After a string of robust clinical trial data, patients with low-risk myelodysplastic syndromes (MDS) now have two newly approved treatment options: luspatercept and imetelstat. These novel agents have unique mechanisms of action that reflect a growing understanding of the biology of MDS, and they have the potential to improve outcomes and quality of life (QOL) for many patients.
“In the last one to two years, there has been an emergence of new agents that changed the treatment paradigm of low-risk MDS by focusing on improving anemia and transfusion dependence associated with this disease,” said Somedeb Ball, MBBS, an Assistant Professor in the Division of Hematology and Oncology, Department of Medicine, at Vanderbilt University Medical Center. “We hope that by improving those aspects for patients, we can give them back some quality time of their life.”
Blood Cancers Today recently spoke with several experts about low-risk MDS, the approvals of these new options, what they mean for patients, and which unmet needs remain.
MDS Burden
“Patients with low-risk MDS have a low risk of transformation to full blown acute myeloid leukemia, and risk of dying from the disease is not imminent,” said Dr. Ball. “However, the burden of disease is still significant enough to have unfavorable effects on patient QOL and day-to-day activities.”
According to Dr. Ball, the bulk of patients with low-risk MDS have low blood counts (cytopenias), which can cause fatigue, dizziness, and shortness of breath. Studies have shown that patients with MDS may report moderate or severe issues related to pain or discomfort, mobility, anxiety or depression, and usual activities.1
“Day-to-day things that patients were able to do before may not be as easy to do now with MDS,” Dr. Ball elaborated.
Patients with cytopenias can also be at increased risk for infection and bleeding and may be in and out of the hospital for related complications, said James M. Rossetti, DO, a hematology specialist at the University of Pittsburgh Medical Center Hillman Cancer Center.
One small, single-center study from Europe found that in a group of patients diagnosed with MDS—two-thirds of whom were low risk—more than half developed infectious episodes, the majority of which were considered severe. For the patients who died, the main cause of death was infection.2
Many patients may also require red blood cell or platelet transfusions, sometimes as often as weekly, Dr. Rossetti said.
“These patients are frequently getting labs on a weekly basis and spending hours in a chair waiting for blood products to arrive and be transfused,” according to Dr. Rossetti. On average, patients with MDS can spend as long as six hours at the infusion center to receive a transfusion.3
Although transfusions aim to relieve MDS symptoms, they are not without complications, Dr. Ball said. “With each bag of red blood cells, we infuse one month’s worth of oral iron into the patient’s body. This excess iron is hard to get rid of,” he explained. “It goes to organs like the liver or the heart. In the long run, that can impact organ function in transfusion-dependent patients.”
Until recently, the only treatments available to decrease transfusion needs and possibly improve survival for patients with low-risk MDS were the erythropoiesis-stimulating agents (ESAs) epoetin alfa and darbepoetin alfa, said Srinivas K. Tantravahi, MBBS, MRCP, an Associate Professor specializing in hematology and hematologic malignancies at the University of Utah’s Huntsman Cancer Institute. ESAs mimic erythropoietin and stimulate the bone marrow to make red blood cells.
“[ESAs] particularly helped patients who had some degree of erythropoietin deficiency, or levels below 200,” Dr. Tantravahi said. “However, only a fraction of patients respond to ESAs, and there was no other effective drug available until luspatercept.”
New Options
Unlike ESAs, luspatercept is an erythroid maturation agent, explained Amer Zeidan, MBBS, MHS, Chief of Hematologic Malignancies and an Associate Professor of Internal Medicine at Yale School of Medicine. Luspatercept acts as a ligand trap, removing the ligands of the TGF-beta superfamily, a pathway that has been shown to be increasingly activated in anemic patients with lower-risk MDS. By interfering with the ligands of this pathway, luspatercept removes these erythropoiesis inhibitory signals, which in turn enables erythroid maturation and subsequent improvement in anemia.4
“Luspatercept restores maturation of red blood cells from their early progenitors so they don’t die prematurely in the bone marrow,” Dr. Zeidan said. “In other words, it reverses the process of ineffective erythropoiesis, which is a hallmark of lower-risk MDS and what causes anemia.”
