Optimizing Anemia Care with Targeted Therapies for Low-Risk MDS

Christopher Benton, MD

Hematologist/Medical Oncologist

Rocky Mountain Cancer Centers

Aurora, CO

This article is part 2 of a 2-part series from a Case-Based Roundtable event.

Targeted Oncology: What are the mechanisms of action of treatments for anemia in myelodysplastic syndromes (MDS)?

Christopher Benton, MD: Some of the mechanisms of action of treatments for anemia in MDS, [such as] luspatercept [Reblozyl], acts through inhibition of TGF beta signaling.¹ There is also imetelstat [Rytelo], which is a telomerase inhibitor. This inhibition of TGF beta signaling is a targeted approach to therapy, and while erythropoietin [EPO] or erythropoiesis-stimulating agents [ESAs] stimulate the stem cells to make more red blood cells, luspatercept acts more towards the end of the maturation pathway and pushes the cells through to full maturation so that they can go out into the bloodstream and carry oxygen. The way that I think about this is that if you're trying to educate these red blood cells, EPO acts at the at the point of kindergarten to initially educate these cells and luspatercept acts as a collegiate education in order to get them out into the workforce. So that's the role of luspatercept, and why we call it an EMA or erythropoiesis maturation agent.

Imetelstat has an interesting story. I would encourage you to read about this. It's a fascinating story about how we've tried to inhibit telomerase over many years, and this drug has found a place in improving anemia in these patients with low-risk MDS.

Can you discuss issues with current anemia management options?

There are transfusion-related issues with treating anemia in these patients. There's decreased quality of life [since] these patients are spending time in the infusion chairs. There are increased healthcare costs; transfusions do cost [money]. It also uses infusion center chairs, which could be used for [other] treatments. There are complications due to iron overload, and this is something that's been studied a lot of different ways, but there may be some associated decreased cardiac and hepatic function and increased mortality. That also gets back to this idea that maybe by decreasing transfusions, maybe by improving anemia, we're impacting the longevity of patients.

Then there are ESA-related issues. There's dosing frequency: how do we dose these things, how much do we use, and how much time between the between the doses? [Some issues include] lack of response and refractoriness to the ESA. There are also reimbursement issues; their hemoglobin has to be below 11 g/dL to get a shot, it has to be below 10 g/dL to start for most insurers, most payers, and the EPO baseline must be established. Sometimes there's a requirement for EPO testing. I don't do that, but I know that some people do, and there's some requirement for that. Then there's prior authorization before every EPO treatment.

What are the current FDA indications for first-line therapy in patients with low-risk MDS?

For ESAs, there's no FDA approval in MDS. We use them, and we all have been using them for years, but the FDA indications for anemia are chronic kidney disease in patients on dialysis or not. [Due to] the effects of concomitant myelosuppressive chemotherapy, and upon initiation of planned chemotherapy, patients may get this growth factor to help support their red blood cells. But again, there is no FDA approval in MDS.

[Luspatercept] is the only EMA on the market right now. Luspatercept is approved for anemia without previous ESA use in ESA-naive adult patients with very low- to intermediate-risk MDS who may require red blood cell transfusions. The indication is somewhat open ended from the standpoint that it can be any patient with low-risk or intermediate-risk MDS.

It can be [also] used in patients who have had ESA or patients who have not had an ESA and who are requiring red blood cell transfusions, or may in your estimation require red blood cell transfusions as time goes on. So luspatercept is a consideration as a frontline agent.

How do the NCCN guidelines recommend treating patients with MDS?

Patients who are ring sideroblast negative with symptomatic anemia and don't have deletion 5q...if their serum EPO level is less than 500 mU/mL, preferred agents are either an ESA or luspatercept and then consider their response….² If they have failed one of these agents, you can consider imetelstat or luspatercept if it wasn't previously used or continue with or switch to an ESA like epoetin alfa or darbepoetin alfa.

