lined up for the next therapy, stopping the ESA-based therapy is OK because it’s probably only adding toxicity and not adding benefit.

Talking about what the next steps are for therapy are inclusive of the exact things that you talked about, like lenalidomide for patients, or even luspatercept if it’s appropriate. For some patients, not only are they having increased transfusion requirements, but there may be other things going on, such as a decreasing platelet count or a decreasing neutrophil count. If we’ve gone from a single line, like if it’s anemia, to other lines being more affected with cytopenia, such as a lowering platelet count or a lowering neutrophil count, that would be a time where we need to readdress and potentially repeat a bone marrow biopsy to reevaluate what’s going on in the blast population and see if there’s progression of disease. If there is, we may need to change the therapy altogether, moving to a higher-risk paradigm such as a hypomethylating-based therapy and address potential progression of disease.

Treatment Goals in Myelodysplastic Syndromes

 Let’s talk a little bit about the patients with lower-risk MDS [myelodysplastic syndromes]. What kinds of therapies might be available to a patient, particularly if they present with an isolated anemia or low hemoglobin? What should they be asking you or thinking about?

 Thank you, Hetty. First of all, I think around 60% of patients with MDS will first present in a lower-risk category. What you do first is look at the bone marrow test, of course, but let’s go one by one. The first line of therapy for someone who just has anemia may be a drug that stimulates red blood cell production. We call those agents erythropoiesis-stimulating agents, or ESAs, and there are a couple of them that can be very effective in the correct subset. We measure something in the blood of the patient called the erythropoietin level, and if that’s low, the patient will most likely respond to ESAs. Those drugs are biological agents. They are actually a hormone that we have in our own body, and they help stimulate the bone marrow to produce red cells.

For the low white blood cell count, my experience is that when it’s isolated, patients can do well for a long time and they don’t really have an increased risk of infection. That’s a small subset of patients. What I find more problematic is when the patient presents with low platelets, particularly if they are really low. When it’s below 30,000, you may be in a situation where you have a spontaneous bleed, and that could be fatal. There are no good agents that stimulate these platelets in the bone marrow. Sometimes we use compounds that we use for other disorders, like ITP [immune thrombocytopenic purpura], but they don’t really work for most patients. So we sometimes consider some very low form of chemotherapy, the hypomethylating agents, for patients who may have anemia with very significant low platelets or thrombocytopenia.

There’s a relatively small group of patients where the therapy is very effective. These patients have anemia, but with a particular chromosomal alteration is called 5q minus, or an alteration of chromosome 5. There is an agent called lenalidomide that is extremely effective. It’s an oral agent, has been approved for many years, and can be very effective for a long time in patients with this particular alteration.

This year, we saw the approval of a new drug for patients with myelodysplastic syndrome. This drug, known as luspatercept, was the first drug that got approved in 14 or 15 years. This is a drug that modulates something we call TGF-beta [transforming growth factor-beta], that basically is involved in the generation of these red cells, so it’s effective in patients with anemia. Right now, the drug is used for a specific subset of MDS called refractory anemia with ring sideroblasts with patients who have already been treated with erythropoiesis-stimulating agents. We are also testing that particular drug in an upfront clinical trial as the first drug to be used for patients with anemia.

There are supportive care issues that are critical. Sometimes we consider prophylactic antibiotics for some of these patients. Of course, transfusional support is very important. Now with COVID-19 [coronavirus disease 2019], we have fewer donors, and this is sometimes challenging in our practices. There’s been some controversy in terms of the use of chelation therapy, meaning treatments to remove iron from our patients. But a paper that was published a few months ago suggested that there’s some benefit in terms of survival for some patients who have high iron levels.

And finally, there is a specific subset of patients with we call hypoplastic MDS. These patients sometimes share some features with a related disease called aplastic anemia, and they may benefit from immune therapy with a treatment called ATG [antithymocyte globulin]. This is an immune-based treatment that can be effective in patients with hypoplastic MDS, which resembles aplastic anemia. I’m not sure about the Cleveland Clinic, but some of the groups may use ATG-based therapy in some other subsets of patients that we know may be responsive to this compound. But this is basically the approach. Very rarely do we consider transplant in low-risk disease—the mortality and toxicity is way too high. We may consider a transplant as a second- or third-line approach in younger patients who are not responding or have lost benefit to whatever early therapy we have for lower-risk disease. Hetty, do you do something different or in addition at the Cleveland Clinic?

