Luspatercept Is Under Evaluation in Non-Transfusion Dependent Lower-Risk Myelodysplastic Syndrome

Guillermo Garcia-Manero, MD

Investigators have initiated the phase 3 ELEMENT-MDS trial (NCT05949684) with the aim of expanding access to the late-stage erythroid maturation agent luspatercept-aamt (Reblozyl) to patients with non-transfusion dependent lower-risk myelodysplastic syndrome (MDS) for the treatment of anemia.¹

“Over the past 4 to 5 years, we have seen an uptick in our ability to approve drugs for patients with MDS,” Guillermo Garcia-Manero, MD, said in an interview with OncLive®. “Oral decitabine and cedazuridine [Inqovi] is now approved for MDS and is now approved for acute myeloid leukemia [AML] in Europe. Around the same time, [as the decitabine/cedazuridine approval we saw] the first indication for luspatercept [in MDS based] on [data from] the [phase 3] MEDALIST trial [NCT02631070]. Then, we had the second indication for luspatercept in frontline [MDS] for basically all-comers with transfusion dependent [MDS]. [In October 2023], we saw the approval of ivosidenib [Tibsovo] in IDH1-mutated MDS, and the telomerase inhibitor imetelstat [Rytelo] in second-line, transfusion-dependent disease [in June 2024].”

Garcia-Manero is the chief of the Section of Myelodysplastic Syndromes, the deputy chair of translational research, the fellowship program director, and a professor all in the Department of Leukemia, Division of Cancer Medicine, as well as the chair of the faculty senate, at The University of Texas MD Anderson Cancer Center in Houston.

“MDS is among the most heterogeneous diseases we treat, [with] a number of molecular lesions and it’s a disease of epigenetics, which has led to an absence of truly blanket approaches, beyond hypomethylating agents,” Rory Shallis, MD, an assistant professor of medicine (hematology) at Yale School of Medicine, in New Haven, Connecticut, added in a sperate interview with OncLive. “We are seeing a transition to targeted therapies, largely borrowing from AML-style therapies, [such as] IDH inhibition, and I believe the role [of these therapies] will increase to some degree.”

In August 2023, luspatercept was approved by the FDA for the treatment of anemia in adult patients with very low- to intermediate-risk MDS who may require regular red blood cell (RBC) transfusions. The expanded indication built upon the April 2020 FDA approval of the agent for the treatment of patients with very low- to intermediate-risk MDS with ring sideroblasts or with a myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis, and anemia after failure with an erythropoiesis stimulating agent who required at least 2 RBC units over 8 weeks. The regulatory decisions were supported by findings from the phase 3 COMMANDS trial (NCT03682536) and MEDALIST studies, respectively.^2,3

COMMANDS was an open-label, multicenter study that enrolled adult patients with Revised International Prognostic Scoring System (IPSS-R) very low-, low-, or intermediate-risk MDS who did not receive a prior erythropoiesis-stimulating agent (ESA), were RBC transfusion dependent, and had a serum erythropoietin concentration of less than 500 U/L. Eligible patients were randomly assigned 1:1 to receive either subcutaneous luspatercept at a dose of 1.0 to 1.75 mg/kg of body weight once every 3 weeks or once-weekly epoetin alfa at a dose of 450 to 1050 IU/kg for a maximum total dose of 80,000 IU for at least 24 weeks. The primary end point was the rate of 12-week RBC transfusion independence with a concurrent mean hemoglobin increase of at least 1.5 g/dL during weeks 1 to 24.⁴

