Rami Komrokji, MD, vice chair, Malignant Hematology Department, head, Leukemia and MDS Section, Moffitt Cancer Center, senior member, Malignant Hematology and Experimental Therapeutics Program, professor, Medicine & Oncologic Sciences, College of Medicine, the University of South Florida, discusses the benefit of agents such as luspatercept-aamt (Reblozyl) in patients with very low– to intermediate-risk myelodysplastic syndromes (MDS) who have not received prior treatment with erythropoiesis-stimulating agents (ESAs).

 for patients with lower-risk MDS with anemia requiring transfusions, he begins. There's a push to consider initiating treatment for patients experiencing symptomatic or significant anemia before the necessity for blood transfusions arises, Komrokji states. The forthcoming phase 3 ELEMENT-MDS study (NCT05949684), which follows the pivotal phase 3 COMMANDS trial (NCT03682536), is specifically designed to investigate this, he says. ELEMENT-MDS intends to focus on patients not in need of blood transfusions and randomly assign them to receive either ESA agents or luspatercept. The goal of the trial is to gather data to support the transition toward treating patients with symptomatic or significant anemia before they require transfusions, Komrokji emphasizes.

Currently, the role of luspatercept in MDS is evolving. Most guidelines suggest its use as a primary treatment option for patients requiring blood transfusions because it has doubled response rates and increased response duration in this subset of patients, Komrokji expands. However, the generalization of these data to patients whose MDS does not have ring sideroblasts (MDS-RS) or is lacking the 

 mutation is debated, he notes. The responses observed with luspatercept in patients without ring sideroblastic disease are similar to those seen with ESA therapies in this population. Yet, specific subsets of patients, especially those anticipated to have a low likelihood of responding to an ESA, may benefit from luspatercept, and the current indication for this agent includes these patients, Komrokji notes.

There's an ongoing effort to explore other disease factors that may favor the use of luspatercept over ESAs, such as baseline mutation burden or specific mutations, he continues. Presently, the consensus is leaning toward using luspatercept as the preferred first-line treatment for all patients with MDS-RS, and as a possible first-line choice for select patients without MDS-RS, Komrokji says. Future research in this area aims to advance treatment strategies so patients can receive therapy before the necessity for blood transfusions, Komrokji concludes.

Videos

Rami Komrokji, MD, discusses the benefit of agents such as luspatercept-aamt in patients with very low– to intermediate-risk myelodysplastic syndromes who have not received prior treatment with erythropoiesis-stimulating agents.

Dr Komrokji on Ongoing Investigations With Luspatercept in MDS

The efficacy demonstrated by luspatercept-aamt (Reblozyl) compared with standard erythropoiesis-stimulating agents (ESAs) in the first-line treatment of anemia in patients with lower-risk myelodysplastic syndrome (MDS) should make this agent the new standard of care (SOC) for those with ring sideroblastic (RS)–positive disease, according to Uwe Platzbecker, MD. However, he noted that more data are needed to determine if frontline luspatercept should be the SOC over ESAs for patients with RS-negative disease.

the FDA approved luspatercept for the treatment of anemia in patients with low- to intermediate-risk MDS

previously been treated with ESA and may require regular red blood cell (RBC) transfusions

 based on results from the phase 3 COMMANDS trial (NCT03682536).

The trial met its primary end point of RBC transfusion independence (RBC-TI) for at least 12 weeks with a mean hemoglobin increase of 1.5 g/dL. Data showed 58.5% of patients treated with subcutaneous luspatercept (n = 147) achieved RBC-TI for at least 12 weeks vs 31.2% of patients who received epoetin alfa (n = 154; 

 < .0001). The median duration of RBC-TI was 126.6 weeks (95% CI, 108.3–not evaluable [NE]) for the luspatercept arm vs 77.0 weeks (95% CI, 39.0-NE) for the epoetin alfa arm.