For ring sideroblast–positive patients, the preferred agent in this case is luspatercept. We know that these patients respond very well to luspatercept, and that's category 1. If they have no response to what you use frontline, then you can try something else. So for ring sideroblast negative, luspatercept is definitely an option according to NCCN as well as the FDA-approved indication. For patients who are ring sideroblast positive, luspatercept is the preferred agent. ESAs also can be used for patients who are ring sideroblast negative.

What trial achieved that luspatercept approval in the frontline setting for all patients with low-risk MDS and anemia?

That's based on the COMMANDS trial [NCT03682536]. The eligibility criteria included very low-, low-, or intermediate-risk MDS by IPSS-R [Revised International Prognostic Scoring System]. These are patients who required 2 to 6 red blood cell transfusions immediately prior to randomization. They had to be ESA naive. Their EPO levels were less than 500 U/L. They were subsequently stratified by various parameters that defined their low-risk MDS.

They were randomly assigned 1:1 to luspatercept, starting at 1 mg/kg that could be titrated 2 dose levels up to 1.75 mg/kg vs epoetin alfa that was administered weekly. Luspatercept was administered every 3 weeks. The primary end point for this was an increase in hemoglobin of 1.5 g/dL and transfusion independence. They had to meet both of those parameters in order to qualify as a responder based on the primary end point.³

The groups were very evenly matched in most all categories [of baseline characteristics]…. This is the first and only study that's ever gone head-to-head against ESA, and so I think it not only tells us about luspatercept, but it also tells us a lot about ESA. We've used ESA for so long, but most studies that have looked at it have been dosing studies or single-arm studies, and this had a good primary end point, and went head-to-head against the ESA.

What was the efficacy in terms of the primary end point for these patients?

When you subgroup these patients based on their characteristics of their MDS, you find that the luspatercept arm won out overall. The primary end point was transfusion independence lasting at least 12 weeks, as well as a concurrent mean hemoglobin increase of at least 1.5 g/dL. This is a high standard for patients that are needing transfusions leading up to this study, and 60% of patients in the luspatercept arm achieved that primary end point vs 35% in the ESA arm.⁴

In addition to that, if you subdivide patients almost across the board, the luspatercept group did better. For patients requiring less than or more than 4 units of packed blood cells in the preceding 8 weeks, the luspatercept arm was clearly superior. For patients with baseline serum EPO levels that were less than 200 U/L or those that were 200 to 500 U/L, the luspatercept arm was superior. For patients with mutated SF3B1 or who did not have SF3B1 mutation, the luspatercept arms did better. For patients who had ring sideroblast–positive MDS, they clearly did better. For patients who were ring sideroblast negative, they were statistically not significantly different. The ESA arm did slightly better according to this primary end point. If you extend the this study out a little bit, what you find is that the luspatercept arm still does better, even in the ring sideroblast–negative patients.

DISCLOSURES: Benton previously reported an advisory board role for Alexion Pharmaceuticals, Inc., Aptitude Health, LLC, Genentech, Inc., GlaxoSmithKline, Novartis Pharmaceuticals Corp., OncoVerity, Inc., and Taiho Oncology, Inc.

_References:

_{1. Meunier M, Park S. Lower-risk myelodysplastic syndromes: Current treatment options for anemia. EJHaem. 2022;3(4):1091-1099. doi:10.1002/jha2.523}

_{2. NCCN. Clinical Practice Guidelines in Oncology. Myelodysplastic syndromes; version 2.2025. Accessed May 19, 2025. www.nccn.org/professionals/physician_gls/pdf/mds.pdf}

_{3. Platzbecker U, Della Porta MG, Santini V, et al. Efficacy and safety of luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, transfusion-dependent, lower-risk myelodysplastic syndromes (COMMANDS): interim analysis of a phase 3, open-label, randomised controlled trial. Lancet. 2023;402(10399):373-385. doi:10.1016/S0140-6736(23)00874-7}

_{4. Della Porta MG, Garcia-Manero G, Santini V, et al. Luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, transfusion-dependent, lower-risk myelodysplastic syndromes (COMMANDS): primary analysis of a phase 3, open-label, randomised, controlled trial. Lancet Haematol. 2024;11(9):e646-e658. doi:10.1016/S2352-3026(24)00203-5}