At respective median follow-up times of 17.2 months (range, 10.4-27.7) and 16.9 months (range, 10.1-26.6), findings from the primary analysis of COMMANDS demonstrated that patients in the luspatercept arm (n = 182) achieved the primary end point at a rate of 60% compared with 35% in the epoetin alfa arm (n = 181), with a common risk difference on response rate of 25.4% (95% CI, 15.8%-35.0%; P < .0001) and an odds ratio of 3.1 (95% CI, 2.0-4.8). Additionally, during weeks 1 through 24, luspatercept was found to be superior vs epoetin alfa in terms of the rate of hematologic improvement-erythroid response for at least 8 weeks (74% vs 53%; P <.0001), 24-week RBC transfusion independence rate (48% vs 31%; P = .0003), and the rate of RBC transfusion lasting at least 12 weeks (68% vs 49%; P < .0001). The median duration of RBC transfusion independence lasting at least 12 weeks was 126.6 weeks (95% CI, 93.0-not estimable) vs 89.7 weeks (95% CI, 62.9-157.3), respectively (HR, 0.61; 95% CI, 0.40-0.95; log-rank P = .026).

In terms of safety, any-grade treatment-emergent adverse effects (TEAEs) occurred at rates of 98% in the luspatercept arm vs 93% in the epoetin alfa arm. The most common any-grade TEAEs included asthenia (15% vs 16%), diarrhea (20% vs 14%), and fatigue (19% vs 8%). Serious TEAEs were present at rates of 49% vs 43%, respectively, the most common of which included pneumonia (5% vs 7%) and COVID-19 (4% vs 6%).

MEDALIST enrolled patients with IPSS-R very low-, low-, or intermediate-risk MDS with ring sideroblasts who were intolerant of or had an inadequate response to ESAs or had a serum erythropoietin greater than 200 U/L. Patients were randomly assigned 2:1 to receive subcutaneous luspatercept at a starting dose of 1 mg/kg every 3 weeks, with 2 dose level increases to 1.33 mg/kg and 1.75 mg/kg permitted after completion of the first 2 cycles if the patient needed at least 1 RBC transfusion in the previous 6 weeks, or placebo; all patients also received best supportive care. The primary end point was the proportion of patients who achieved RBC transfusion independence for at least 8 weeks during weeks 1 through 24.^3,5

At the time of the 2020 FDA approval, patients in the luspatercept arm (n = 153) achieved the primary end point at a rate of 37.9% (95% CI, 30.2%-46.1%) compared with 13.2% (95% CI, 6.5%-22.9%) among patients in the placebo arm (n = 76), for a common risk difference of 24.6% (95% CI, 14.5%-34.6%; P < .0001). Additionally, patients achieved RBC transfusion independence for at least 12 weeks during weeks 1 to 24 at rates of 28.1% (95% CI, 21.1%-35.9%) vs 7.9% (95% CI, 3.0%-16.4%), respectively, and RBC transfusion independence for at least 12 weeks during weeks 1 to 48 at rates of 33.3% (95% CI, 25.9%-41.4%) vs 11.8% (95% CI, 5.6%-21.3%), respectively. These increases corresponded to respective common risk differences of 20.0% (95% CI, 10.9%-29.1%; P = .0002) and 21.4% (95% CI, 11.2%-31.5%; P = .0003).⁵

The most common any-grade adverse effects (AEs) in the luspatercept and placebo arms included fatigue (41% vs 22%), musculoskeletal pain (20% vs 14%), and dizziness/vertigo (18% vs 7%). Among all patients who received luspatercept (n = 242), 2.1% died, 4.5% were forced to discontinue treatment, and 2.9% had a dose reduction, due to AEs.

“The label for luspatercept [provides] patients with an indication for transfusion, even if they are not yet transfusion dependent,” Garcia-Manero said. “The field is moving towards early intervention in patients with anemia and low-risk MDS, because all of the data that we are accumulating suggest that if you start these drugs at the time or before these patients become dependent, the results will be much better.”

“The toxicity profile that we saw in MEDALIST and COMMANDS was excellent; there were no deaths, early mortality, or increased risk of transformation to AML with this intervention. [Therefore], we feel that it’s not dangerous or unethical to start this drug in this context in patients who we used to observe because the drug is safe and well tolerated,” he added.