Luspatercept was first approved for anemia in patients with MDS with ring sideroblasts in whom prior ESAs have failed and who required two or more red blood cell units over eight weeks before study entry.5 In 2023, the US Food and Drug Administration (FDA) expanded the approval of luspatercept to the first-line setting in patients with low-risk MDS who may require red blood cell transfusion, regardless of ring sideroblast status.6
This expanded indication was based on data from the phase III COMMANDS trial, which enrolled patients with anemia and previously untreated lower-risk MDS patients with or without ring sideroblasts. Patients were randomly assigned to receive either luspatercept or epoetin alfa.7 Almost 60% of patients assigned to luspatercept achieved transfusion independence for at least 12 weeks and had an increase in hemoglobin of at least 1.5 g/dL, compared with only about one-third of patients assigned to ESAs.
Updated data presented in 2024 showed that more than 70.0% of patients assigned to luspatercept had achieved the primary endpoint of transfusion independence for at least 12 weeks compared with 43.1% of those assigned ESAs (P<.0001).8
“This was the first time we ever had a drug that beats ESAs in a head-to-head comparison in MDS,” said Dr. Zeidan, who was an investigator on the COMMANDS trial. “It beat ESAs in a conclusive fashion in terms of rate of transfusion independence and durability of response.”
The cumulative duration of all response episodes was almost three years (154.7 weeks) for luspatercept compared with less than two years (91.1 weeks) for ESAs (P=.0016).
“Administration of luspatercept is typically every three weeks, a less intense schedule than ESAs, which are given every one to two weeks,” Dr. Tantravahi said. “The main side effect is mild local infusion reactions like itching and discomfort, and we don’t see any hematologic toxicities like neutropenia or thrombocytopenia.”
Imetelstat
In June 2024, the FDA approved imetelstat, an oligonucleotide telomerase inhibitor. This approval is for adults with low-risk MDS with transfusion-dependent anemia requiring four or more red blood cell units over eight weeks and who have not responded to or are ineligible for ESAs.9
“The greater the telomere length of a cell, the longer that cell lives. With each cell division we lose a portion of telomere, and its length is maintained by an enzyme called telomerase,” Dr. Ball said. “In MDS, we see that diseased cells have higher telomerase activity than normal bone marrow cells.”
Imetelstat inhibits the telomerase enzyme, thereby selectively targeting MDS cells in the bone marrow.
“What is cool about this mechanism of action is that you are allowing restoration of normal hematopoiesis, normal production of blood cells, by selectively killing bone marrow cells harboring MDS,” Dr. Ball said.
Imetelstat was approved based on results from the phase III IMerge study, which randomly assigned 178 patients with low-risk MDS to receive either imetelstat or placebo. The primary endpoint of eight-week red blood cell transfusion independence was met in 40% of patients who received imetelstat, compared with 15% of patients who received placebo (P=.0008). Transfusion independence for at least 24 weeks was shown in 33% of patients assigned to imetelstat compared with 3% assigned to placebo (P=.0001).10
The median duration of transfusion independence was about one year with imetelstat compared with about 13 weeks with placebo.
Dr. Ball noted that there was no clear subgroup of patients that seemed to benefit more or less from imetelstat. However, data did seem to indicate that patients “who had eight-week transfusion independence were more likely to stay transfusion independent at 16 or 24 weeks.” This is encouraging, Dr. Ball said, because it tells physicians within a relatively short period of time whether this agent will work for a patient.
“Importantly, [imetelstat] benefits were seen in both the ring sideroblast-positive and -negative setting,” said Dr. Zeidan, who was an investigator and senior author of the pivotal IMerge trial.
