Lower-Risk MDS: What to Do When First-Line Therapy Fails

Managing myelodysplastic syndromes (MDS) remains one of the more nuanced challenges in clinical oncology, particularly when patients progress beyond first-line therapy. The second-line setting is an area of active investigation and evolving treatment options.

During a Case-Based Roundtable event in Charlotte, North Carolina moderated by Thomas LeBlanc, MD, associate professor of medicine, Duke University School of Medicine, Durham, North Carolina, LeBlanc explored the principles of risk stratification and treatment goals in MDS, which are essential to guiding any therapeutic decision. Specifically, he addressed the patient with lower-risk MDS and the critical question of what to do when initial treatment is no longer sufficient, drawing on the latest data to help define best practices in the second-line setting. Central to that conversation is a close look at 2 agents at the forefront of this space: luspatercept (Reblozyl) and imetelstat (Rytelo).

Targeted Oncology: How do you manage the dosing decisions when using luspatercept?

Thomas LeBlanc, MD: I want to briefly review the 3 dose levels available with luspatercept, as well as the guidance around when to hold the drug, because this is an important practical consideration that comes up in clinical practice.

The key challenge with luspatercept, much like with an erythropoiesis-stimulating agent (ESA), is that if a patient has a robust response, you may need to hold the drug.

Let me give you an example from my own practice. I have a patient with MDS/myeloproliferative neoplasm [MPN] overlap, essentially a chronic myelomonocytic leukemia [CMML]-type presentation, with symptomatic anemia.

I started him on luspatercept at 1 mg/kg to address the MDS component, and he had a really strong response. His hemoglobin climbed above 11.5 and stayed around 12 g/dL. He felt significantly better, but that meant I couldn't give him another dose for nearly 3 months. His hemoglobin slowly drifted back down to around 11 g/dL, I re-dosed him, and again, another 3 months passed before he was eligible for his next dose.

This is something you do have to watch for. With ESAs, we worry about cardiovascular risk when hemoglobin is driven too high, but a robust response like this, while clearly a good outcome for the patient, does create a logistical and management challenge.

This sets up an important distinction when we turn to imetelstat. Unlike luspatercept, imetelstat does not carry this same limitation. You can continue dosing, and in some patients, hemoglobin may normalize completely without triggering the same kind of hold that you would see with luspatercept or an ESA. That is one of the features of imetelstat that I find particularly appealing.

What are the criteria for dose reduction?

When it comes to dose reduction, it comes down to hemoglobin kinetics and tolerability. If a patient is experiencing significant toxicity at the starting dose but is deriving clinical benefit, that is when you might consider stepping down to a lower dose level.

I have never had to use a dose below 1 mg/kg in my practice, and that is largely because most patients do not respond at the starting dose to begin with.

If you look at the COMMANDS trial data,¹ 60% to 70% or more of patients required dose escalation to achieve their best response. So in practice, you are almost always moving up to the middle or higher dose level to see meaningful benefit in MDS.

The challenge arises when significant adverse events require you to step down. Even then, you typically do not need to go all the way to the lowest dose levels, and if you do, you are generally not going to see the clinical benefit you are hoping for.

This may become more relevant as we start to explore luspatercept in MPNs, where there appears to be greater responsiveness at lower dose levels. But that is still an emerging area, and frankly, it is not something I have had to navigate yet in my own patients.

How do the designs of the COMMANDS and MEDALIST trials (NCT02631070)² inform sequencing of luspatercept and imetelstat?

To me, this is one of the central challenges in lower-risk MDS: we simply do not yet know the optimal sequencing of these therapies, or whether the benefit of certain agents may diminish if they are used later in the treatment course rather than earlier.

Some data suggest that imetelstat performs consistently well regardless of line of therapy with relatively comparable efficacy across those settings.³ Luspatercept, however, tells a somewhat different story. If you compare the efficacy seen in the COMMANDS trial, which was conducted in the first-line setting, to the MEDALIST trial, which evaluated luspatercept in the second-line setting and was restricted to ring sideroblast–positive patients, arguably the population most likely to respond, the response rates in MEDALIST are actually lower. That suggests we are probably losing some degree of efficacy with luspatercept when it is used later in the treatment sequence, and possibly even after prior ESA exposure.

This is part of the reason I tend to move to luspatercept first in my own practice, and then sequence to imetelstat next. That said, I want to be clear that the optimal sequencing strategy has not been definitively established, and this remains an evolving area where we are still waiting for more definitive data.

DISCLOSURES: LeBlanc previously reported receiving honoraria for consulting/advisory boards from AbbVie, Agilix, Agios/Servier, Apellis, Astellas, AstraZeneca, Beigene, BlueNote, BMS/Celgene, Genentech, GSK, Lilly, Meter Health, Novartis, and Pfizer; speaking-related honoraria from AbbVie, Agios, Astellas, BMS/Celgene, Incyte, and Rigel; equity interest in Dosentrx (stock options in a privately held company); royalties from UpToDate; research funding from the AbbVie, American Cancer Society, AstraZeneca, BMS, Deverra Therapeutics, Duke University, GSK, Jazz Pharmaceuticals, the Leukemia and Lymphoma Society, the National Institute of Nursing Research/National Institutes of Health, and Seattle Genetics.

REFERENCES

1. 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

2. Fenaux P, Platzbecker U, Mufti GJ, et al. Luspatercept in patients with lower-risk myelodysplastic syndromes. N Engl J Med. 2020;382(2):140-151. doi:10.1056/NEJMoa1908892

3. Platzbecker U, Santini V, Fenaux P, et al. Imetelstat in patients with lower-risk myelodysplastic syndromes who have relapsed or are refractory to erythropoiesis-stimulating agents (IMerge): a multinational, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2024;403(10423):249-260. doi:10.1016/S0140-6736(23)01724-5