New data presented at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting may reshape the way anemia associated with lower-risk myelodysplastic syndrome (MDS) is managed.
Treatment goals for patients with lower-risk MDS (LR-MDS) include improving cytopenias and health-related quality of life (HRQoL). Transfusion dependency impacts HRQoL and has been linked to overall survival.
“The endpoints that we oftentimes investigate in LR-MDS are not overall survival," said Anand Ashwin Patel, MD from the University of Chicago Medical Center as he began his discussion. “Thinking about what is associated with an improved quality of life for our patients, how they report it or otherwise, is incredibly important, and transfusion independence has been associated with improved quality of life in both lower-risk and higher-risk MDS.”
At ASCO, two international phase 3 studies examined the use of novel treatments for non-del(5q) MDS-associated anemia at different disease stages.
Luspatercept Bests Epoetin Alfa for MDS-Associated Anemia
Luspatercept (Reblozyl) is a monoclonal antibody that binds to ligands that activate the transforming growth factor-beta (TGF-b) pathway. It is currently indicated by the U.S. Food and Drug Administration (FDA) for anemia in patients with very low- to intermediate-risk MDS with ring sideroblasts who have not responded to erythropoiesis-stimulating agents (ESAs).
The COMMANDS study randomly assigned 356 patients with ESA-naïve LR-MDS, with or without ring sideroblasts, who required blood transfusions and had less than 5% bone marrow blasts and serum erythropoietin levels lower than 500 U/L to receive luspatercept or epoetin alfa (Abstract 7003). The primary endpoint of the study was achievement of red blood cell (RBC) transfusion independence for 12 weeks or more, with a concurrent mean hemoglobin increase of at least 1.5 g/dL within the first 24 weeks.
The median patient age was 74 and 75 years, and time since diagnosis was 8.02 and 5.17 months in the luspatercept arm and epoetin alfa arms, respectively. Most patients were positive for ring sideroblasts (73.0% and 71.9% on the luspatercept and epoetin alfa arms, respectively).
Of the 301 patients included in the efficacy analysis, 58.5% of patients on luspatercept achieved the primary endpoint, compared with 31.2% receiving epoetin alfa (P<.0001). The benefit with luspatercept was demonstrated across prespecified subgroups, with the exception of those patients without ring sideroblasts (41.0% with luspatercept vs. 46.3% with epoetin alfa).
When asked about the potential role of luspatercept in the treatment of patients without ring sideroblasts, Guillermo Garcia-Manero, MD, from the University of Texas MD Anderson Cancer Center in Houston stated, “the response rate is not inferior. The toxicity profile is similar, and, actually, the duration of response is in favor of luspatercept. I think most patients and physicians will gravitate towards luspatercept in the first line.”
The median duration of response and time to first RBC transfusion was longer with luspatercept (126.6 vs. 77.0 weeks, hazard ratio [HR]=0.456; 168.0 months vs. 42.0 months, respectively).
Any-grade treatment-emergent adverse events were more common with luspatercept (92.1% vs. 85.2%). Grade 3/4 adverse events with luspatercept included anemia (7.3%), thrombocytopenia (3.9%), neutropenia (3.9%), dyspnea (3.9%), and thromboembolic events (2.8%).
“In patients with anemia with lower-risk MDS who depend on red blood cell transfusions, luspatercept almost doubles the number of people who achieve independence from transfusions for a period lasting 12 weeks or more, when compared with epoetin alfa, a current standard of care treatment.” Olatoyosi Odenike, MD, FASCO, director of the leukemia program at UChicago Medicine stated, “Luspatercept may be an effective first treatment option for anemia associated with lower-risk MDS.”
Imetelstat Benefits Heavily Transfusion-Dependent Relapsed or Refractory LR-MDS
The emerging therapy imetelstat, a novel inhibitor of telomerase activity that specifically targets malignant clones with high telomerase activity enabling recovery of hematopoiesis, was evaluated in patients with relapsed or refractory LR-MDS (Abstract 7004).
The placebo-controlled phase 3 IMerge study evaluated 178 patients with heavily transfusion dependent non-del(5q) LR-MDS relapsed or refractory to ESAs. The primary endpoint of the study was eight-week RBC transfusion independence.
At baseline, 62% of all patients were positive for ring sideroblasts. Participants had a high-level of transfusion dependence, with 48% and 45% of patients requiring more than six RBC units every eight weeks in the imetelstat and placebo arms, respectively. Most patients had received prior ESA treatment (92% on imetelstat, 87% on placebo), but few patients had received prior luspatercept (6% on imetelstat, 7% on placebo).
More patients on imetelstat reached eight-week transfusion independence (39.8% vs. 15.0%; P<.001) which was seen across subgroups. Longer transfusion independence rates with imetelstat were also seen at 16 weeks (31.4% vs. 6.7%; P<.001), 24 weeks (28.0% vs. 3.3%; P<.001), and one year (13.6% vs. 1.7%; P=.012).
“Clinical endpoints that we aim for with LR-MDS need to be informed by improving the quality of life of our patients,” said Dr. Patel, “What is the minimum interval of transfusion independence that's meaningful? We see eight-week, transfusion independence looked at in the IMerge study. However, even when you look at periods beyond that—16 weeks, 24 weeks, et cetera—the benefit of imetelstat was maintained.”
Most of those with eight-week responses experienced durable continued RBC transfusion independence episodes and longer duration of transfusion independence compared with placebo (51.6 vs. 13.3 weeks; HR=0.23; P<.001). There was a significant and sustained increase in hemoglobin among patients treated with imetelstat (median rise 3.6 g/dL vs 0.8 g/dL). In addition, eight-week transfusion independence rates with imetelstat were demonstrated in patients negative for ring sideroblasts (31.8% vs. 23.1%) and in patients who required more than six RBC units every eight weeks (33.9% vs. 7.4%).
Approximately, 75% of patients treated with imetelstat required dose modifications due to adverse events. Grade 3 and 4 hematologic adverse events were common, including thrombocytopenia (62%), neutropenia (68%), anemia (19%), and leukopenia (8%). Most side effects resolved with dose modification, and less than 15% of patients discontinued therapy due to treatment-related adverse events.
The COMMAND and IMerge studies were positive in different patient populations. Although longer follow up will provide more insight, the results will likely have lasting impacts across care for patients with lower-risk MDS.
“The number of positive phase 3 trials in MDS in the last 25 years, you can count them in fingers [on] one hand—less than five,” said lead author of the IMerge study Amer Zeidan, MBBS from Yale School of Medicine in New Haven, Connecticut. “So to see two back-to-back randomized positive phase 3 trials in MDS, you cannot know how this is so unique for us who have been in this field for a very long time.
“It’s really an indication of the progress we have been seeing in MDS.”
Dr Zeidan reported various financial relationships.
Dr. Odenike reported no financial relationships.
Dr. Garcia-Manero reported various financial relationships.
Dr. Patel reported various financial relationships.