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

Uwe Platzbecker, MD

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.

In August 2023, the FDA approved luspatercept for the treatment of anemia in patients with low- to intermediate-risk MDS who have not previously been treated with ESA and may require regular red blood cell (RBC) transfusions, based on results from the phase 3 COMMANDS trial (NCT03682536).¹

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; P < .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.

In an interview with OncLive®, 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.

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

Platzbecker: 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].

References

1. 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.
2. 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.