Although improving efficacy outcomes remains a key component for the development of therapies and the treatment of anemia in patients with lower-risk myelodysplastic syndrome (MDS), striking a balance between efficacy and quality of life (QOL) is a key consideration when selecting a treatment for this patient population, according to Jorge Cortes, MD.

The first-line treatment paradigm for anemia in this patient population expanded when, in August 2023, 

the FDA approved luspatercept-aamt (Reblozyl)

 for the treatment of anemia without prior erythropoiesis-stimulating agent (ESA) use in adult patients with very low– to intermediate-risk MDS who may require regular red blood cell transfusions. Cortes explained that along with the addition of an efficacious treatment option in the first-line setting for this patient population, the frontline approval of luspatercept added another well-tolerated treatment option in this setting.

“We need to think about improving the overall health of the patient [when treating for anemia in lower-risk MDS, including] the QOL of the patient,” Cortes said in an interview with 

In the interview, Cortes discussed the implications of the expanded indication for luspatercept, highlighted the need to consider QOL when selecting a treatment for anemia in patients with lower-risk MDS, and expanded on the ultimate treatment goals for this patient population. 

Cortes serves as director and Cecil F. Whitaker Jr., GRA Eminent Scholar Chair in Cancer at the Georgia Cancer Center in Augusta.

: How has the first-line approval of luspatercept affected the treatment paradigm for patients with lower-risk MDS?

: It's valuable. In patients with low-risk MDS, their main problem is frequently anemia, and with that, all the symptoms [of anemia]. Our [treatment] options that we've had historically have been limited [for anemia in patients with lower-risk MDS]. If patients have 5q deletions, we know that lenalidomide [Revlimid] works well. If patients do not have 5q deletions, some may respond [to lenalidomide], but it's not as good, and [responses] are not as durable.

We also have ESAs, and we use them, but in this context, [patients] have a much better response to luspatercept. That changes the main problem that these patients have. With anemia, patients feel fatigued, they cannot do activities [that come with] daily living, and they can sometimes feel mental fogginess. These are all things that affect the QOL of patients; therefore, it becomes critical to have something that's more effective [in treating anemia for patients with lower-risk MDS without compromising QOL]. The difference [of luspatercept] compared with ESAs was quite significant [in the phase 3  COMMANDS trial (NCT03682536)].

What has been observed regarding QOL for luspatercept vs ESAs in the first-line setting for anemia in patients with lower-risk MDS?

Hemoglobin is not just a number or a value that you're trying to improve. Patients with anemia feel it. They are more tired, and they may be unable to take care of themselves or others. Frequently, [patients with lower-risk MDS] are older, where all these [QOL] issues are amplified, and they may put them at risk of [additional] problems. For example, if a patient is anemic and [already] has a risk of heart attack, [anemia] may increase the risk of developing one of these complications.

[Treating anemia] is not just [seeing] the hemoglobin level rise from 9 g/dL to 10 g/dL. The [QOL] impact is a lot more significant, particularly when talking about a drug that is very well tolerated. Therefore, you are not exchanging one symptom for another [in the form of an adverse effect]; instead, you are providing mostly benefit.

What factors influence risk stratification for treatment in patients with lower-risk MDS?

We always need to look at other factors, such as gene mutations, cytogenetics, and so on. That's part of what goes into classifying a patient as lower-risk. In terms of the anemia itself, you also need to see how symptomatic it is and other elements. All of these factors need to go into the equation when defining that they are low-risk. Not all patients with low-risk MDS are anemic; sometimes they have low-risk [disease] and there's [anemia]; that is not the patient [to consider] for luspatercept.

[We also need] to assess those other elements, such as mutations and cytogenetics, because they also determine the probability that these patients will progress to higher-risk [disease] and require other interventions beyond the management of anemia.

What are the ultimate treatment goals when selecting a therapy for patients with lower-risk MDS?

Patients [with lower-risk MDS] tend to be symptomatic; these are the patients in which you worry about managing anemia. That is what you want to address in these patients. You want to ensure that the patients are tolerating the drug and that they are feeling better and able to do their daily activities. [This is true] whether they are living by themselves and must take care of themselves, or if they are living with others. They may just want to enjoy life, which is [important].

However, we need to be clear that [luspatercept] is not a curative approach; we don't have curative strategies for MDS other than [stem cell] transplant, but [transplant] is not what you're thinking about in a patient with a low-risk MDS. The main goal for these patients is to improve their symptoms and QOL.

Even with luspatercept integrated into the first-line setting for anemia in patients with lower-risk MDS, how could ongoing research address remaining challenges?

The main challenge [is that] the disease will eventually progress and can be fatal. We need to focus on how we can change the natural history of the disease for these patients. Although [stem cell] transplant [is sometimes an option], it is very invasive, and it's not available for many patients with MDS, who tend to be older.

Although we have some good treatments and developments, we're still lacking a transformative approach that could be accessible to most patients that can eradicate the disease and provide a cure, which has been elusive.

US FDA approves Bristol Myers Squibb's Reblozyl (luspatercept-aamt) as first-line treatment of anemia in adults with lower-risk myelodysplastic syndromes who may require transfusions. News release. Bristol Myers Squibb. August 28, 2023. Accessed October 24, 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

Articles

Jorge Cortes, MD, discusses the need to balance outcomes and quality of life in the treatment of anemia in low-risk myelodysplastic syndrome.

