Recent Data Shed Further Light on the MDS Treatment Paradigm as the SOC Evolves

When considering current and emerging treatment options for patients with myelodysplastic syndrome (MDS), Jeremy Allred, MD, looks to data from the 2023 American Society of Hematology (ASH) Annual Meeting and Exposition, noting that findings presented at the meeting have informed current therapeutic strategies.

“Therapeutic options for patients with low-risk MDS have been somewhat limited, although there are new agents coming [into practice] more frequently, and we were lucky at this most recent ASH Meeting to have findings from 2 phase 3 trials that helped to guide therapy. Although therapeutic options have been limited, it does seem like the future is more optimistic,” Allred said in an interview with OncLive®. Allred is an oncologist and assistant professor of medicine in the Division of Hematology, Oncology and Transplantation, at the University of Minnesota Medical School in Minneapolis.

Following the 2023 ASH Annual Meeting, findings from the phase 3 COMMANDS trial (NCT03682536) and phase 3 IMerge trial (NCT02598661) in patients with low-risk MDS have shed light on treatment strategies for this population of patients. Data from the full analysis of COMMANDS revealed that 60.4% of patients with very low-, low-, or intermediate-risk MDS treated with luspatercept-aamt (Reblozyl; n = 182) achieved the primary end point of red blood cell-transfusion independence (RBC-TI) for at least 12 weeks with concurrent mean hemoglobin increase of at least 1.5 g/dL compared with 34.8% of those treated with epoetin alfa (n = 181; P < .0001). The median duration of treatment was also longer in the luspatercept arm at 51.3 weeks (range, 3-196) vs 37.0 weeks (range, 1-202) in the epoetin alfa arm.¹

“The COMMANDS data are an excellent example of head-to-head trial [findings] that show superiority of luspatercept over erythropoiesis-stimulating agents for the treatment of lower-risk, transfusion-dependent MDS and [luspatercept] likely represents the new standard of care,” Allred said. “I have found luspatercept to be very well tolerated and patients like it, so if it’s working, it’s a very good option for patients.”

In addition to data from COMMANDS that were presented at the 2023 ASH Annual Meeting, findings presented from IMerge demonstrated that patients with MDS treated with imetelstat achieved a higher RBC-TI rate compared with those treated with placebo regardless of Molecular International Prognostic Scoring System risk group. Patients with very low-, low-, or moderate low-risk disease who received imetelstat (n = 91) experienced a 24-week or greater RBC-TI rate of 28.6% vs 2.3% for patients who received placebo (n = 43; P < .001). These rates were 8.3% vs 0.0% among patients with moderate high-, high-, or very high-risk disease treated with imetelstat (n = 12) vs placebo (n = 9), respectively (P = .414).²

“[For] the low-risk [population], there are newer agents that should be more readily available for patients who develop refractory anemia in the next couple of years; more options are always better for this patient population,” Allred said.

For patients with high-risk MDS, the combination of the hypomethylating agent (HMA) azacitdine with venetoclax (Venclexta) has shown promise, according to Allred. Patients with de novo treatment-naive, high-risk MDS who received the combination (n = 107) experienced a complete response rate of 29.9% (95% CI, 21.4%-39.5%) in the phase 1b M15-513 study (NCT02942290). The median number of treatment cycles prior to transplantation was 3.0 (range, 1.0-11.0) and 57.9% of patients received subsequent treatment, which included transplantation in 39.3% of patients. Further, the median overall survival (OS) was 26 months (95% CI, 18.1-51.5).³

“Venetoclax has become a mainstay of treatment [for] non-intensive chemotherapy eligible, primarily elderly patients with acute myeloid leukemia [and] given the considerable relationship between MDS and leukemia, there is strong scientific rationale for venetoclax’s use,” Allred explained. “Preclinical and now early clinical data are showing accelerated responses as well as deeper responses in a particularly difficult to treat patient population. Whether [treatment with venetoclax plus an HMA] improves OS or allows patients to transition to transplant are questions that remain in the field.”

Regarding next steps for research in MDS, Allred noted that “more focus should be paid to addressing the MDS stem cells and the variant allele frequencies of the genes associated with driving MDS; therapeutic strategies should be designed around better control over the specific molecular pathways that lead to stem cell growth.”

References

1. Garcia-Manero G, Platzbecker U, Santini V, et al. Efficacy and safety of luspatercept versus epoetin alfa in erythropoiesis-stimulating agent (ESA)-naive patients (Pts) with transfusion-dependent (TD) lower-risk myelodysplastic syndromes (LR-MDS): full analysis of the COMMANDS trial. Blood. 2023;142(suppl 1):193. doi:10.1182/blood-2023-178596
2. Komrokji RS, Santini V, Fenaux P, et al. Efficacy of imetelstat in achieving red blood cell transfusion independence (RBC-TI) across different risk subgroups in patients with lower-risk myelodysplastic syndromes (LR-MDS) relapsed/refractory (R/R) to erythropoiesis-stimulating agents (ESAs) in IMerge phase 3 study. Blood. 2023;142(suppl 1):194. doi:10.1182/blood-2023-181237
3. Efficacy and safety of venetoclax in combination with azacitidine for the treatment of patients with treatment-naive, higher-risk myelodysplastic syndromes. Blood. 2023;142(suppl 1):319. doi:10.1182/blood-2023-189446