In patients who were RS-positive, those treated with luspatercept (n = 77) experienced a median duration of RBC-TI of 120.9 weeks (95% CI, 76.4-NE) vs 47.0 weeks (95% CI, 36.6-NE) for those given epoetin alfa (n = 48; HR, 0.626; 95% CI, 0.361-1.085). In the RS-negative population, the median duration of RBC-TI was NE (95% CI, 46.0-NE) for luspatercept (n = 21) and 95.1 weeks (95% CI, 35.3-NE) for epoetin alfa (n = 23; HR, 0.492; 95% CI, 0.148-1.638).

“In general, we can say that [luspatercept's frontline approval is] a paradigm change [in lower-risk MDS]. We are grateful for the decision made by the FDA and hope [this agent will be approved] for [patients in] the European Union,” said Platzbecker, who is the director of the Clinic and Polyclinic for Hematology, Cell Therapy and Hemostaseology at the Leipzig University Hospital, Leipzig, Germany.

, Platzbecker discussed how to navigate decisions for the first-line treatment of anemia in patients with lower-risk MDS in light of luspatercept’s approval, expanded on the key data from COMMANDS, and addressed potential concerns from clinicians who are uncertain about when to utilize this agent in the frontline setting in clinical practice.

: How could data from COMMANDS affect the sequencing of luspatercept in clinical practice?

: We are very grateful that the FDA granted this approval. My colleagues in the United States now have the choice of giving patients luspatercept as a first-line therapy because the approval allows [for its use] in ESA-naïve patients, irrespective of their RS status. This is a great opportunity for patients to get [luspatercept] as a first-line therapy.

We know from the COMMANDS trial that patients with a RS phenotype experienced significant benefit with regard to the initial response rate. The response rates for patients with RS-negative [disease] was [similar for luspatercept vs ESA]. However, the durability seemed to be better for luspatercept compared with ESA [in the RS-negative population]. The story to me is clear for patients who are RS positive: luspatercept should be the preferred treatment. For patients who are RS negative, it's the choice of the treating hematologist or oncologist.

Treatment decisions may be based on a lot of factors, [including] the preferred choice of the patient with regard to the mode by which a drug is actually given, such as every three 3 vs once a week for ESA therapy. It's also important that we gather more data in these patients who are RS negative to [better] understand which patients benefit most from this novel therapy.

Are there any challenges managing toxicities associated with luspatercept?

What we know from COMMANDS and the phase 3 MEDALIST trial [NCT02631070] is that the drug can be administered in a very safe manner. There are some minor adverse effects [AEs], especially fatigue, which has been observed in some patients, but this can be easily managed with dose reductions. No [unique] safety signals have arisen from these studies. The prescribing information is the backbone for counseling patients, but so far, we are not aware of any severe or very common AEs this drug is causing. [Notably], patients are exposed to [luspatercept] for years sometimes if they do respond.

What makes luspatercept an optimal treatment for patients with low-risk MDS?

First, luspatercept is an outpatient therapy. This is very important for patients with low-risk MDS, where QOL is the focus of the treating hematologist. Inpatient therapy is not something these patients prefer. Second, the response with regard to RBC-TI is superior to prior SOC therapy with an ESA, especially in patients with a RS-positive phenotype. The drug is special because it supersedes response rates of current or prior standard approaches. Patients are benefiting, not only with regard to the initial response with less transfusions, but also with the durability of response, meaning longer and sustained periods of transfusion-free intervals. Those are the major results of those pivotal trials.

QOL is always an issue, especially in patients with lower-risk MDS. From the phase 3 trials available, we don't have any signal that AEs [associated with luspatercept] deteriorate QOL in these patients. [Luspatercept] maintains, and sometimes improves, QOL in these patients with lower-risk MDS. This makes the drug very special.

What would you say to clinicians who may be more comfortable with using an ESA in patients with lower-risk MDS and may be hesitant to incorporate luspatercept into their practice?

We must acknowledge that ESA therapy has been the backbone to treat anemia for patients with lower-risk MDS for more than 2 decades. It's a drug that can be easily given at home to our patients.

