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.

Guillermo Garcia-Manero, MD, MD Anderson Cancer Center

A Multidisciplinary Team in Treating Myelodysplastic Syndromes

Possible Treatment Options for Myelodysplastic Syndromes

Luspatercept in the Treatment of Myelodysplastic Syndromes

Understanding the MEDALIST Trial

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