First-Line and Second-Line Treatment Options for Lower-Risk MDS


Dr. Zeidan discusses first-line treatment options and the role of ESAs, while Dr. Savona reviews second-line treatment options and factors influencing treatment decisions in lower-risk MDS.

Dr. Michael Savona: So, with that in mind, knowing that we have low risk patients, sometimes we can observe, but sometimes we can't, we need to treat. Maybe Amer, you can talk a little bit about some of the options currently out there in the market for patients with low risk MDS.

Dr. Amer Zeidan: Yeah. Thanks, Mike. And I love your drone analogy. I might start using it, and I think it's important to remember a couple of things kind of you alluded to. One of them is that most patients have lower risk MDS, however, lower risk MDS is a cancer, and most patients die from MDS, not with MDS. And if you ask most patients, actually, what's your biggest worry when you have MDS? Most of the patients tell you they are concerned about progressing to acute myeloid leukemia. But in fact, that happens in less than one third of the patients. Most patients with MDS will not progress into acute leukemia. However, most of the patients, as I mentioned, still die from MDS. So those complications of anemia, thrombocytopenia, and neutropenia should not be really under managed. They should be managed aggressively because certainly they can limit survival. They can lead to a lot of comorbidities. And I think, for a long time, we've been always thinking about prognosis and how the risks ratify and we did not have a lot of therapeutic developments. But in the last few years, both on the lower and high risk MDS, there has been, I think, a very promising increase in the number of exciting agents. And we are going to talk about some in the next few minutes for lower risk MDS. But the traditional treatment has been and continues to be most commonly used as erythropoiesis stimulating agents, because 80% of lower risk MDS patients, the main problem is anemia. More than half of these patients have transfusion dependent anemia where they need regular transfusions. You can have isolated neutropenia or thrombocytopenia, but it's not common in patients with lower risk MDS. It tends to be more as part of the whole cytopenia that we see in high risk disease. So the most common approach is ESA's. So ESA's come in different versions. There, the short acting, and there's a long acting PROCRIT or RNS, those are given generally subcutaneously every one to three weeks. And effectiveness in inducing transfusion independence is around 40% if you take an unselected patient population. But that varies significantly based on whether the patient has a high EPO level or whether they are heavily transfusion dependent. Patients with high EPO level and heavy transfusion dependency more than two units per month. The chance of response is around 7%. It's very low chance, which justifies trying a different option if you have, for a long time we did not, but now we have. And this is why I think it's important to look at the erythropoietin level, which we actually have done some real life studies that showed many physicians don't even check the IPO level. They just start the patients right off on ESA's when the problem is anemia. So after ESA's failure, which is a common problem, because as I mentioned, only 40% respond, and those who respond, the average duration is 12 months to 18 months. So they will progress at one point. What other options do you might use in your practice as a second line treatment?

Dr. Michael Savona: Yeah, I agree that the majority of these folks, we will start on erythropoietin stimulating agents. And I really like the longer acting one simply because of quality of life and ease for the patients. But there are patients who just, they don't handle the long-acting like they do erythropoietin and so be it. I think that, the point you made is a good one. You really do need to check the EPO level in these patients. Once the patients become refractory erythropoietin, the question is, is there any way to work erythropoietin back into their schedule? And I think that's usually not the case. That usually, that when the refractory, with the exception of patients who are 5Q minus who are treated with erythropoietin, and then found out their 5Q minus then switched to lenalidomide and then become refractory lenalidomide, there is some data to indicate that maybe given erythropoietin and lenalidomide can rescue some of the response to lenalidomide. Although that's not quite as strong and as the data. I think now, the probably most pervasively used therapy is the luspatercept, which is not exactly TGF-beta but like that with this fusion active and receptor antibody where basically you're blocking the negative regulator of late erythropoiesis. And the nice thing about this is that unlike ESAs, where we can really drive people to hemoglobins that become dangerous with respect to thrombosis and there is risk of stimulation, of tumor cells that may be existing. I mean, back in the nineties, we learned that breast cancer patient kidney EPO had EPO receptors on some of their breast cancer cells. So this is part of the black box warning of with ESAs, but with luspatercept, there's really not to a danger that we have in creating clots by blocking this negative regulator. Luspatercept is a fairly effective drug. This has been shown first in patients with ring sideroblasts, but now has been used in all kinds of low risk patients. And I won't spend a lot of time going over the pace medalist and command study, but those are the three studies that you should know if you're interested in reading more about on the approval luspatercept and luspatercept is a drug that's given every three weeks. And it has about a third or so, or 40% of the patients can respond after they have failed erythropoietin stimulating, or if their EPO was just high to begin with. And it really works across all low risk MDS although the signals and pace that it worked in SF3B1 mutated ring centroblast patients was strongest. So that's why it was pursued in the original phase three study, the medalist study. My personal experience with Luspatercept as follows, I think that patients come referred from the community often on, one milligram per kilogram every three weeks. And they're starting to lose response and people have to remember that unlike the thalassemia dosing with luspatercept, you can dose up to 1.75 milligrams per kilogram with luspatercept, and people can really resurrect a response after losing that lower dose response. So that's an important take home point. And the other take home point is that the drug is relatively benign, but it does cause profound fatigue, at least in the beginning and a good number of patients, and enough that we have to stop the drug in some patients. Now, patients who continue after cycle one, they do OK. There is a reasonable side effect profile, but that fatigue can be really debilitating. You asked about other options and there's lots of clinical trials that Dr. Zeidan and I are involved in. So we won't really talk about those yet, the spice to say we're excited about some new things coming down the pike for low risk MDS. But as far as what's on the market, I sometimes use danazol. Danazol gets overlooked. Women don't like it because it causes some hirsutism, but in some patients, but in about one out of 10, one out of eight patients, it really can give a phenomenal response, and it's a fairly benign androgen worth trying. So those are the things I would say after the use of erythropoietin stimulating agents.

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