At this stage, [as we] expect and hope that [luspatercept’s potential] approval as first-line therapy will be the same in the EU Union [as it is in the United States], there is no doubt that patients with a RS-positive phenotype should preferentially receive luspatercept as a first-line therapy, because we see a superiority in response and durability of response [vs ESAs].

The jury is still out, and may be debated, on whether every patient with a RS-negative phenotype should get luspatercept a first-line therapy based on the results of the COMMANDS trial. On the other hand, if you put a patient on luspatercept as a first-line therapy and the patient is not responding or losing response, we don't have much data available for second-line ESA therapy. The question is always what comes next, and more data need to be gathered on this special clinical situation.

Secondly, we have data for [luspatercept] as second-line therapy in patients who are RS-negative who were exposed to ESA, did not respond, and then got luspatercept. Responses seem lower when compared with [luspatercept] as a first-line approach. These kinds of observations and data need to be considered in clinical practice. I can't give a standard operating procedure here on what to do in every patient. It's so personalized, especially the care in these patients with lower-risk MDS. However, if you make a decision in the RS-negative patients, you need to balance pros and cons. You need to also look at transfusion burden with regard to the prognosis and the response of these patients. Several factors have to be taken into consideration.

The bottom line is that the data we have are not enough. We need data from registries in other clinical trials to better [define] the patient population that we should put on first-line luspatercept, especially talking about the RS-negative patient population,

What is your take home message for academic and community oncologists about the current role for luspatercept in patients with lower-risk MDS?

We were involved in the development of this drug from the very beginning. It takes serendipity, good science, and passion. As we say in Germany: it takes a long, long breath to bring a drug into the clinic. We also know that there have been a lot of success stories in acute myeloid lymphoma and MDS in the past, but there also have been a lot of unsuccessful stories in the same disease, especially in higher-risk MDS. We tend to always see the positive results, but we also need to see that a lot of failures also occur in this space, which are not as visible to many of us or to the public.

It takes a very good preclinical rationale and a company that takes the risk to develop a drug in a disease where QOL is more the focus [of care]. Survival studies are not as common in lower-risk MDS, so it's more about novel end points. At the end of the day, it took almost 11 or 12 years from the first phase 1/2 study of luspatercept to its approval in the first line. I would call this a real success story, and repeats are welcome.

The next step should be to combine luspatercept with older or novel agents. We should not agree that this is the [answer] for all patients with lower-risk MDS. It's a great drug to have for our patients, but we need to explore novel avenues, combination therapies, and other schedules to improve the response rates for [this patient population].

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, 2023.

Garcia-Manero G, Platzbecker U, Santini V, et al. Luspatercept Versus Epoetin Alfa (EA) for Treatment of Anemia in Patients With Erythropoiesis-Stimulating Agent (ESA)-Naive Lower-Risk Myelodysplastic Syndromes (LR-MDS) Requiring Red Blood Cell (RBC) Transfusions: Data from the Phase III COMMANDS Study. Presented at: 11th Annual Meeting of the Society of Hematologic Oncology (SOHO 2023); September 6, 2023; Houston, Texas.

Articles

Uwe Platzbecker, MD, discusses how to navigate decisions for the first-line treatment of anemia in patients with lower-risk MDS in light of luspatercept’s approval, expands on key data from the COMMANDS trial, and addresses potential concerns from clinicians who are uncertain about when to utilize this agent in the frontline setting in clinical practice. 

Luspatercept Approval Shifts Treatment Landscape of Anemia in Lower-Risk MDS 

Uwe Platzbecker, MD, director, Medical I, University Hospital Leipzig, discusses key findings from the phase 3 COMMANDS trial (NCT03682536) with luspatercept-aamt (Reblozyl) in patients with lower-risk myelodysplastic syndrome (MDS) with anemia, as well as the clinical implications of FDA approval of luspatercept for patients in this population.

 for the treatment of anemia in erythropoietin stimulating agent (ESA)–naïve patients with very low– to intermediate-risk MDS who may require regular red blood cell (RBC) transfusions. This regulatory decision was backed by interim findings from the phase 3 COMMANDS trial, which evaluated luspatercept vs the ESA epoetin alfa in patients with MDS with who had not received prior ESAs and required RBC transfusions. Patients were enrolled regardless of ring sideroblast status. In COMMANDS, 58.5% of patients who received luspatercept achieved RBC transfusion independence of at least 12 weeks with a concurrent mean hemoglobin increase of at least 1.5 g/dL in weeks 1 to 24 vs 31.2% of those who received epoetin alfa.