 You gracefully walked through all of the options that are out there when we think about a patient with a lower-risk MDS. Certainly in the upfront setting, much of what we start with is the ESA-based therapy to help reverse or support transfusion dependence in somebody who has low hemoglobin. These therapies are well tolerated. The duration of response for some of these patients can be longer than a year, particularly if they have a low erythropoietin level or low serum erythropoietin level, which is a laboratory value that we check by looking at the blood. Also, if they have a low transfusion burden, those two pieces together help us predict whether somebody has a higher or lower likelihood of responding to ESA-based therapy.

Some of those molecular mutation tests from the NGS [next-generation sequencing] testing can also give us some clue as to whether people are more likely to have a durable response. You alluded to those patients with refractory anemia with ring sideroblasts, and patients who have that particular finding on their bone marrow aspirate more often have a mutation called SF3B1. We’ve learned that those patients respond quite nicely to a new agent that was FDA-approved called luspatercept. This was a pretty exciting thing this year. This is the first time in a long time that we’ve had newer agents approved for patients with MDS, such as luspatercept. I recall when AZA [azacitidine] and decitabine were FDA-approved in 2004, 2006, and we’ve waited a long time for another agent to be approved. That was huge this year. We’re now investigating this agent, luspatercept, in the upfront setting to better understand if this is an agent that we should use before we even consider using ESA-based therapy. I’m eagerly awaiting the results of that study as well.

Therapy Options in Low-Risk Myelodysplastic Syndromes

 Let’s briefly switch to therapy for MDS [myelodysplastic syndromes] as a topic, now that we’ve covered the presentation of MDS and some of the things that we use in terms of testing and diagnosis. Can you talk about some of the first-line treatment options for patients with MDS and what type of patient might be in that first line of therapy?

 Before we go into that, I think the key factor is to briefly discuss the prognostic systems, because that’s basically how we then think of therapy. There are two scoring systems used simultaneously. One is an older scoring system that we call the IPSS [International Prognostic Scoring System], and a more recent one called the IPSS-R [Revised International Prognostic Scoring System] that is almost 10 years old. Using these two classifications, we can divide patients into lower-risk or higher-risk categories. If it’s IPSS lower, it’s low and intermediate-1; high is intermediate-2 and high. If you’re using IPSS-R, it’s a little bit more complicated because it has five categories. What we call very low/low is lower risk. High/very high is higher risk. Then there is the intermediate subset, which we tend to break it into two: low/intermediate and high/intermediate. That’s a little bit complicated. That’s why the IPSS is still better, and we’re looking for molecular classification to help us. The bottom line is that you will divide patients into lower and higher categories.

The other thing that you look at is the age of the patient, because most patients are older than 70. The median age is around 72 or 73 years, but we see patients in their 50s and 60s, so it’s not that this cannot happen to even kids in some particular situations. So you look at their age, the risk by the IPSS, and you also look at comorbidities. Does the patient have some other comorbidity, such as cardiovascular disease, diabetes, or what have you? Then you put all of that together. For lower risk, where traditionally the goal may be in improving cytopenias, the goal is to make the anemia better and see if we can increase the platelet count. It’s not so much about being aggressive in terms of curing this disease, because lower-risk disease for many patients can be something that takes many years to become problematic.

I believe there are some patients with lower-risk disease where prevention is really important. This is not prevention per se, but the question is if it’s possible that there are some patients with lower-risk MDS for whom you can predict a more aggressive behavior, where perhaps an early, slightly more aggressive type of therapy could be considered. Then you have the patients with the higher-risk disease. This now requires more aggressive treatment because some of these cases can transform to acute leukemia, or more frequently, have major complications from the myelodysplastic syndrome itself, such as infections or bleeding. This, unfortunately, can cause the death of the patient.

