This has been a real eye-opener since we got to see the presentation yesterday. I think that it holds a lot of promise. I’m very excited that we potentially will have this option. I would be surprised if the FDA didn’t think this was a worthwhile therapy, but only time will tell. If that’s the case, to think that we can have almost 60% of patients who are no longer transfusion-dependent, almost 75% of patients that’ll have at least a benefit, if not becoming transfusion-independent, with a relatively safe safety profile there. There’s nothing better than that I think for this population of patients.

 I think it’s so promising. I do agree. I worry that there’s more patients on the study that are ring sideroblasts SF3B1-positive, so that data are fantastic and provocative. The remaining question is: Is that representative in general of our lower-risk MDS [myelodysplastic syndromes] population as a whole? The way that you’re framing it is 75% of people are going to have a response. I hope that’s the case, and hopefully we’ll get there to have that type of impact on our patients.

Looking at the different subsets has been looking at patients who were SF3B1-positive or -negative, those who had the higher or lower transfusion burden, the higher or lower under 500, of course, EPO [erythropoietin]levels, it seems like the luspatercept [Reblozyl] data was always better. Response rates always higher than the ESA [erythropoiesis-stimulating agent] data.

 It’s true for the ring sideroblasts-positive and the SF3B1 mutated. But for the patients that were ring sideroblasts-negative or SF3B1 unmutated, they had similar responses and some similar durability. We’re hopeful that all patients will benefit from this, and we’re hopeful that the FDA will really want to see all of the data when it’s fully mature, particularly the safety data as you talked about. We’re really excited about having a potential new option for patients with MDS.

I don’t think the FDA’s going to approve ring sideroblasts-negative patients, but hopefully they will see there were enough patients that were ring sideroblasts-positive to feel that this is a reasonable therapy to give us approval for.

 Although we use ESA-based therapies in the upfront management of patients with MDS, I am not sure that we really have an FDA-approved agent in that space. I think [it] is also really an exciting time.

I agree. No doubt about it. Being a hematologist oncologist today is an exciting field.

 I completely agree. It truly is humbling. And an honor to be in this field

I want to thank you, Dr Boccia, for this discussion. Before we conclude, I would like to get your closing thoughts on unmet needs and future perspectives in the field.

The unmet need is not still met. I think we would all agree that even with this very nice, statistically significant data that we still have further to go. I really am excited that we have the other options of we’ve got the HIF [hypoxia-inducible factor]inhibitors, we’ve got luspatercept [Reblozyl] and some other things coming along. And as we begin to further evaluate them and combine them, I think we have a bright future that certainly will push the envelope and bring us to a better and better state every year or so.

 Well, I think this data that we’ve talked about with the COMMANDS study [NCT03682536] is really exciting and promising. I’m looking forward to the role of imetelstat and looking at the data that have been presented here and the promising hematologic improvements that we see in patients with that agent, particularly in patients that have a high transfusion burden and nice responses. And so, two really exciting agents for lower-risk MDS patients. A high transfusion burden is really challenging, and it challenges our patients in terms of symptoms. Even in the high-risk MDS, which we didn’t even get to talk about today, there are ongoing phase 3 studies that we’re eagerly awaiting data for their final outcomes in the coming months to year. I’m hopeful that we’re inching forward to better outcomes for our patients and a better understanding of the pathogenesis of disease, particularly because of the molecular annotation that we’ve been able to do for our patients. I want to thank you and thank our viewing audience. We hope you found our 

 Insights discussion to be useful and valuable in the treatment of your patients with lower-risk MDS.

Videos

Expert oncologists discuss unmet needs and share final thoughts on the future of treatment of patients with lower-risk MDS.

Unmet Needs and Future Perspectives in Treatment of MDS

 Let’s talk about the management of our patients with low-risk MDS [myelodysplastic syndromes]. What might the future look like? If it was approved in the upfront setting, you could choose luspatercept [Reblozyl] or ESA [erythropoiesis-stimulating agent]-based therapy. How might you approach that with your patients in the future?

The first thing we do is sit down with a patient, talk about the drugs themselves, the cost of the drugs themselves, the dosing—meaning schedules and everything else. The potential adverse event effects and events for both of the drugs. Then, you make a decision jointly. It is very important today to have that conversation with patients in all aspects of the therapies that we offer. And this one in particular because there’s a new therapy that is soon to be available.