ELEMENT-MDS Looks to Expand Luspatercept to Non-Transfusion Dependent MDS

The open-label, multicenter ELEMENT-MDS study is recruiting patients with IPSS-R very low-, low-, or intermediate-risk MDS with anemia who are non-transfusion dependent and have not received an ESA. To be eligible for the trial, patients must also have less than 5% blasts in bone marrow and less than 1% blasts in peripheral blood, a baseline endogenous serum erythropoietin level of no greater than 500 U/L, symptoms of anemia, and a baseline hemoglobin concentration of no greater than 9.5 g/dL prior to random assignment. Those with secondary MDS, and/or a history or diagnosis of AML, pure red cell aplasia and/or antibody against erythropoietin, cerebrovascular accident, transient ischemic attack, deep venous thrombosis, pulmonary or arterial embolism, arterial thrombosis, or other venous thrombosis within 6 months prior to random assignment, will be excluded.^1,6

“[In COMMANDS], findings from patients with low erythropoietin levels and a low transfusion burden prompted enthusiasm for ELEMENT-MDS,” Shallis said. “What about introducing [luspatercept] before a patient becomes RBC transfusion dependent, which is most patients with low-risk MDS at diagnosis? This is what ELEMENT-MDS is attempting to answer.”

Approximately 360 eligible patients will be randomly assigned 1:1 to receive either luspatercept once every 3 weeks at a starting dose of 1.0 mg/kg, with dose escalation up to 1.75 mg/kg, or epoetin alfa once a week at a starting dose of 450 IU/kg, with dose escalation up to 1050 IU/kg.6

The primary end point is the proportion of patients who become transfusion dependent, defined as needing at least 3 RBC units per 16 weeks, during any continuous 16-week interval during weeks 1 through 96. The proportion of patients with hemoglobin increase of at least 1.5 g/dL sustained for at least 16 weeks during weeks 1 through 48 is the key secondary end point; other secondary end points include time to RBC transfusion dependence, transfusion-free survival, time to achieve modified hematologic improvement-erythroid response, transfusion independence of at least 24 weeks, time to AML progression, safety, and quality of life.

“To be on this trial, [patients] can’t be transfusion dependent and 1 of the key eligibility criteria is symptomatic anemia, defined in 1 of 4 ways: fatigue, dizziness, weakness, or shortness of breath,” Shallis added. “It’s subjective and patients also need to have hemoglobin [levels] of less than 9.5 g/dL. This might be a point [in treatment] that patients may not have reached yet, and it might take time to accrue [patients] in this trial.”

References

1. Zeidan AM, Komrokji RS, Buckstein R, et al. The ELEMENT-MDS trial: a phase 3 randomized study evaluating luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, non-transfusion-dependent, lower-risk myelodysplastic syndromes. Blood. 2023;142(suppl 1):6503. doi:10.1182/blood-2023-178635
2. 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. News release. Bristol Myers Squibb. August 28, 2023. Accessed August 30, 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
3. FDA approves luspatercept-aamt for anemia in adults with MDS. FDA. April 3, 2020. Accessed August 30, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-luspatercept-aamt-anemia-adults-mds
4. Della Porta MG, Garcia-Manero G, Santini V, et al. Luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, transfusion-dependent, lower-risk myelodysplastic syndromes (COMMANDS): primary analysis of a phase 3, open-label, randomised, controlled trial. Lancet Haematol. 2024;11(9):e646-e658. doi:10.1016/S2352-3026(24)00203-5
5. Reblozyl. Prescribing information. Celgene; 2020. Accessed September 3, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761136orig2lbl.pdf
6. ELEMENT-MDS: a study to compare the efficacy and safety of luspatercept in participants with myelodysplastic syndrome (MDS) and anemia not receiving blood transfusions (ELEMENT-MDS). ClinicalTrials.gov. Updated September 2, 2024. Accessed September 3, 2024. https://clinicaltrials.gov/study/NCT05949684