QOL Remains Key Consideration for First-Line Treatment of Anemia in Lower-Risk MDS 

Dr Sallman on the Significance of the FDA Approval of Luspatercept for Lower-Risk MDS

David Sallman, MD, assistant member, Department of Malignant Hematology, Moffitt Cancer Center, discusses the clinical implications of 

the 2023 FDA approval of luspatercept-aamt (Reblozyl)

 for the first-line treatment of anemia in patients with very low– to intermediate-risk myelodysplastic syndrome (MDS). Notably, the agent was approved for those without prior erythropoiesis-stimulating agent (ESA) use who may require regular red blood cell (RBC) transfusions.

The regulatory approval of luspatercept was supported by findings from the phase 3 COMMANDS trial (NCT03682536). Treatment with luspatercept demonstrated superior rates of concurrent RBC transfusion independence (RBC-TI) and hemoglobin (Hb) increase vs treatment with epoetin alfa, irrespective of ring sideroblast status. As such, 58.5% (n = 86) of patients who were treated with luspatercept achieved the primary end point of RBC-TI of at least 12 weeks with a mean Hb increase of at least 1.5 g/dL within the first 24 weeks vs 31.2% (n = 48) of those given epoetin alfa (

Sallman says that in patients with MDS with ring sideroblasts, luspatercept is the most effective frontline therapy. In COMMANDS, the overall response rate with luspatercept was high, particularly in patients who were transfusion-dependent, he explains. For optimal treatment decisions, it is essential to perform a bone marrow biopsy and conduct molecular testing for the 

 mutation, Sallman notes. This ensures accurate diagnosis, as ring sideroblasts may be missed during staining, according to Sallman. Despite luspatercept’s proven efficacy in this population, its widespread adoption has not yet occurred in the broader medical community, though this agent should be more universally accepted as the optimal therapy for MDS with 

However, the use of luspatercept in non–ring sideroblast cases is controversial, Sallman continues. Although outcomes with luspatercept vs epoetin alfa were not inferior in these patients, the agent’s superiority was not dramatic, he states. Erythropoietin levels are also a key consideration, as patients with levels greater than 200 U/L tend to respond less well to ESAs than those with lower levels, he emphasizes. This strengthens the case for the use of luspatercept in this group, he notes. Although opinions may differ on whether luspatercept should be applied universally in MDS, it has undeniably revolutionized the treatment of frontline patients with MDS harboring 

mutations, with most of these patients achieving a favorable response with the agent, Sallman concludes.

Videos

David Sallman, MD, discusses the clinical implications of the 2023 FDA approval of luspatercept for patients with very low– to intermediate-risk MDS.

Dr Sallman on the Significance of the FDA Approval of Frontline Luspatercept for Lower-Risk MDS

Treatment with the first-in-class erythroid maturation agent luspatercept-aamt (Reblozyl) resulted in high rates of transfusion independence among patients with lower-risk myelodysplastic syndrome (MDS), according to data from a real-world analysis of this heavily pretreated patient cohort.

Among response evaluable patients (n = 31), 52% achieved erythroid responses and 48% of those who were transfusion-dependent achieved at least 16 weeks of transfusion independence. The median duration of transfusion independence was 48 weeks; this was comparable between high- vs low- transfusion burden responders. Although 22% of patients (n = 37) lost transfusion independence, it was restored following dose increases in 50% of patients initially receiving less than 1.75 mg/kg of luspatercept.

“Luspatercept achieved high rates of durable transfusion independence in heavily pretreated patients with lower-risk MDS patients; dose escalation restored transfusion independence in 50% [of those] who lost response at submaximal dosages,” Marisa L. Kometas, MD, lead study author and second-year internal medicine resident at UT Southwestern Medical Center in Dallas, Texas, stated in a presentation of the data. “Response was associated with a serum erythropoietin [EPO] level [of] less than 100 mU/mL, but not with baseline transfusion burden.”

Anemia, which is the most common cytopenia in patients with lower-risk MDS, can lead patients to develop transfusion dependence and experience inferior responses with standard-of-care treatment options. To combat this, 

 for the treatment of anemia in adult patients with very low– to intermediate-risk MDS who were not previously treated with an erythropoiesis-stimulating agent (ESA) in August of 2023.

 This regulatory decision was supported by interim findings from the phase 3 COMMANDS trial (NCT03682536), in which luspatercept demonstrated superior efficacy vs epoetin alfa.

Investigators further evaluated real-world responses with luspatercept in patients with lower-risk MDS according to baseline characteristics and prior treatments. These results were shared at the 

Study Methodology and Patient Characteristics

The retrospective, single-center, real-world analysis was initially launched at an academic tertiary referral center. Patients with lower-risk MDS who underwent treatment with luspatercept from January 2020 through December 2023 were eligible for study inclusion.

Baseline characteristic data on prior therapies, serum erythropoietin levels, ring sideroblast status, karyotype, and gene mutations were collected. Baseline transfusion burden—which was categorized as no transfusion dependence—low transfusion burden and high transfusion burden were calculated for all patients. Hematologic improvement-erythroid was assessed in those receiving 16 weeks of therapy or more. Mann-Whitney U tests were utilized for continuous variable comparisons and Fisher's Exact Tests were applied to categorical variables. Leukemia-free overall survival (OS) was determined using the Kaplan-Meier method, and group comparisons were performed using log-rank testing.