So the question is deciding which type of chemotherapy to use. Traditionally, most patients are treated with a low-intensity type of chemotherapy with drugs that we call hypomethylating agents, such as azacitidine or decitabine. Some patients who are younger or have particular chromosomes or mutations may be candidates for more intensive therapy, like treatment for acute myelogenous leukemia. Likely for some of the patients with high-risk disease, the way to cure this disorder is to proceed with an allogeneic stem cell transplantation. That’s a very aggressive procedure that requires donors, and also requires probably younger patients who are able to sustain and survive that type of procedure. That is the thought process that we go with on our first visit: lower or high risk, age, the cytogenetics, and molecular classification; because with all this information, we can then map the more appropriate approach in terms of therapy.

 That was beautiful in terms of clarifying. We use these prognostic scoring systems: the IPSS, which is the International Prognostic Scoring System, or the IPSS-R, which is the Revised International Prognostic Scoring System, and Dr. Garcia-Manero just went through the way we use those tools to get a score that helps us to identify each patient as having lower-risk MDS or higher-risk MDS. Once we know that classification in terms of score, that helps us understand if this particular MDS is at high risk of progression to an acute myeloid leukemia. If it is, it classically sits in this high-risk or higher-risk MDS category, and we want to move forward to recommend interventions, such as chemotherapy with hypomethylating agents, to delay the time to progression to leukemia. We potentially even talk about a curative therapy, such as a bone marrow transplant, for those who qualify for such an aggressive therapy.

Obviously, the treatment goals for patients with a diagnosis of MDS include trying to cure the disease, such as through a transplant, to improve the overall survival, and lower the risk of transformation to leukemia. We also hope to get the disease under control such that there’s better production, if you will, from that bone marrow factory where you have normalization of counts such as the hemoglobin, the platelet count, and the neutrophils. For those patients who have issues with counts being low, manyneed and require transfusion support. So doing things to decrease the need for transfusion support can also be very meaningful for patients in terms of their quality of life. It means that they spend less time at the hospital or in the clinic. If they have issues with frequent infections because of low counts, if we can have normalization of the counts, that can decrease their risk of infection and problems in terms of quality of life.

We’ve talked a lot about the higher-risk MDS category, and I’m sure we’ll talk more about the therapies for the high-risk category.

Treatment Approach in Myelodysplastic Syndromes

 I think the biggest message is that, at the time of diagnosis, we recommend sending off a mutation test called a next-generation sequencing test, or NGS testing. By and large, my experience is that most any patient that goes through a bone marrow biopsy is having next-generation sequencing done, and it can take two to three weeks to get that information. It may not be something you hear about at the time of diagnosis, but after two or three weeks, that information should come back and your doctor should go over it. Sometimes, it can come back after such a long time that it’s lost in the shuffle. It’s one of those things where you really want to make sure you get that information from your physician and talk about the results for the mutation testing.

I would agree that the reasons it’s helpful are threefold as Guillermo just talked about. It’s helpful for prognostication, in terms of whether it’s TP53

 which is a gene that is more worrisome for a disease that can be refractory to therapy and quickly progress to a more aggressive kind of cancer called acute myeloid leukemia. The predictive use is helpful in terms of if the MDS [myelodysplastic syndromes] will be more likely to respond to specific types of therapies. We’ll talk about that in relation to agents including luspatercept. It’s even helpful with germline predisposition.

Although it’s rare, this is a very exciting area of research, and many of us are interested in better understanding why it is that certain patients have MDS or succumb to MDS at some point, whether it’s a treatment-related MDS or something that happened out of the blue, and if there is some biological rationale for why some patients get this versus others. Our understanding is that the genetic or germline predisposition to MDS is incredibly rare, but we want to understand the underpinnings of the disease and those familial situations so that we have a better handle on the disease in and of itself and how best to treat it or even potentially prevent it. Prevention is the dream for many of us who spend our lives invested in managing and treating this disorder.

NGS in Myelodysplastic Syndromes

 We didn’t go through all the details of the cytogenetic testing, and I’m not sure we need to other than to say that there are specific types of chromosomal aberrations that put somebody at higher risk and at lower risk.

Do you describe MDS [myelodysplastic syndrome] in any other way to your patients? Tell me a little more about how you walk them through.