The FDA approval of luspatercept provides oncologists practicing in the United States with the choice of administering this agent in the frontline setting for ESA-naïve patients with lower-risk MDS with anemia, irrespective of ring sideroblast status, Platzbecker says. In COMMANDS, patients with ring sideroblast–positive disease achieved favorable response rates with luspatercept compared with epoetin alfa, Platzbecker explains. The response rates with luspatercept in the ring sideroblast–negative population were similar to those with epoetin alfa, according to Platzbecker. However, the patients who received luspatercept experienced a longer duration of response than those who received epoetin alfa, Platzbecker notes. These data support the use of luspatercept as the preferred frontline treatment for patients with ring sideroblast–positive disease, Platzbecker emphasizes.

The choice of treatment for patients with ring sideroblast–negative disease should be determined by each patient’s treating hematologist/oncologist, Platzbecker says. Many factors can influence this decision, including patient preferences regarding the dosing schedule and administration method of each drug, Platzbecker notes. For instance, in COMMANDS, patients received either subcutaneous luspatercept starting at 1.0 mg/kg once every 3 weeks or epoetin alfa starting at 450 IU/kg once weekly.

Additional data are needed to understand which patients with ring sideroblast–negative disease may benefit most from treatment with luspatercept, Platzbecker emphasizes. However, the FDA approval of luspatercept in patients with lower-risk MDS with anemia is paradigm shifting, and the approval of this agent in the European Union is anticipated, Platzbecker concludes.

Uwe Platzbecker, MD, discusses key findings from the phase 3 COMMANDS trial with luspatercept in patients with lower-risk myelodysplastic syndrome with anemia, as well as the clinical implications of FDA approval of luspatercept for patients in this population.

Dr Platzbecker on the COMMANDS Trial in Lower-Risk MDS With Anemia

Luspatercept-aamt (Reblozyl) is a novel addition to the transfusion-dependent, lower-risk myelodysplastic syndrome (MDS)–associated anemia armamentarium, particularly for patients with ring sideroblastic disease, according to Guillermo Garcia-Manero, MD.

The phase 3 COMMANDS trial (NCT03682536) investigated luspatercept vs the erythropoiesis stimulating agent (ESA) epoetin alfa in ESA-naïve patients with transfusion-dependent, lower-risk MDS with anemia. The primary end point of this trial was red blood cell 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. In total, 58.5% of patients in the luspatercept arm achieved the primary end point vs 31.2% in the epoetin alfa arm (

 < .0001), regardless of ring sideroblast status.1 The interim COMMANDS data supported the 

August 2023 FDA approval of frontline luspatercept for patients in this population

“This compound will be important in the community because now have in the front line a good drug for the treatment of patients with anemia,” Garcia-Manero said in an interview with 

In the interview, Garcia-Manero discussed key efficacy and safety findings from the COMMANDS trial; the significance of the FDA approval of luspatercept in patients with lower-risk MDS; and considerations for bringing this agent into clinical practice.

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

: What are the implications of the FDA approval of luspatercept in patients with lower-risk MDS?

: [This approval is] significant because anemia and transfusion independency are major problems for patients with low-risk MDS. For as long as I remember, we only had 1 class of first-line agents, ESAs. They are great drugs that helped patients for many years, but we needed better compounds.