In the total dataset (n = 37), the median age at the start of luspatercept was 74 years (range, 58-93). When divided into responder (n = 18) and non-responder (n = 13) groups, the median age was 77 years (range, 58-86) vs 82 years (range, 65-93), respectively. Approximately half of all patients (51%) were female and 16% had therapy-related MDS. Patients had previously received an ESA (total dataset, 92%; responders, 94%; non-responders, 100%), a hypomethylating agent (19%; 11%; 23%), lenalidomide (14%; 6%; 23%), or 2 or more prior therapies (22%; 11%; 31%), respectively. Regarding EPO levels, patients had less than 100 mU/mL EPO (32%; 50%; 8%), between 100 and 200 mU/mL (19%; 17%; 31%), between 200 and 500 mU/mL (14%; 6%; 15%), greater than 500 mU/mL (30%; 17%; 46%), or no available data (5%; 11%; 2%).

The median baseline transfusion burden was 3 units (range, 0-11) per 16 weeks prior to treatment in the overall population, 5 units (range, 1-11) in the responder group, and 3 units (range, 1-9) in the non-responder group. Patients were also grouped according to high transfusion burden (41%; 44%; 39%), low transfusion burden (41%; 39%; 54%), or were not transfusion dependent (19%; 17%; 8%).

Morphologic, Cytogenetic, and Prognostic Characteristics

In the overall population, ringed sideroblasts were present in 78% of patients, absent in 19%, and the aspirate quality was too poor for morphology in 13%. Respective values were 94%, 6%, and 0% in the responder group vs 69%, 23%, and 8% in the non-responder group. In total, 73%, 78%, and 77% of patients in the total, responder, and non-responder groups, respectively, harbored a 

 mutation. Notably, 32%, 17%, and 39% of patients across these respective groups displayed a high-risk mutation, such as 

). No next generation sequencing (NGS) data were available in 8%, 17%, and 0% of patients from the overall, responder, and non-responder groups, respectively.

Patients enrolled onto the trial showed signs of any cytogenetic abnormality (35%; 22%; 54%), del(5q) (8%; 0%; 23%), and cytogenetic abnormalities other than del(5q) (30%; 22%; 39%). Most patients had low risk scores (78%; 89%; 62%) according to the Revised International Prognostic Scoring System (IPSS-R), followed by intermediate IPSS-R scores of 3.5 or less (11%; 6%; 23%) and IPSS-R scores of 4.0 or greater (11%; 6%; 15%). Patients were also classified as having very low, low, or moderate-low risk (73%; 72%; 69%) according to the Molecular International Prognostic Scoring System (IPSS-M) and moderate-high, high, or very high IPSS-M scores (19%; 11%; 31%). This could not be calculated in 8%, 17%, and 0% of patients in the overall, responder, and non-responder groups, respectively, due to the absence of NGS data.

The median leukemia-free OS was not reached with luspatercept and did not differ between responders vs non-responders. Disease progression to higher-risk MDS or acute myeloid leukemia was observed in 11% of patients. Notably, serum EPO levels less than 100 mU/mL were found to significantly predict responses with luspatercept (

Furthermore, patients achieved transfusion independence at equal rates for doses of 1.00, 1.33, and 1.75 mg/kg of luspatercept, respectfully.

Investigators noted that common adverse effects included shortness of breath, falls, fatigue, and hypertension. These precipitated treatment discontinuation in 8% of patients on the study.

“As luspatercept gains prominence as a first-line therapy, further investigation is [needed] to define predictors of response,” Kometas concluded.

Kometas ML, Hyak J, Hoff F, et al. Real-world efficacy of luspatercept in patients with lower-risk myelodysplastic syndromes/ neoplasms (LR-MDS); a single-center study in a heavily pretreated cohort. Presented at: 2024 SOHO Annual Meeting; September 4-7, 2024; Houston, Texas.

US FDA approves Bristol Myers Squibb's Reblozyl (luspatercept-aamt) as first-line treatment of anemia in adults with lower-risk myelodysplastic syndromes who may require transfusions. News release. Bristol Myers Squibb. August 28, 2023. Accessed October 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

Luspatercept generated high rates of durable transfusion independence for patients with lower-risk myelodysplastic syndrome in a real-world analysis.

Real-World Analysis Shows High, Durable Transfusion Independence Rates With Luspatercept in Lower-Risk MDS 

, which provides oncology professionals with the resources and information they need to provide the best patient care. In both digital and print formats, 

 covers every angle of oncology practice, from new technology to treatment advances to important regulatory decisions.

In today’s episode, supported by Bristol Myers Squibb, we had the pleasure of speaking with Guillermo Garcia-Manero, MD, about research in myelodysplastic syndromes (MDS) that was presented at the 2024 EHA Congress. Dr Garcia-Manero is a professor, chief of the section of Myelodysplastic Syndromes, and deputy chair of Translational Research in the Department of Leukemia in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston. 