 What you just said is exactly what I do. Going back to COVID-19, there’s always something a little good that happens after a bad thing, like how we’ve been better about telehealth visits. I don’t know how it is at the Cleveland Clinic, but it takes us a little less than a week to get the chromosome and molecular tests. The morphology we get in one day. Many times, patients who have lower-risk disease go home, and then a week later I set up a telehealth visit. A good part is that we finally have the ability to do this.

Then I joke with the patients. When they are with me in the clinic, I go over a piece of paper about how it’s like a factory, as you said. Then I tell them, “When I call you, you need to ask me back this question. You’re going to examine me.” I’ll say, “These are the three questions. What is the percentage of blasts? What are the chromosomes? What are my mutations? What were the cytopenias?” When I call back, I say, “Do you have the piece of paper with you?” Sometimes they don’t, so you need to look for it. That is key because you have to enable those patients to have that information. They need to understand what the characteristics are and how you’re going to score this disease and make these decisions. I find that extremely important. So I do exactly as you said, and I use the same analogy, but the key is for them to understand what the parameters are because, of course, when we go back through the therapy later, you’re going to look to see if those blasts improve or if the chromosomes change. So the patients and families really need to understand that. In my practice, I follow exactly what you do.

 I’m curious to hear a little more. We are doing this next-generation sequencing testing, and you talked about MRD [minimal residual disease]. Tell me how you walk them through the mutation testing and what you say, even at the time of diagnosis, with regard to that information?

 This is a complex conversation, and maybe you can teach me the right word, because when you talk about genetic testing, people who have children immediately worry about their children and their family. It’s almost universal, that even before we have the genetic testing, the patients will ask, “Is this a family thing? Is this a genetic thing?” I always used to say, “No, this is very rare.” But now we know that there’s some relevance.

The first issue is the terminology. If you start using the word 

, you have to immediately explain that you’re talking about a mutation on a gene and not something you carry. That can be, particularly with older patients, a little complex to explain germline mutations versus somatic mutations. I tell them that just because these are genes that may be mutated or affected doesn’t mean this runs in your family.

I explain that there are a set of genes that are commonly mutated, that we test for them, and that this just has, in our practice, two different values. One is that although there are no formal molecular classifications of this disease—we know that one hopefully will be coming—at the bottom line, we use this to add information that allows us to prognosticate this disease. For instance, if you have a 

 gene mutated, the course of this disease will most likely be more aggressive and possibly more difficult to treat. If you have a gene called 

, in the right context, this could be something that could be associated with a slow-growing disease that may not cause problems for many years. I also tell them that we are now using genetic or genomic information to decide on therapy more often. If you have an 

 mutation, we may be more inclined to use drugs. Those are rare, but probably 30 or 40 percent of patients benefit from some type of targeted approach based on these pieces of genetic information.

What I see from patients who come to see me is that those genetic tests are being incorporated by most hematologists who do a bone marrow test. The community, once they do the bone marrow, now know what to order: the cytogenetics. I don’t know if you remember, but when you and I started practicing, it would be very common that there would be no chromosome test on the bone marrow, and you would have to repeat the bone marrow just to get that. This improved, and now these genetic tests are added to most of our patients when they come for a second opinion. Sometimes they come faster than the cytogenetic test. So that’s an important discussion. But this issue of what is familial genetic versus not sometimes gets a little complicated to explain.

Risk Assessment & Genetic Testing in Myelodysplastic Syndromes

 One of the things I find really interesting is that for many of our patients, we look at their differential. For patients who have a monocytosis or have had a monocytosis for a number of months, it can be something that is evasive and has been present for many months but hasn’t been noticed by the primary care doctor. Can you talk about the presence of monocytosis and how that factors into the work-up for a patient with MDS [myelodysplastic syndrome] and what you do with that information?

 It is a very important issue. When we say you look at the CBC [complete blood count], it’s simple but a little more complex than just looking at those three parameters. Many times, before we go to the monocytes, the clue is just looking at the MCV [mean corpuscular volume], this parameter in the CBC that lets you see how big or small those cells are, and that is already potentially an indicator of what may be happening in that bone marrow. Most patients with MDS have an increased MCV value.