We developed luspatercept, [which received its] first indication in 2020 in the second-line setting in patients with ring sideroblastic anemia. Those data formed the basis for the randomized COMMANDS trial, published in 

 in June 2023, where we randomly assigned [previously untreated], transfusion-dependent patients with low-risk MDS to either luspatercept or an ESA, in this case, epoetin alfa. The results are clear. [In the] intention-to-treat [ITT] population, responses [with luspatercept] were doubled, at 58.5% [vs] 31.2% [with epoetin alfa]. The duration of response [DOR] was 126.6 weeks [with luspatercept] with an excellent safety profile. We are excited.

What patient population did COMMANDS enroll?

This is a multicenter, multi-country trial. There were 178 patients enrolled in each arm, comparing luspatercept vs epoetin alfa. It was well balanced. There were more patients with ring sideroblastic anemia enrolled in the study; [73.0% and 71.9% of patients] were ring sideroblastic positive [in the luspatercept and epoetin alfa arms, respectively]. We don’t know why that happened. However, the data we have published [that were] presented at [the 2023 ASCO Annual Meeting and the 2023 EHA Congress] are on an ITT basis.

There is some question about the activity of this compound vs epoetin alfa in the ring sideroblastic–negative phenotype. The reality is that if you look at the data, the DOR is also longer in the ring sideroblastic–negative subset of patients. That, together with the schedule, toxicity profile, and so forth, [shows that] most patients with this disease will be treated with luspatercept, although one could argue [whether there is a drawback to] using an ESA in ring sideroblastic–negative disease in the front line as opposed to luspatercept, and the answer is no.

What safety considerations with luspatercept are important to note?

[Safety] is important because in low-risk MDS, where we’re trying to mitigate anemia, we don’t want to cause other problems, such as thrombocytopenia, neutropenia, infections, bleeding, and so forth. The COMMANDS trial, where we compared epoetin alfa vs luspatercept, showed a similar safety profile between those compounds, nothing that the community will not know, and there were no major differences between both drugs. There was no increased rate of transformation to high-risk MDS or acute leukemia.

Overall, [both are] well tolerated compounds. It’s important to reflect on the fact that in the United States, at least, we never had randomized studies for the approval of ESAs. The COMMANDS data also teach us about how those drugs behave in this context and the types of toxicities we see with those drugs. In general, these are easy, well-tolerated compounds.

How quickly may luspatercept be adopted in clinical practice, and will this agent become the standard of care for patients with lower-risk MDS?

It’s a new drug. The reality is, it’s already been approved for a couple of years in another indication, so the community is familiar with the drug already. However, on the other hand, we have had ESAs for a long time, and they’re part of our daily practice. It will be interesting to see how [the field will] shift from ESAs to luspatercept.

What is your main message for colleagues regarding advances in the MDS treatment paradigm?

[The presentations from SOHO show] quite a bit of progress. [In the] first line, [we have] luspatercept. [In the] second line, [we may have] the imetelstat compound. [There is also] the development of oral hypomethylating agents [HMAs] and better data with transplant. Furthermore, we are waiting [the results of] one of the last randomized trials in high-risk [MDS] with venetoclax [Venclexta] in combination with azacitidine [Vidaza]. If that is positive, we’re starting to check all the boxes. People are starting to talk about early intervention and maybe starting to [ask]: Can we cure some patients with this disease? We still have a problem of [disease progression in the] second line after HMAs, but we’ll get there.

Garcia-Manero G, Platzbecker U, Santini V, et al. Luspatercept versus epoetin alfa for treatment of anemia in patients with erythropoiesis-stimulating agent-naive lower-risk myelodysplastic syndromes requiring red blood cell transfusions: data from the phase 3 COMMANDS study. Presented at: 2023 SOHO Annual Meeting; September 6-9, 2023; Houston, TX.

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 September 21, 2023. 

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

Guillermo Garcia-Manero, M, discusses key efficacy and safety findings from the COMMANDS trial; the significance of the FDA approval of luspatercept in patients with lower-risk MDS; and considerations for bringing this agent into clinical practice. 