In our exclusive interview, Dr Garcia-Manero discussed findings from a post hoc analysis of the phase 3 COMMANDS trial (NCT03682536) evaluating the relationship between hemoglobin levels and quality of life in transfusion-dependent patients with lower-risk MDS receiving luspatercept-aamt (Reblozyl) or epoetin alfa; real-world dose-escalation outcomes among patients with lower-risk MDS receiving luspatercept; and multilineage and safety findings from the COMMANDS trial.

That’s all we have for today! Thank you for listening to this episode of 

, supported by Bristol Myers Squibb. Check back on Mondays and Thursdays for exclusive interviews with leading experts in the oncology field.

For more updates in oncology, be sure to visit www.OncLive.com and sign up for our e-newsletters.

 is also on social media. On X, follow us at @OncLive. On Facebook, like us at OncLive, and follow our OncLive page on LinkedIn.

, please consider subscribing to our podcast on Apple Podcasts, Spotify, Amazon Music, and many of your other favorite podcast platforms,* so you get a notification every time a new episode is posted. While you are there, please take a moment to rate us!

*OncLive On Air is available on: Apple Podcasts, Google Podcasts, Spotify, Amazon Music, Audacy, CastBox, Deezer, iHeart, JioSaavn, Listen Notes, Player FM, Podcast Addict, Podchaser, RadioPublic, and TuneIn.

Podcasts

Dr Garcia-Manero discusses findings from research in myelodysplastic syndromes that were presented at the 2024 EHA Congress. 

Garcia-Manero on MDS Treatment Updates With Luspatercept and Beyond

, Guillermo Garcia-Manero, MD, highlighted 3 key analyses of luspatercept-aamt (Reblozyl) in low-risk myelodysplastic syndrome (MDS) presented at the 

and expanded on their implications for the treatment paradigm.

According to data from a real-world study investigating the clinical benefit of luspatercept dose escalation among patients with low-risk MDS in the United States, more patients achieved red blood cell transfusion independence (RBC-TI) with luspatercept after undergoing their first dose escalation. Data presented at the meeting by Kashyap Patel, MD, of Carolina Blood & Cancer Care Associates, also showed that 47% and 43% of those who were previously RBC transfusion dependent (RBC-TD) achieved TI for at least 8 weeks following their first and second dose escalation, respectively.

Additionally, findings from a post-hoc analysis of 

the phase 3 COMMANDS trial (NCT03682536) 

were presented by Esther Oliva, MD, of Massachusetts General Hospital, and demonstrated a correlation between increasing hemoglobin levels and clinically significant improvements in quality of life (QOL) for RBC-TD patients with low-, very low–, or intermediate-risk MDS. Moreover, patients who were RBC-TI and achieved a hemoglobin level of 10 g/dL or higher were more likely to experience a meaningful improvement in patient-reported outcomes (PROs) for all primary domains, including anemia-related toxicities and fatigue.

“We’re starting to gain momentum [in low-risk MDS],” Garcia-Manero stated during the interview regarding this research. “To see real-world data from Dr Patel [showing] this kind of activity [with luspatercept] is quite satisfactory, [as is] seeing the data from Dr Oliva showing an improvement in QOL.”

Lastly, results from a study conducted by Garcia-Manero and colleagues showed that luspatercept significantly improved erythroid (HI-E), neutrophil (HI-N), and platelet (HI-P) lineages in the COMMANDS study population. More patients achieved HI-E with luspatercept vs epoetin alfa, and a numerical improvement in platelet and neutrophil counts was observed during the initial 24 weeks of treatment.

Together, these studies underscore the safety and real-world potential of luspatercept in lower-risk MDS, substantiate the current practice of luspatercept dose escalation, and support re-evaluation of target hemoglobin levels in this population, Garcia-Manero stated.

Garcia-Manero is a professor, chief of the Section of Myelodysplastic Syndromes, deputy chair of Translational Research, and the fellowship program director in the Department of Leukemia in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston, where he is also the chair of the Faculty Senate.

: What is the importance of assessing the impact of dose escalation on real-world clinical benefit with luspatercept? Please highlight the key findings reported from the study.

 The way we administer luspatercept and the way it is approved follows a dose-escalation schema. You start with 1 mg/kg, and the drug is given every 3 weeks. You give a couple of doses and if there’s no response, then you can increase the dose to 1.3 mg/kg and then 1.75 mg/kg, [which is] the cap dose. My understanding is that this was determined by the FDA. It is a bit of a safety issue, saying that if we go too high with hemoglobin which we would like to see in the majority of our patients, this could be detrimental because if you have uncontrolled erythrocytosis with a hemoglobin level of 20 g/dL, our patients may experience complications. Fortunately, or unfortunately, we are never able to achieve levels that high in MDS, but this is a safety concern, and we need to follow the FDA guidelines.

Here, the questions are: How many patients are dose escalated and what is the impact? This real-world analysis shows that the majority of patients were dose escalated. This means that the first 1-mg dose may not be the most effective way to start, and that perhaps, at some point, authorities should reconsider this issue. Should we start at 1.3 mg/kg? Is 1.75 mg/kg actually the highest dose level we can administer? This is being evaluated in a couple of clinical trials looking at luspatercept up front. It will be interesting to know whether instead of 1 mg/kg we could go directly to 1.3 mg/kg, and whether we could escalate beyond that in the future.