This is totally anecdotal, if you’ll allow me two seconds. I’ve had a very interesting patient for many years who has a type of leukemia that is very easy to cure. He and his wife are engineers who work for a company that makes them do a yearly blood analysis. He’s very smart. He asked me to look at why the MCV, in a totally normal CBC, has increased substantially over 20 years. I said, “I don’t know.” But his wife had very early stage low-risk myelodysplastic syndrome. There is no indication for therapy. But I was fascinated to see the value go from the 70s to 110 fL over 20 years. I expect that the doctors may sometimes miss this.

The monocyte is really important because when you look at the differential, you are looking to see if the neutrophil count is decreased, and sometimes you may see some blasts. These are kind of leukemic cells. But in a subset of patients, we see this increase in the cells that are monocytes, and that can be seen in a disorder that we call chronic myelomonocytic leukemia, or CMML. Until very recently, we used to consider this a subtype of MDS.

Today this is considered a different entity, but it shares a lot of the same characteristics and thought process that we use in myelodysplastic syndrome, although the disease can have a different behavior. Sometimes those patients may present more with inflammatory types of symptoms or with a little fever, night sweats, or lack of appetite. This is a rare condition that we approach a little differently from myelodysplastic syndrome, but you could see it by this growing number of cells.

You need to understand that it’s not the percentage that you look for. You actually look at the absolute number of these cells. Sometimes people say, “Oh, this percentage is off.” But the number is actually normal. The CBC can provide a lot of information if you pay attention to it.

 I love your story about families and patients or caregivers paying attention to all the details of that information. That does allow them to have a better handle on what things mean and which things are important, particularly at the time of diagnosis but even as we manage their MDS over time.

 Hetty, let me emphasize this. This is crucial, particularly in this COVID-19 time. A few years ago, one of my really dear patients was a very intelligent man who was a very accomplished lawyer. We had to admit him to the hospital because he required a more intensive therapy. I was rounding on the patient that month, and almost every day we talked about how we were looking at the end of the month for the percentage of blasts and minimal residual disease.

At the end of the month, we did the bone marrow test, and he was MRD [minimal residual disease] negative. I was so excited. He was living in the hotel attached to The University of Texas MD Anderson Cancer Center, and I called him. I told him he was MRD negative, and he went silent. “What’s happening?” he asked. “Doctor, I don’t understand what you’re saying.” I told him, “This is because my accent is so bad.” He said, “No, no. I don’t know what MRD means.” I said, “But I’ve explained to you almost daily that this is what we were looking for.” So I said, “Let’s meet together.” This is two seconds from my research office. He said, “When you are in that room, we pretend that we understand, but 90 percent flows over. We’re so stressed and this is so difficult that things that are very easy for you are extremely complex for us.” And this was a patient with incredible intellect.

That was one time that I was really shocked by this because things like the MCV or monocytes are very simple. Our patients tend to be older, and when they come to this clinic by themselves without support, this is critical. For years, I’ve tried to make sure that the family somehow is there or on the phone, on FaceTime. You need to make sure that you have an extra set of eyes and ears listening to these conversations because this is very complex, and sometimes it is not that easy to convey whatever message you are giving. This is now becoming crucial. With COVID, the way we’re practicing is going to stay with us for a long period of time—at least the coming year—so we need to make a big effort to communicate better with our patients because this is a really complex set of disorders. So your question is right on target.

 Thank you for that story. I think it can be overwhelming for patients and for caregivers to try to wrap their heads around this big word, 

, because it’s such a medical term. Typically, when I’m describing to patients, I try to explain to them that it’s really that this bone marrow is a factory in making three cell lines: white blood cells, red blood cells, and platelets. In the bone marrow factory itself, there’s an issue with quality control. It’s an issue of quantity and quality.

There is a decreased production of cells, whether it’s the red blood cells, the white blood cells, or the platelets, and also a decrease in terms of the quality or functioning of those cells. For example, the majority of patients present with anemia. In that setting, those red blood cells are made at lower numbers, and the red blood cells that are there are just not as good with their oxygen-carrying capacity as a normal red blood cell. That combination of both those entities, quantity and quality, lead to many of the symptoms that patients with myelodysplastic syndromes have.

There are different ways we can look at these cells, both in quantity and quality. When we talk about these numbers, and as we eventually continue to manage patients, they begin to realize what the numbers are that we’re looking at, why we are looking at them, and why we are focusing on them in terms of this bone marrow factory. Ultimately, the data that we collect and go over repeatedly really matter.