What excites me is the notion that as we bring new drugs closer to frontline therapies, what’s the next step? The next step might be pre-transfusion-dependent patients. The majority of the patients that we see with low-grade MDS are not transfusion-dependent when they walk through the door, but they are symptomatic. Using some of these newer therapies before the patient actually needs a transfusion and subs potentially switching from the old ESAs in that population of patients is an exciting idea. That, plus the knowledge of whether or not in a transfusion-dependent ring sideroblasts-negative patient, whether the luspatercept therapy is better than ESA therapy. Unfortunately, the data is way too immature. We don’t have enough patients to know that, but there is at least some possibilities based on the data that that might be the case.

 Can we bring some of these therapies earlier for patients and can that really impact the evolution of their disease and impact their quality of life? One of the challenges in this space is that previously patients were on or have been on ESA-based therapy and were often reluctant to take something away. How much of a challenge has that been for you?

I ask myself that same question every time. I typically will leave the patient on the ESA fearing that if I stop it, they will have more transfusion burden before they actually have the onset of action of the luspatercept.

 A lot of practices that do that same behavior. Every time we wonder if the therapies are actually helping or causing harm. Our patient populations are often older patients that have drug-drug interactions and/or trouble with hypertension. With regard to their medical history, that would be reasons for us to stop a therapy like ESA-based therapy if we think it’s not helping. If I am not convinced it’s helping them, I will stop it. We worry about stopping medicines, but if we have other options for patients, I think it’ll be interesting to see how some of the practices may change with regard to some of those behaviors.

 Exactly. I think the landscape for our patients with lower-risk MDS has really got a lot of promise. I’m looking forward to what emerges in the coming months to see the final outcome of this study and kind of the overall analysis and how it impacts our practice.

Ralph Boccia, MD, FACP, highlights emerging therapies and the importance of next-generation sequencing for patients with MDS.

Clinical Management of Patients with Lower-risk MDS

 There are other novel therapies that are being evaluated and presented here at ASCO [American Society of Clinical Oncology annual meeting]. Do you have any thoughts that you’d like to bring forth for discussion today with regard to that?

I think the combinations and the … agents are exciting. That’s where the field seems to be moving right now. I’m anxious to actually hear the presentations, but we have opened the door and we are now ready to step through and meet more of those unmet needs.

 Yeah. I would agree with that. You had mentioned earlier that in the management of your patients with MDS [myelodysplastic syndromes], you’re not always getting the mutational data on your patients. In light of some of the conversations that we were talking about with the COMMANDS study [NCT03682536] and the presence of ring sideroblasts or the presence of mutations like SF3B1, how important is it for your practice to get that mutational data. Will it impact your choice of upfront therapy, whether it’s [an] ESA [Erythropoiesis-stimulating agent] or luspatercept [Reblozyl], if luspatercept were approved in the upfront setting?

 I’m not quite sure. But we have been getting myeloid NGS [next-generation sequencing] on our patients for the last 4-5 years. I think that everyone needs to be doing that. I can remember probably 10 or 15 years ago having a patient come in who was anemic and had a del(5q) [deletion 5q]. I talked to them about what a great prognosis they were going to have and put them on lenalidomide [Revlimid].

Within 6 months, the patient died of acute leukemia.

We didn’t have next-gen [generation] sequencing then, but I can bet then they had an EVT6 [deletion], or RUNX1 or an ANXA1, or TP53 [mutation], or something like that, that if we had known that we would have started the process of thinking about disease modification and transplants sooner. We would’ve been prepared as soon as we saw anything evolving.

 With the IPSS-M [Molecular International Prognostic Scoring System], we get more information about how to pivot for our patients in ways that we wouldn’t have anticipated if we didn’t have the molecular information. I think the molecular information is a real important piece to the story. Even in patients that we see as second opinions. For some patients when we evaluate for ring sideroblasts, there can be a difference with regard to the bone marrow biopsy and who’s reading the bone marrow biopsy as to even if ring sideroblasts were reported on the marrow. So some of those pieces I think we’re going to be even more particular about as we look to the evaluation of all of our patients with MDS.

And now that we have drugs that work in that setting.

Expert oncologists discuss management strategies for patients with lower-risk MDS considering upcoming treatment options.