What are the implications of these data for patients with LR-MDS who are RBC-TD vs RBC-TI?

What these data are telling us is that this may not be a very effective way to use this drug. One has to think about cost of the drug, cost of transfusions, and whether we could maybe skip this and go directly. We need more data, but these findings strongly suggest that this [dosing scheme] needs to be investigated [further]. These data will not support us switching our practice and starting at 1.3 mg/kg. However, it gives ideas to people who do clinical research in this area in terms of new trial design and [could] perhaps [engender] discussions with authorities [regarding] the most efficient and safe dose of this compound. It also shows that dose escalation [of luspatercept] is important not only in transfusion-dependent patients, as there was a cohort of patients that were RBC-TI. This is interesting because the level of the drug [was determined] for patients who are candidates for transfusion. So [a patient] could have a hemoglobin level of 8 g/L and never receive a transfusion but be a candidate for transfusion. In a way, the drug could be started early. It appears that those patients who were RBC-TI also benefited from the dose escalation. That is quite intriguing, and something that we need to understand better.

What knowledge gaps did the post-hoc analysis of the COMMANDS study aim to address, and what did it reveal about the relationship between hemoglobin and QOL in patients with lower-risk MDS?

Over the past couple of years, we’ve seen 3 new indications for patients with lower-risk MDS, 2 of them for luspatercept. The main goal or primary end point of these clinical trials that led to the approval of luspatercept was improvement in hemoglobin. The question is, what happens when you achieve that? Do the patients feel better? Do they have any improvement in QOL? This was a very important presentation by Dr Oliva, who’s an expert in this area and has been working on this for a long period of time. She utilized the data from COMMANDS, [which is a] phase 3 randomized study comparing luspatercept vs an erythropoiesis-stimulating agent [ESA].

She used these PRO tools that have different domains and related this to increases in hemoglobin. What she showed is that those patients who had an improvement in hemoglobin experienced a benefit in terms of their reported PRO issues. What was more interesting was that this [benefit] was clearer for those who have a hemoglobin increase over 1.5 g/dL and for those who achieved hemoglobin levels over 10 g/dL. What this suggests is that designing this trial with a goal of increasing hemoglobin should improve the QOL and wellbeing of our patients, which is what we want as clinicians.

How might these findings inform clinical decisions regarding the target hemoglobin level for anemic, RBC-TD patients within this population?

This sounds easy to do, but it’s quite complex. There are many variables that affect how we analyze these QOL end points in clinical trials. When we do this in a randomized study, we have strict guidelines for transfusion. For instance, in the prior 

[NCT02631070], we compared luspatercept vs placebo, but then we were trying to achieve levels of hemoglobin that were predetermined on the trial. In a way, we were achieving that with transfusions, meaning that affected hemoglobin levels that we were trying to achieve with the drug. Sometimes this is not as straightforward in clinical trials. [However,] this [study is a] successful example [suggesting] that it can be done. It also suggests that we should incorporate this clearly into all our trials for lower-risk MDS, and that we need to learn about these implications. What is the [target] hemoglobin level? Is it just [reaching RBC-TI]? Is it [a level] of 9, 10, or 11 g/dL? This has implications for the use of luspatercept, where there [could be] a dose-escalation schema in which one could aim [to achieve] higher hemoglobin levels. Also, the analysis is agnostic for the drug, so it was not specifying whether this was for luspatercept or an ESA, and patients were treated with either drug. Understanding the difference between luspatercept and ESAs and understanding these issues related to dose escalation will be quite important. Overall, it’s a very important first step.

What was the rationale for assessing the impact of luspatercept on erythroid, neutrophil, and platelet lineages in ESA-naive low-risk MDS?

When these drugs were designed, they were thought to be erythroid-maturation agents, and were thought to act in the later steps of blood cell formation. I was not anticipating any effect on white blood cells [WBC] or platelets. In one of the SOHO Annual Meetings a few years ago, someone asked leaders in the field whether you could see [those kinds of] responses, and I was curious about this question. The reality is that when we did the MEDALIST trial and we saw those responses. Now, that study compared [luspatercept with] placebo, and we saw that there was not only an increase in hemoglobin, but also an increase in platelets and WBC. It’s, [therefore,] logical to ask the same question in the phase 3 COMMANDS trial.

How did hematologic improvement rates and safety profiles compare between patients treated with luspatercept and those treated with epoetin alfa in the study you presented?

If you look at the HI-E [rate], it was 74.2% with luspatercept and 53.0% with an ESA; the HI-N [rate] was 33.3% vs 25.0%, and HI-P [rates] were 42.3% vs 30.0%, [respectively]. The HI-E is very significant, because that’s the erythroid level, which is the end point of the study. However, these patients are not always cytopenic. This means that they always have anemia, but they may or may not have neutropenia and may or may not have thrombocytopenia. The number of patients may not be enough to show statistical significance. However, there is a clear numerical trend [indicating] that luspatercept improves platelet counts and may improve neutrophil count in patients with lower-risk disease. [These data show that] this drug doesn’t cause cytopenia, so it’s quite safe. That is very clear, even if these 

 values are not significant. [The agent] does not induce neutropenia, and it will not induce thrombocytopenia. The next question is, why does this happen? Also, do these drugs have another role beyond erythropoiesis? The overall message is that this drug is safe and may improve platelet and neutrophil counts. Hopefully, in the future, we’ll better understand why this happens.