Within the diagnosis of MDS, we were talking a little about that bone marrow aspirate and how the chromosome tests help us identify what chromosomes might put a patient at higher risk of progression to leukemia versus somebody that may be less at risk. Some of those details—with regard to the number of cell lines affected, the types of chromosomes changed, and the blast population, or the percentage of leukemia cells—ultimately help us clarify the risk for a patient with MDS, whether it’s a lower or higher risk.

Monocytosis in Myelodysplastic Syndromes

 When this happens, what is the standard work-up for myelodysplastic syndrome [MDS] that you recommend for patients with MDS that may help your colleagues in the region?

 The standard first test is to do a simple CBC [complete blood count]. That is going to tell you if you have a low white blood cell count, if you have anemia—the most common feature that we see in our patients—or if you have low platelets, something that we refer to as thrombocytopenia. Seeing that will prompt a number of secondary tests. You will test to see if there’s a reason for the anemia, looking for iron deficiency, vitamin B12, and folate, for instance. Sometimes the patients will present with some inflammatory type of feature, so you might want to make sure there’s no connective tissue disorder or some type of infection.

The bottom line is that the patient will need a test we call a bone marrow examination. A bone marrow examination has two different procedures. In one, the bone marrow aspirate, we retrieve blood from inside the bone marrow cavity with a relatively thin needle. That’s where the stem cells of the bone marrow, which later create the blood, reside. The other test is a bone marrow biopsy, where we retrieve a little bit of bone from that area with a slightly thicker needle, and it allows us to look at the architecture of the bone marrow. Those two specimens allow us to look at the shape of the cells, which we call morphology. This is how we confirm the diagnosis, as do other tests such as the chromosome test and genomic analysis. Sometimes we use something called flow cytometry, which is another way to look at the shape, or paint the cells if you will, to confirm the diagnosis when we are in doubt.

This is very important because a number of years ago, we did an analysis here at The University of Texas MD Anderson Cancer Center that questioned whether we should do a bone marrow test on every patient that comes to our center. Like the Cleveland Clinic, MD Anderson is basically a referral hospital. To my surprise, we found a 15 to 20 percent discrepancy rate between the inside and outside tests. It’s not to say that the doctors outside Cleveland Clinic or MD Anderson don’t know how to perform these diagnostic procedures, but sometimes these diseases can be complex to diagnose. Sometimes the time from the original visit to the second visit makes the disease change. The bottom line is that a second look in our referral center results in changing the diagnosis and, often, the treatment in close to 20 percent of our patients. This is a key part of the assessment of our patients. When they come to see you for a second opinion, you need to confirm the diagnosis, the percentage of blasts, cytogenetics, and molecular alterations.

 I completely agree. The work-up for a patient with myelodysplastic syndrome is pretty complex, and we often get patients with their first diagnosis. But when patients come for a second opinion, we review the outside bone marrow biopsy if we can get it. That can be challenging because it takes so much time. There are occasions when we just repeat the bone marrow biopsy in order to make sure our diagnosis is at the same level. We’ll talk more about this in terms of the risk level for MDS.

But all the things you highlighted really do matter in assessing the state of the myelodysplastic syndrome for that individual patient. The bone marrow aspirate is a key component to understanding a patient’s inherent risk of progression to a more aggressive type of disorder such as leukemia, or even if there are certain features to the MDS that tell us if it will be a slower-progressing MDS. For all those reasons, it helps us guide therapy and some of the ultimate decisions that we come together to make.

We also do a lot of the same blood work that you talked about with regard to working up any inflammatory disorder. We look for other entities like LGL [large granular lymphocytic] and PNH [paroxysmal nocturnal hemoglobinuria] by blood work, and even an EPO [erythropoietin] level. We’ll talk about why that’s something we check for patients specifically if they have anemia as part of their presentation, which many of our patients with MDS do.

Work-up of Myelodysplastic Syndromes

®. I’m Dr. Carraway from the Cleveland Clinic, and I’d like to welcome my colleague, Dr. Guillermo Garcia-Manero from The University of Texas MD Anderson Cancer Center. Today we are going to discuss myelodysplastic syndromes, what a patient journey of this diagnosis looks like, as well as treatment, management, and novel agents in treating MDS [myelodysplastic syndrome] with anemia. Welcome, Dr. Garcia-Manero. Good morning.

