FDA Approves Luspatercept for First-line Treatment of Anemia in Lower-Risk MDS

FDA

The FDA has 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 myelodysplastic syndrome (MDS) who may require regular red blood cell (RBC) transfusions.¹

The regulatory decision is supported by interim findings from the phase 3 COMMANDS trial (NCT03682536), in which luspatercept had superior efficacy of concurrent RBC transfusion independence (RBC-TI) and hemoglobin (Hb) increase vs epoetin alfa, irrespective of ring sideroblast status.

Specifically 58.5% (n = 86) of patients who received luspatercept vs. 31.2% (n = 48) of those given epoetin alfa 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 (P <.0001).

“For patients with lower-risk MDS, current standard therapies, including ESAs, have provided limited benefit in controlling anemia with only 1 in 3 patients responding for a duration of 6-18 months," Guillermo Garcia-Manero, MD, lead investigator and chief of the Section of Myelodysplastic Syndromes at The University of Texas MD Anderson Cancer Center, stated in a press release. “Results from the COMMANDS study showed nearly twice as many patients treated with [luspatercept] achieved transfusion independence of at least 12 weeks and concurrent hemoglobin increase compared to epoetin alfa. Today’s approval represents an important advancement for patients with lower-risk MDS.”

In November 2019, the FDA greenlit luspatercept for the treatment of anemia in adult patients with β-thalassemia who require regular RBC transfusions.² Additionally, in April 2020, the FDA approved the agent for the treatment of anemia failing an ESA and requiring 2 or more RBC units over 8 weeks in adult patients with very low- to intermediate-risk MDS with ring sideroblasts or with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis.³

COMMANDS enrolled patients who had a documented diagnosis of MDS by World Health Organization 2016 criteria whose disease met the Revised International Prognostic Scoring System classification of very low risk, low risk, or intermediate risk with less than 5% blasts in the bone marrow.⁴ Patients needed to be at least 18 years of age, naïve to ESAs, require RBC transfusions, and have an endogenous serum erythropoietin concentration of lower than 500 U/L at the time of screening.

If patients previously received ESAs, disease-modifying drugs like lenalidomide (Revlimid), hypomethylating agents, or luspatercept, they were excluded. Other exclusion criteria included having a diagnosis of MDS with del(5q) or unclassifiable MDS.

The study enrolled patients who were randomly assigned 1:1 to receive luspatercept or epoetin alfa. Luspatercept was administered subcutaneously once every 3 weeks, at a starting dose of 1.0 mg/kg which could be increased to 1.33 mg/kg and then to 1.7 mg/kg maximum. Epoetin alfa was also given subcutaneously once weekly, at a starting dose of 450 IU/kg . that could be increased to 787.5 IU/kg and then to 1050 IU/kg maximum. Patients were allowed to receive best supportive care in the form of transfusions, antivirals, antibiotics, and antifungals.

RBC-TI for at least 12 weeks with a concurrent mean Hg increase of at least 1.5 g/dL in weeks 1 to 24 served as the trial’s primary end point. Key secondary end points assessed during weeks 1 to 24 comprised RBC-TI for at least 12 weeks, TI for 24 weeks, and hematological improvement–erythroid (HI-E) response by International Working Group criteria.

At the time of the cutoff date of August 31, 2022, a total of 356 patients underwent randomization; 178 received luspatercept and 178 received epoetin alfa.

Baseline characteristics were well balanced between the arms. The median age was 74 years (interquartile range [IQR], 69-80), and 56% of patients were male. The median transfusion burden in the 8 weeks prior to baseline was 3 units per 8 weeks (IQR, 2-4). Moreover, the median endogenous serum erythropoietin at baseline was 84.5 U/L (IQR, 40.9-179.1), and the median Hg concentration at baseline was 7.8 g/dL (IQR, 7-8). Of 355 evaluable patients, 73% had ring sideroblasts.

Additional data published in The Lancet showed that 67% of patients in the luspatercept arm vs 46% of those in the epoetin alfa arm achieved RBC-TI for at least 12 weeks during weeks 1 to 24 (common risk difference on response rate, 19.1; nominal P =.0002). RBC-TI for 24 weeks during weeks 1 to 24 was achieved in 48% and 29% of patients, respectively (common risk difference on response rate, 17.0; nominal P =.0006).

Moreover, HI-E response was experienced by 74% of those who received luspatercept vs 51% of those given epoetin alfa (common risk difference on response rate, 22.3; nominal P <.0001). RBC-TI for at least 24 weeks during weeks 1 to 48 was achieved in 58% and 35% of patients, respectively (common risk difference on response rate, 21.8; nominal P <.0001).

Regarding safety, the most common adverse effects occurring in more than 10% of patients included diarrhea, fatigue, hypertension, peripheral edema, nausea, and dyspnea.¹

“Today's expanded approval of [luspatercept] marks an important milestone in our commitment to MDS patients with anemia by providing a durable and more effective treatment option, with more convenient and less frequent administration,” Wendy Short-Bartie, senior vice president and general manager of US Hematology and Cell Therapy at Bristol Myers Squibb, added in the press release.¹ “We remain dedicated to addressing hard-to-treat diseases with significant burden to patients and look forward to bringing this important option earlier in the treatment process.”

WATCH: Uwe Platzbecker, MD, of University Hospital Leipzig, discusses the significance of the FDA approval of luspatercept-aamt for patients with lower-risk myelodysplastic syndrome with anemia.

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 August 28, 2023.
2. FDA approves luspatercept-aamt for anemia in patients with beta thalassemia. FDA. November 8, 2019. Accessed August 28, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-luspatercept-aamt-anemia-patients-beta-thalassemia
3. FDA approves luspatercept-aamt for anemia in adults with MDS. FDA. April 3, 2020. Accessed August 28, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-luspatercept-aamt-anemia-adults-mds
4. Platzbecker U, Porta MGD, Santini V, et al. Efficacy and safety of luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, transfusion-dependent, lower-risk myelodysplastic syndromes (COMMANDS): interim analysis of a phase 3, open-label, randomised controlled trial. Lancet. 2023;402(10399):373-385. doi:10.1016/S0140-6736(23)00874-7