Are any next steps planned based on this research?

We have a study ongoing here, at The University of Texas MD Anderson Cancer Center. In this investigator-initiated trial, we are enrolling patients with low-risk MDS who have significant cytopenias, such as thrombocytopenia or neutropenia, in addition to anemia. We want to understand the dynamics of changes in platelet count and WBC count, so we selected a population that is more cytopenic than the typical population [enrolled onto the] COMMANDS trial or other studies [in this space]. That will allow us to better visualize this bi- or tri-lineage effect. Each cohort will accrue approximately 20 patients. We also have designed an ambitious correlative analysis looking at single-cell RNA sequencing profiling, to understand what happens at the molecular level when we administer these drugs.

Looking ahead, where do you see the treatment paradigm heading in MDS?

We’re seeing a lot of progress all of a sudden. A lot of it is occurring in low-risk disease, but I’m seeing some improvement in [other areas,] as well. We saw luspatercept 

in the second line. One potent drug, KER-050, is going into phase 3 trials. We saw the phase 3 SINTRA-REV trial [NCT01243476] in Spain [evaluating] low-dose lenalidomide [Revlimid} in [patients with] RBC-TD MDS and deletion 5q [mutations, as well as] data with oral hypomethylating agents [HMAs.]

In high-risk disease, we are waiting for something that will improve the survival of our patients. We’re particularly waiting [to see more from] the phase 3 VERONA trial [NCT04401748] of [azacitidine (Vidaza) in] combination with venetoclax [Venclexta], but we’ve done quite a bit of work with oral HMAs. My group led the development of oral decitabine and cedazuridine, which has been approved now for MDS [by the FDA] and for acute myeloid leukemia in Europe. We have also shown very potent combinations within oral decitabine, venetoclax, and [others], and we’re starting to see quite a bit of improvement in transplant outcomes in MDS. There was also the recent 

FDA approval of the IGF1 inhibitor ivosidenib 

[Tibsovo] in relapsed/refractory MDS. These drugs are being tested in frontline trials, and we have similar data with IDH2 inhibitors.

[Overall,] we are moving in a good direction [in MDS], certainly better than we were 3 or 4 years ago. We have unmet needs, [including efforts to] target p53, HMA failures, and we saw a couple of disappointing studies with sabatolimab and magrolimab, but [overall], we are making quite a bit of progress.

Oliva E, Yucel A, Lord-Besse J, et al. Relationship between hemoglobin and quality of life in RBC-TD patients with lower-risk myelodysplastic syndrome receiving luspatercept or epoetin alfa. Presented at: 2024 EHA Congress; June 13-16, 2024; Madrid, Spain. Abstract P774.

Patel K, Chatterjee D, Hughes C, et al. Real-world dose escalation and outcomes among patients with lower-risk myelodysplastic syndromes receiving luspatercept in clinical practice. Presented at: 2024 EHA Congress; June 13-16, 2024; Madrid, Spain. Abstract P768.

Garcia-Manero G, Della Porta MG, Santini V, et al. Multilineage and safety results from the COMMANDS trial in RBC-TD, erythropoiesis-stimulating agent–naive patients with very low-, low- or intermediate-risk myelodysplastic syndromes. Presented at: 2024 EHA Congress; June 13-16, 2024; Madrid, Spain. Abstract P780.

Guillermo Garcia-Manero, MD, spotlights 3 key analyses of luspatercept in low-risk myelodysplastic syndrome presented at the 2024 EHA Congress.

Real-World and Post-Hoc Analyses Support Luspatercept Use in Low-Risk Myelodysplastic Syndrome

Dr Garcia-Manero on the Impact of Luspatercept on Hematopoietic Lineages in Lower-Risk MDS

Guillermo Garcia-Manero, MD, professor, chief, Section of Myelodysplastic Syndromes, chair, Translational Research, fellowship program director, Department of Leukemia, Division of Cancer Medicine, chair, faculty senate, The University of Texas MD Anderson Cancer Center, discusses the clinical implications of treatment with luspatercept-aamt (Reblozyl) on erythroid, neutrophil, and platelet lineages, as well as its safety in transfusion-dependent, erythropoiesis-stimulating agent (ESA)–naive lower-risk, myelodysplastic syndrome (MDS).

Anemia is a primary concern in patients with lower-risk MDS, yet other cytopenias, such as neutropenia and thrombocytopenia, also play a critical role in treatment strategies and patient outcomes. Accordingly, investigators evaluated specific responses of cytopenias in 3 hematopoietic lineages: erythroid (HI-E), neutrophil (HI-N), and platelet (HI-P) in patients from the phase 3 COMMANDS trial (NCT03682536). Time to HI-E, prior and on-treatment transfusions, and safety were also assessed.

 showed that luspatercept significantly improved erythroid, neutrophil, and platelet lineages in the study population, Garcia-Manero states. Notably, a higher proportion of patients treated with luspatercept achieved HI-E compared to those treated with epoetin alfa, which is crucial given that erythroid improvement was the primary end point of the study, he reports.