Emerging Therapies for Treatment of MDS

 I’m so pleased that you talked with us a little bit about the PACE study [NCT01749514] and the MEDALIST study [NCT02631070]. And you led very nicely to the story that we’re now excited about with regard to the COMMANDS trial [NCT03682536].

This study focused on patients that were dependent on 2 to 6 transfusions within an 8-week time period. They were low-risk MDS [myelodysplastic syndromes], with and without ring blasts. Patients on this study received either luspatercept [Reblozyl], ESA [erythropoiesis stimulating agent]-based therapy, or epoetin alfa. Patients were randomized in a 1:1 upfront setting to receive 1 or the other. The question we were hoping to answer is if luspatercept will actually be able to be used in the upfront setting in a way that might be better in terms of outcome compared to ESA-based therapy, which has been the gold standard of the treatment of patients with low-risk MDS with anemia.

It was a little bit different than the MEDALIST study, which looked only at patients that had lost response to ESA-based therapies. That patient population was different than the COMMANDS study, which is in the upfront setting. The end points are also different with regard to accomplishing transfusion independence.

Patients needed to meet 2 criteria: They needed to become transfusion-independent, and they needed hemoglobin elevation greater than 1.5 grams per deciliter. It was pretty stringent with regard to hematologic improvement also because they were looking at a duration of 12 weeks, not just a duration of 8 weeks.

The secondary end points looked at 8 weeks, 12 weeks, 24 weeks. Additionally, it looked at duration of that transfusion independence. Some of that data was presented here at this year’s ASCO [American Society of Clinical Oncology annual meeting]. About 59% of the patients on this study became transfusion-independent with both of those criteria. Only about 30% of patients receiving EPO [erythropoietin] had met this criteria. The duration of that was also longer for patients that had received luspatercept.

I will say though that the patient population was a little bit different in regards to the percent SF3B1, or percent ring sideroblasts SF3B1-mutated, or the percent ring sideroblasts that were in the entire cohort. So 70% of the patients that were in the COMMANDS study were either ring sideroblasts-positive or harbored an SF3B1 mutation. This is a lot higher than what we would normally expect for a lower-risk MDS population.

Close to 60% of patients are going to be transfusion-independent in the entire population, closer to 75% in the population of patients that were ring sideroblast-positive. You can expect 3 out of 4 patients to have at least a hematologic improvement, or in 58% a hematologic improvement plus transfusion independence, which is a big deal. Iron overload is not a fun thing to treat.

 The patients that were enrolled in this study had a low transfusion burden. Those things would mean that we should start therapy in patients sooner, or at least at a time where they don’t have a high transfusion burden. Some of that will have an impact on the way we are practicing, especially in terms of how important is it for us to identify patients with lower-risk MDS versus higher-risk MDS. This may underscore some of that importance.

During the evaluation of the MEDALIST trial, different quartiles of transfusion dependency were looked at and the response rates for each one. It was very clear that the patients with the lowest transfusion burden had 60% to 70% response rates were the patients who were transfusion-dependent, requiring 6 or more units, had 10% to15%. Earlier disease management does affect outcomes and can be disease-modifying.

 It is important to highlight the safety parameters with luspatercept versus ESA-based therapy. We need to see all of the data when it comes out with regard to safety, [and] also patient-reported outcomes. That data is yet to come out and to see how it impacts their quality of life.

Oncologists review study design and discuss key safety and efficacy data of the COMMANDS trial investigating luspatercept in frontline setting in patients with lower-risk MDS.

Safety and Efficacy of Luspatercept in Frontline Setting in Patients with MDS

Ralph Boccia, MD, FACP, shares his clinical experience using luspatercept to treat patient with lower-risk MDS.

Clinical Use of Luspatercept on Patients with Lower-risk MDS 

Expert oncologists discuss standard-of-care frontline treatments for patients with lower-risk MDS. 

Ralph V. Boccia, MD, FACP, LLC, Georgetown University Medical Center

Articles

Unmet Needs and Future Perspectives in Treatment of MDS

Clinical Management of Patients with Lower-risk MDS

Emerging Therapies for Treatment of MDS

Safety and Efficacy of Luspatercept in Frontline Setting in Patients with MDS

Clinical Use of Luspatercept on Patients with Lower-risk MDS

Frontline Treatment Options for Lower-Risk MDS