Dr. Zeidan also pointed out that imetelstat can cause cytopenias, including neutropenia and thrombocytopenia. Patients have to be monitored closely, he said.
“Like luspatercept, imetelstat is also less cumbersome for patients,” Dr. Rossetti added. “This is about a two-hour infusion given monthly.”
Additionally, the median increase in hemoglobin during the longest transfusion-independent period was 3.50 g/dL with imetelstat, compared with 0.80 g/dL with placebo.
“Often, when a patient is given two units of blood, we see a transient increase of a couple grams,” Dr. Rossetti said. “If we can push hemoglobin upward by three to four grams in a durable manner, we can significantly improve QOL.”
Incorporating New Options
With these two new approvals, one important research area is how to sequence the available treatment options.
“For example, we know that luspatercept works after ESAs—at least with ring sideroblasts—but we don’t have data about ESA use after luspatercept,” Dr. Zeidan said. “Now that luspatercept has frontline approval, these data should accumulate quickly from real-world analyses and from COMMANDS follow-up.”
Another important question is how imetelstat works after first-line luspatercept. In IMerge, only a small number of patients had previous treatment with luspatercept after ESA failure. Of these patients, 86% had a reduction in transfusion burden with imetelstat, but none achieved transfusion independence.10
“These are very small numbers to be able to draw any conclusion from, but what I see happening is that most patients are probably going to get luspatercept or ESA frontline. If they don’t respond, they will then likely get imetelstat,” Dr. Ball said. “In years to come, I will be interested to see real-world or retrospective studies about how one of these agents performs after exposure to the other.”
Dr. Ball also pointed out that COMMANDS and IMerge had stringent endpoints to measure efficacy. For example, COMMANDS measured 12-week transfusion independence and IMerge measured eight-week transfusion independence.
“Many patients went on to have transfusion independence for even longer, and a lot of patients gained benefit from these agents even if that did not amount to the predefined standard set by the clinical trial,” Dr. Ball said. “It is unlikely that the other 40% to 60% of patients who did not meet these strict trial endpoints had no benefit at all. For our patients in clinic, even a smaller reduction in transfusion burden may be meaningful.”
Additionally, given these two agents’ different mechanisms of action, Dr. Tantravahi wonders if they could be combined.
Questions Remain
Despite this progress, MDS remains incurable, and many unmet needs remain.
Among the research needs is determining whether the benefits of new agents translate into true QOL improvement and better survival.
“This is challenging to measure in MDS because of the need for long follow-up,” Dr. Ball said. “These studies were not powered to measure it. I would be interested to know if the improvement these patients are experiencing on these drugs translates into an overall survival benefit.”
The hope is that these newer agents can help transform MDS into a sort of “chronic condition” like diabetes or hypertension, where a patient cannot be cured but can live a long time while they remain on treatment with good QOL, Dr. Zeidan said.
“This is where we are headed, but eventually every patient will progress,” Dr. Zeidan added.
While the QOL benefits and duration of response of these two agents are very good, “the unfortunate reality is that most patients will likely lose response to virtually any agent over time,” Dr. Rossetti noted.
Obtaining extended durations of response is necessary for these patients, but experts believe it’s also important to gain a better understanding of how to sequence these drugs to maintain the longest possible duration of transfusion independence.
Additional new agents are eagerly awaited, especially those that target genetic mutations or pathways specific to MDS. For example, in 2023, the FDA approved ivosidenib for patients with relapsed or refractory MDS with IDH1 mutations.11
“IDH1 mutations are fairly rare in the MDS space,” Dr. Rossetti said. “Other more commonly occurring mutations have been identified but don’t have targeted therapies available yet.”
Agents with consistent activity against TP53 mutations are also lacking, Dr. Rossetti mentioned.