However, the significance of these findings extends beyond erythroid response, Garcia-Manero continues. Although the sample size was limited for HI-P and HI-N assessments, and results were not statistically significant, more patients on luspatercept showed an improvement in platelet and neutrophil counts during the initial 24 weeks of treatment compared with epoetin alfa, he details. Luspatercept’s ability to improve platelet and neutrophil counts therefore suggests a broader hematopoietic benefit, Garcia-Manero says, adding that the lack of induced cytopenias also positions luspatercept as a safe treatment option.

Ultimately, the COMMANDS trial results underscore the potential of luspatercept to safely enhance hematopoietic function in multiple lineages in patients with lower-risk MDS, Garcia-Manero emphasizes. Future studies will hopefully elucidate the mechanisms behind these effects, as current data suggest that luspatercept may have roles beyond erythropoiesis, he concludes.

Guillermo Garcia-Manero, MD, discusses the safety and impact of luspatercept on hematopoetic lineages in transfusion-dependent lower-risk MDS.

Luspatercept-aamt (Reblozyl) elicited superior erythroid response rates and duration of red blood cell (RBC) transfusion independence across all end points compared with epoetin alfa in patients with lower-risk myelodysplastic syndromes (MDS), according to findings from an analysis of the clinical benefit of the agent from the phase 3 COMMANDS trial (NCT03682536) presented at the 

At a data cutoff of September 22, 2023, compared with patients in the epoetin alfa arm, patients in the luspatercept arm achieved a longer median duration of RBC transfusion independence and higher rates of RBC transfusion burden reduction of at least 50%. Additionally, more patients in the luspatercept arm achieved at least 2 separate RBC transfusion independence response episodes lasting at least 12 weeks.

“Overall, luspatercept led to durable and clinically meaningful responses beyond the achievement of the primary end point, supporting its use as the treatment of choice over ESAs in patients with transfusion-dependent lower-risk MDS–associated anemia who are ESA naive,” lead study author Amer Zeidan, MBBS, of Yale School of Medicine and Yale Cancer Center in New Haven, Connecticut, and coauthors, wrote in a poster of the data.

In the COMMANDS trial, 58.5% of patients who received luspatercept (n = 182) achieved the trial’s primary end point of RBC transfusion independence for at least 12 weeks with a concurrent mean hemoglobin increase of at least 1.5 g/dL within the first 24 weeks of treatment.2 This rate was 31.2% among patients who received epoetin alfa (n = 181; 

< .0001). Based on these findings, in August 2023, 

 for patients with erythropoiesis-stimulating agent (ESA)–naive, transfusion-dependent, lower-risk MDS, regardless of ring sideroblast status.

The open-label, randomized, controlled COMMANDS trial enrolled patients at least 18 years of age with very low–, low-, or intermediate-risk MDS as defined by the Revised International Prognostic Scoring System.

 Eligible patients were ESA naive, had less than 5% bone marrow blasts, and had endogenous serum erythropoietin levels of less than 500 U/L. These patients were eligible if they were RBC transfusion dependent, defined as needing 2 to 6 packed RBC units every 8 weeks for at least 8 weeks prior to randomization.

Patients were randomly assigned 1:1 to receive either subcutaneous luspatercept at 1.0 mg/kg (titration up to 1.75 mg/kg was allowed) once every 3 weeks or subcutaneous epoetin alfa at 450 IU/kg (titration up to 1050 IU/kg was allowed; the maximum total dose was 80,000 IU) once per week.

The clinical benefit analysis presented at the 2024 ASCO Annual Meeting evaluated the achievement and duration of the primary and key secondary end points over the entire treatment period (week 1 to end of treatment [EOT]) in responders. Beyond the criteria for the primary end point, RBC transfusion independence for at least 12 weeks and at least 24 weeks following treatment initiation were evaluated. Hematologic improvement-erythroid for at least 8 weeks was assessed per International Working Group 2006 criteria. Other secondary end points and assessments included transfusion burden on treatment between weeks 1 and 24; time to RBC transfusion after treatment initiation between week 1 and EOT; the achievement and duration of at least a 50% reduction in RBC units transfused over at least 12 weeks between week 1 and EOT; the achievement and cumulative duration of multiple RBC transfusion independence episodes lasting at least 12 weeks between week 1 and EOT; the achievement of a mean hemoglobin increase of at least 1.5 g/dL between weeks 1 and 24; the mean hemoglobin change over 24 weeks between weeks 1 and 24; and the mean hemoglobin change from baseline over time.

Patients in the luspatercept and epoetin alfa arms had respective median ages of 74.0 years (range, 46.0-93.0) and 74.0 years (range, 31.0-91.0), and respective mean hemoglobin levels of 7.8 g/dL (range, 4.7-9.2) and 7.8 g/dL (range, 4.5-10.2). Both arms had respective median transfusion burdens of 3.0 RBC units per 8 weeks (interquartile range [IQR], 2.0-4.0). The median endogenous serum erythropoietin level in each arm was 77.2 U/L (range, 7.8-495.8) and 85.4 U/L (range, 4.6-462.5), respectively.