Luspatercept Broadens Lower-Risk MDS Treatment Landscape 

Farhad Ravandi-Kashani, MD, Janiece and Stephen A. Lasher Professor of Medicine, chief, Section of Developmental Therapeutics, professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses the FDA approval of luspatercept-aamt (Reblozyl) in myelodysplastic syndrome (MDS).

the FDA approved luspatercept for the treatment of

 with erythropoiesis-Stimulating Agent (ESA)–naïve very low– to intermediate-risk MDS who may require regular red blood cell (RBC) transfusions. The regulatory decision was supported by data from the phase 3 COMMANDS trial (NCT03682536). The open-label, randomized study investigated the use of luspatercept vs the ESA epoetin alfa. Luspatercept was shown to produce superior RBC transfusion independence (RBC-TI) and hemoglobin (Hb) increase vs epoetin alfa.

, Guillermo Garcia-Manero, MD, of MD Anderson Cancer Center, presented data from the phase 3 trial, showing that the study met its primary end point of RBC-TI. Of the patients (n = 178) who were treated with luspatercept, 58.5% remained RBC-TI for 12 weeks or more with a concurrent mean hemoglobin increase of at least 1.5 g/dL, compared with 31.2% of patients treated with the ESA epoetin alfa (n = 178; 

Anemia and transfusion dependence has been one of the biggest challenges issues associated with the use of ESAs in this patient population. Although they are considered standard treatment, Ravandi-Kashani explains, ESAs have limited efficacy. Therefore, having a new agent with a different mechanism of action that can elicit significant improvement in RBC-TI is an important step forward in this space, Ravandi-Kashani emphasizes. The COMMANDS trial demonstrated that luspatercept can be superior to ESAs in the frontline for in this subset of patients, he concludes.

Farhad Ravandi-Kashani, MD, discusses the FDA approval of luspatercept in myelodysplastic syndrome.

Dr Ravandi-Kashani on the FDA Approval of Luspatercept in 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 investigation of luspatercept-aamt (Reblozyl) vs epoetin alfa in patients with erythropoiesis-stimulating agent (ESA)–naïve, lower-risk myelodysplastic syndromes (MDS) and disease-related anemia who requires red blood cell (RBC) transfusions.

, the phase 3 COMMANDS trial (NCT03682536) was reported to have met its composite primary end point of RBC transfusion independence (RBC-TI). Of the 178 patients in the luspatercept arm and the 178 patients in the ESA epoetin alfa arm, 58.5% vs 31.2%, respectively, remained RBC-TI for 12 weeks or more with a concurrent mean hemoglobin increase of at least 1.5 g/dL (

 in August, 2023, for the treatment of anemia in patients who have notreceived prior ESA treatment, have very low– to intermediate-risk MDS , and may require regular RBC transfusion. This regulatory decision was based on data from the multicenter, global COMMANDS trial.

In a presentation of the data, Garcia-Manero shared that 73% of patients in the luspatercept arm and 71.9% of patients in the ESA epoetin alfa arm had ring sideroblastics. Moreover, this analysis was conducted in the intent-to-treat population, Garcia-Manero emphasizes. However, questions remain regarding the activity of this compound in other patient subsets, he explains.

Moreover, Garcia-Manero notes that the duration of response with luspatercept was is longer in the ring sideroblastic subset. Based on these data, most patients with this disease will be treated with luspatercept going forward, Garcia-Manero concludes. 

Guillermo Garcia-Manero, MD, discusses the investigation of luspatercept vs epoetin alfa in patients with erythropoiesis-stimulating agent-naïve, lower-risk myelodysplastic syndromes and disease-related anemia who requires red blood cell transfusions.

2023 SOHO Meeting Reporter | Supplements and Featured Publications

Dr Komrokji on Ongoing Investigations With Luspatercept in MDS

Luspatercept Approval Shifts Treatment Landscape of Anemia in Lower-Risk MDS

Dr Platzbecker on the COMMANDS Trial in Lower-Risk MDS With Anemia

Luspatercept Broadens Lower-Risk MDS Treatment Landscape

Dr Ravandi-Kashani on the FDA Approval of Luspatercept in MDS

Dr Garcia-Manero on the Investigation of Luspatercept in Transfusion-Dependent MDS