However, the MDS field is moving forward to fill these treatment gaps. For example, the second-generation TGF-beta modulator KER-050 (elritercept) is being investigated in an ongoing phase II trial. Based on data presented at the European Hematology Association 2024 Hybrid Congress, more than 50% of patients were transfusion independent for at least eight weeks.12
“To my knowledge, this drug is principally being investigated in Europe, but a US trial has recently opened. It has the potential to fill some of the loopholes that luspatercept has,” Dr. Ball said. “With this second-generation molecule, we are seeing responses in some additional subgroups, improved platelet counts, and improved red blood cells counts, which is very encouraging.”
Leah Lawrence is a freelance health writer and editor based in Delaware.
References
- Stauder R, Yu G, Koinig KA, et al. Health-related quality of life in lower-risk MDS patients compared with age- and sex-matched reference populations: a European LeukemiaNet study. Leukemia. 2018. doi:10.1038/s41375-018-0089-x
- Ontiveros-Austria J, Rodriguez-Rodriguez S, Demichelis R, et al. Risk factors associated to severe episodes of infection in myelodysplastic syndromes. Blood. 2023. doi:10.1182/blood-2023-179673
- DiNardo KW, Houk A, Shim C, et al. The mental health burden and quality of life impact of myelodysplastic syndromes in patients and their caregivers. Blood. 2022. doi:10.1182/blood-2022-155893
- Feld J, Navada SC, Silverman LR. Myelo-deception: luspatercept & TGF-beta ligand traps in myeloid diseases & anemia. Leuk Res. 2020. doi:10.1016/j.leukres.2020.106430
- FDA approves luspatercept-aamt for anemia in adults with MDS. FDA. Accessed August 1, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-luspatercept-aamt-anemia-adults-mds
- U.S. FDA approves Bristol Myers Squibb’s Reblozyl® (luspatercept-aamt) as first-line treatment of anemia in adults with lower-risk myelodysplastic syndromes (MDS) who may require transfusions. Bristol Myers Squibb. Accessed August 1, 2024. https://news.bms.com/news/details/2023/U.S.-FDA-Approves-Bristol-Myers-Squibbs-Reblozyl-luspatercept-aamt-as-First-Line-Treatment-of-Anemia-in-Adults-with-Lower-Risk-Myelodysplastic-Syndromes-MDS-Who-May-Require-Transfusions/default.aspx
- Garcia-Manero G, Platzbecker U, Santini V, et al. Efficacy and safety results from the COMMANDS trial: a phase 3 study evaluating luspatercept vs epoetin alfa in erythropoiesis-stimulating agent (ESA)-naive transfusion-dependent (TD) patients (pts) with lower-risk myelodysplastic syndromes (LR-MDS). Abstract #7003. Presented at the 2024 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2024; Chicago, Illinois.
- Zeidan AM, Platzbecker U, Della Porta MG, et al. Clinical benefit of luspatercept treatment (tx) in transfusion-dependent (TD), erythropoiesis-stimulating agent (ESA)–naive patients (pts) with very low-, low- or intermediate-risk myelodysplastic syndromes (MDS) in the COMMANDS trial.
J Clin Oncol. 2024. doi:10.1200/JCO.2024.42.16 - FDA approves imetelstat for low- to intermediate-1 risk myelodysplastic syndromes with transfusion-dependent anemia. FDA. Accessed August 1, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-imetelstat-low-intermediate-1-risk-myelodysplastic-syndromes-transfusion-dependent
- 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. doi:10.1016/S0140-6736(23)01724-5
- FDA approves ivosidenib for myelodysplastic syndromes. FDA. Accessed August 1, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ivosidenib-myelodysplastic-syndromes
- Keros Therapeutics presents clinical data from its elritercept (KER-050) program at the 29th Annual Hybrid Congress of the European Hematology Association. Keros Therapeutics. Accessed August 1, 2024. https://ir.kerostx.com/news-releases/news-release-details/keros-therapeutics-presents-clinical-data-its-elritercept-ker
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