When evaluated between week 1 and EOT, 70.9% of patients who received luspatercept achieved the trial’s primary end point vs 43.1% of those who received epoetin alfa (

< .0001). The median longest duration of response (DOR) until EOT was 128.1 weeks (95% CI, 108.3–not evaluable [NE]) in the luspatercept arm vs 95.1 weeks (95% CI, 75.6-186.1) with epoetin alfa (HR, 0.709; 95% CI, 0.444-1.132; 

In total, 76.4% of patients who received luspatercept achieved RBC transfusion independence for at least 12 weeks between week 1 and EOT vs 55.8% of those who received epoetin alfa (

< .0001). Among these patients, those in the luspatercept arm had a median DOR until EOT of 126.6 weeks (95% CI, 93.0-NE) vs 75.6 weeks (95% CI, 47.0-111.1) for those in the epoetin alfa arm (HR, 0.569; 95% CI, 0.308-0.851; 

A total of 65.9% of patients who received luspatercept achieved RBC transfusion independence for at least 24 weeks between week 1 and EOT vs 45.3% of those who received epoetin alfa (

< .0001). In this population, the median longest DOR until EOT was 135.9 weeks (95% CI, 112.7-NE) with luspatercept vs 91.1 weeks (95% CI, 74.9-157.3) with epoetin alfa (HR, 0.541; 95% CI, 0.339-0.862; 

Hematologic improvement-erythroid for at least 8 weeks between week 1 and EOT was achieved by 80.2% and 57.5% of patients in the luspatercept and epoetin alfa arms, respectively (

In the luspatercept and epoetin alfa arms, the median number of RBC units transfused between weeks 1 and 24 was 1.0 (IQR, 0-5.0) and 3.0 (IQR, 0-8.0), respectively.

Eighty-three percent and 66.9% of patients in the luspatercept and epoetin alfa arms, respectively, achieved a 50% or greater reduction in RBC units transfused over at least 12 weeks between week 1 and EOT (

= .0002). In these patient populations, the median DORs were 130.0 weeks (95% CI, 99.0-NE) and 77.0 weeks (95% CI, 54.9-123.9), respectively (HR, 0.528; 95% CI, 0.360-0.774; 

= .0009). This benefit with luspatercept was observed regardless of baseline transfusion burden. This reduction was observed in 89.0% and 73.9% of patients in the luspatercept (n = 118) and epoetin alfa (n = 111) arms, respectively, with a baseline transfusion burden of less than 4 units per 8 weeks. In that population, the median DORs were 129.9 weeks (95% CI, 85.9-NE) and 95.7 weeks (95% CI, 62.4-186.1), respectively (HR, 0.826; 95% CI, 0.532-1.282). This reduction was observed in 71.9% and 55.7% of patients in the luspatercept (n = 64) and epoetin alfa (n = 70) arms, respectively, with a baseline transfusion burden of at least 4 units per 8 weeks. In that population, the median DORs were 164.0 weeks (95% CI, 127.0-NE) and 36.4 weeks (95% CI, 21.9-73.7), respectively (HR, 0.374; 95% CI, 0.200-0.698).

In the luspatercept and epoetin alfa arms, the median time to RBC transfusion after treatment initiation was 155.0 days (95% CI, 80.0-266.0) and 42.0 days (95% CI, 23.0-55.0), respectively (HR, 0.579; 95% CI, 0.446-0.750; 

Among the patients in the luspatercept (n = 139) and epoetin alfa (n = 101) arms who achieved RBC transfusion independence for at least 12 weeks between week 1 and EOT, 20.1% and 16.8%, respectively, achieved at least 2 separate response episodes. The median cumulative durations of all response episodes were 154.7 weeks (95% CI, 118.4-NE) and 91.1 weeks (95% CI, 73.1-123.9) in these respective arms (

Mean hemoglobin increases of at least 1.5 g/dL between weeks 1 and 24 were achieved by 74.2% and 52.5% of patients in the luspatercept and epoetin alfa arms, respectively (

< .0001). In these respective arms, the mean hemoglobin changes between weeks 1 and 24 were 2.0 g/dL (standard deviation [SD], 1.14) and 1.5 g/dL (SD, 1.12). The study authors noted that luspatercept treatment consistently increased hemoglobin from baseline levels vs epoetin alfa.

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;42(suppl_16):6565. doi:10.1200/JCO.2024.42.16_suppl.6565

US FDA approves Bristol Myers Squibb's Reblozyl (luspatercept-aamt) as first-line treatment of anemia in adults with lower-risk myelodysplastic syndromes who may require transfusions. News release. Bristol Myers Squibb. August 28, 2023. Accessed June 11, 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

Luspatercept-aamt (Reblozyl) demonstrated superior efficacy over epoetin alfa in achieving and maintaining red blood cell (RBC) transfusion independence in patients with lower-risk myelodysplastic syndromes (MDS). The phase 3 COMMANDS trial showed that luspatercept led to higher rates and longer durations of transfusion independence, significant hemoglobin increases, and greater reductions in transfusion burden. These findings support luspatercept as the preferred treatment for transfusion-dependent, erythropoiesis-stimulating agent (ESA)-naive lower-risk MDS patients, leading to its FDA approval in August 2023.

Luspatercept elicited superior erythroid response rates and duration of RBC transfusion independence compared with epoetin alfa in lower-risk MDS.