 Good morning. Please call me Guillermo, Dr. Carraway.

 Let’s start with talking about the presentation of myelodysplastic syndrome. I’m going to start by launching the first question. Can you provide a brief overview of MDS for our patients and caregivers?

 Myelodysplastic syndrome, or MDS, represents a very heterogeneous group of disorders of the bone marrow. The disease is really diverse. It could range from a very indolent disorder, which may take many years to cause any problems for the patients, to very aggressive disease that could be as fast as acute leukemia. Basically, we use different classifications to determine these different subtypes, and we base our risk prognostic scoring system on a number of factors: things like the percentage of blasts, chromosomal abnormalities, and more recently genetic or molecular alterations that are really helping us determine the prognosis and type of therapy for our patients. It is crucial that when a patient is diagnosed with this condition, he or she understands the specific subtype and what the characteristics of the diagnosis are, because that’s going to make a major difference in terms of how we approach this disease.

 Are there any risk factors that patients or caregivers should know about with regard to being somebody that might be diagnosed with MDS?

Yes. Unfortunately, the major risk factor is something that we cannot avoid: age. This is a disease that is more frequent in older individuals, especially once you pass 70 years of age. We consider that a large majority of patients are suffering from disease because of the aging process in the stem cell in the bone marrow. There are some other risk factors. We know that there are some toxic exposures that could be associated with earlier development of these diseases. There are some patients with prior cancers who develop something we now call therapy-related leukemias or therapy-related MDS. These are patients who had other treatments for some other cancers. In my hospital, this is not uncommon in patients with myeloma or lymphoma who received an autologous stem cell transplant. Unfortunately, many years later, they can develop this secondary type of leukemia.

In the last few years, we have learned that there is some genetic background where this disease can be inherited through family through specific genes. Most hospitals that take care of these patients, like the Cleveland Clinic, already have genetic screening programs that are helping us identify this rare, but not infrequent, subset of patients who have a family history of these myelodysplastic syndromes. In summary, aging is the major risk factor for the vast majority, but exposure to chemicals, therapy-related disease, and—for some families—genes may predict development of this type of disease.

 That’s a fantastic overview. When patients typically present with MDS, what does that usually look like? When you see patients, how is it that they come to your attention?

 This has changed over the years, and I wonder if it’s the same thing at the Cleveland Clinic. Most recently, what we’re seeing is that on our routine follow-up for an annual physical examination or something like that, the primary care doctor or internist notices that the blood counts in the peripheral blood on a regular CBC [complete blood count] are a little abnormal. That triggers referral to a hematologist, who will then do a bone marrow test. That is the most common presentation here. It is not uncommon for the patient to present to the doctor because he or she is fatigued, has anemia, or notices some easy bruising possibly caused by the platelets being low. Sometimes, the patient presents with an unexplained infection that is a result of a low white blood cell count. But most of our patients are incidentally diagnosed at a regular checkup with a doctor. Things to look for would be fatigue, easy bruising, fever, and unexplained infection.

 That’s definitely been our experience as well, Guillermo: patients being identified because of an annual physical exam. Some patients that are active start to notice that during the normal routine things they always do regularly, they need to stop and rest. Those scenarios usually come to our attention, and then patients have an abnormal CBC and get worked up. All the things you’re describing are recapitulated with our experience at the Cleveland Clinic as well.

What is interesting is that if you ask the patients, many times the symptoms started just a few weeks before presentation. But sometimes patients will tell you they’ve had these symptoms for months or even a couple of years before they come. It can be so smoldering or indolent that some of these patients can have a very slow progression over a long period of time.

 I definitely agree. It’s pretty uncommon for patients to present with overt signs of the disease or active bleeding. Typically, when that happens, it’s a quicker pace, and that’s pretty infrequent. The majority of patients with myelodysplastic syndrome are going to land in the scenario where they’re at a lower risk of myelodysplastic syndrome, and we’re finding that there’s been this gradual onset of some issue with cytopenia, whether that’s a lower platelet count, a lower hemoglobin, or a lower white blood cell count.