Luspatercept ‘a paradigm shift’ in transfusion-dependent myelodysplastic syndrome
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Key takeaways:
- Significantly more patients who received luspatercept vs. epoetin alfa achieved the study’s primary endpoint of transfusion independence.
- The treatments exhibited similar toxicity profiles.
Treatment with luspatercept vs. epoetin alfa nearly doubled the number of patients with lower-risk myelodysplastic syndrome who no longer required red blood cell transfusions for anemia, results of the phase 3 COMMANDS trial showed.
The findings, scheduled for presentation at ASCO Annual Meeting, showed luspatercept (Reblozyl; Celgene, Bristol Myers Squibb) — an erythroid maturation agent — provided significantly longer transfusion independence than standard-of-care treatment with epoetin alfa, an erythropoiesis-stimulating agent (ESA). As a result, patients with (MDS) may require fewer trips to the clinic for treatment of anemia, the investigators noted.
“Luspatercept is the first and only therapy to demonstrate superiority in a head-to-head study against an ESA in patients with transfusion-dependent low-risk MDS,” Guillermo Garcia-Manero, MD, professor in the department of leukemia and chief of the section of myelodysplastic syndromes at The University of Texas MD Anderson Cancer Center, said during a press conference. “It should be considered a paradigm shift in the treatment of those with low-risk MDS-associated anemia.”
Background
Anemia represents a major burden for patients with MDS and is likely the most important issue that clinicians must address, according to Garcia-Manero.
The first-line option for these patients is epoetin alfa — an ESA — which has limited efficacy and durability for treatment of anemia in these patients, he added.
“Chronic anemia and transfusion dependency are significant clinical challenges in [patients with] lower-risk MDS, increasing the risk [for] death by more than 50% compared [with] patients who are transfusion independent,” Garcia-Manero said. “There is an unmet need for effective and durable options other than ESAs for treating anemia in patients with lower-risk MDS.”
The FDA previously approved luspatercept for treatment of anemia in patients with very low- to intermediate-risk MDS with ring sideroblasts after ESA failure or among those who are ineligible for treatment with ESAs.
Methodology
The COMMANDS trial assessed the safety and efficacy of luspatercept compared with epoetin alfa for treatment of anemia in adults with transfusion-dependent lower-risk MDS who have not previously received an ESA. About 60 percent of patients had ring sideroblasts, Garcia-Manero said.
Investigators randomly assigned the study participants in a 1:1 ratio to either subcutaneous luspatercept (n = 178; starting dose, 1 mg/kg, titration up to 1.75 mg/kg) once every 3 weeks or epoetin alfa (n = 176; starting dose, 450 IU/kg, titration up to 1,050 IU/kg) weekly for at least 24 weeks.
Achieving red blood cell transfusion independence of at least 12 weeks within the first 24 weeks of treatment, with a concurrent mean hemoglobin increase of at least 1.5 g/dL, served as the study’s primary endpoint. Secondary endpoints included safety and durability of red blood cell transfusion independence.
Key findings
The COMMANDS trial met its primary endpoint by demonstrating a clinically superior increase in the proportion of patients who achieved transfusion independence of at least 12 weeks, with a concurrent mean hemoglobin increase of at least 1.5 g/dL, in the luspatercept vs. epoetin alfa group (58.5% vs. 31.2%; P < .0001).
Investigators reported a 41.6-week median treatment duration with luspatercept compared with a median 27 weeks with epoetin alfa.
Study participants treated with luspatercept also demonstrated significantly longer median duration of transfusion independence compared with those treated with epoetin alfa (126.6 weeks vs. 77 weeks; HR = 0.46; 95% CI, 0.26-0.79).
The luspatercept group had higher rates of treatment-emergent adverse events (92.1% vs. 85.2%) and treatment-related adverse events (30.3% vs.17.6%).
Thirty-two patients in each group died during the treatment and post-treatment follow-up periods, resulting in a similar death rate between the two treatment arms (18% vs. 18.2%).
Five patients treated with luspatercept went on to develop high-risk MDS compared with seven participants in the epoetin alfa group (2.8% vs. 4%). Similarly, four patients in the luspatercept group progressed to acute myeloid leukemia compared with five treated with epoetin alpha (2.2% vs. 2.8%).
Clinical implications
“The results from the COMMANDS study support the upfront use of luspatercept in patients with transfusion-dependent low-risk MDS who are naive to prior therapy,” Garcia-Manero told Healio. “Luspatercept will likely take the place of traditional erythropoiesis-stimulating agents as front-line therapy.”
Perspective
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Lisa Law, MD
The interim results of this study are exciting and suggest that luspatercept may be a more effective treatment option for patients with lower-risk MDS. Nevertheless, further details of this study — including the breakdown of treatment-emergent adverse events and patients’ quality of life — are eagerly awaited.
In addition, it would be useful to know how many patients in the study carried the SF3B1 mutation, as we know this subgroup of patients may have a more favorable response with luspatercept.
Although the current cost of luspatercept is much higher than epoetin alfa, one must also factor in the cost of blood transfusion, chair time, blood product availability and patient convenience when determining the value of this new therapeutic option. Luspatercept may be a good option overall despite its current price.
The results of the COMMAND trial are convincing. I firmly believe there is a role for luspatercept in selected patients with lower-risk MDS patients because it clearly reduces transfusion burden. I commend the researchers for the success of this randomized phase 3 study and eagerly await its full publication.
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Garcia-Manero G, et al. Abstract 7003. Scheduled for presentation at: ASCO Annual Meeting; June 2-6, 2022; Chicago.
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