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The More, the Merrier: New Therapeutic Options for Myelodysplastic Syndromes

December 10, 2023
Diego Adrianzen Herrera, MD, MSc, (@diegoah66) 
Division of Hematology and Oncology, Larner College of Medicine, University of Vermont, Burlington

We are living through exciting times when it comes to the treatment of myelodysplastic syndromes (MDS). Following several years without new therapeutic options, the 2020s began with the approval of luspatercept. More recently, in October 2023, we experienced a watershed moment with the first approval of a targeted therapy in MDS: ivosidenib for IDH1-mutant relapsed or refractory myelodysplasia. The oral and poster sessions at #ASH23 reaffirm the evolving landscape of therapeutic options in MDS and provide a glimpse into a more auspicious future for our patients. 

In patients with low-risk MDS (LR-MDS), transfusion-dependent anemia remains one of the most important clinical challenges, especially in those who are refractory to erythropoietin stimulating agents (ESA). Novel agents targeting hematologic response constitute an unmet need in this population and #ASH23 covers updated efficacy data on three medications with exciting mechanisms of action. Will they make it to the clinic soon? 

Imetelstat, a first-in-class telomerase inhibitor, can achieve meaningful and durable transfusion independence in LR-MDS1. In yesterday’s session Myelodysplastic Syndromes – Clinical and Epidemiological: Treatment Options and Decision Making in Low Risk MDS, Rami Komrokji, MD, presented the abstract “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.” The abstract broke down results from the IMerge study, which compared Imetelstat to placebo in transfusion-dependent ESA-refractory patients, across International Prognostic Scoring System revised (IPPS-R) and molecular (IPSS-M) risk categories. Remarkably, sustained transfusion independence was achieved in 45% of IPPS-R intermediate (25% 24-week/20% 1-year) and 17.2% of IPSS-M moderate low/moderate high risk (10.3% 24-week/6.9% 1-year) patients, suggesting clinical efficacy of imetelstat independent of risk category. 

Leveraging a different therapeutic strategy, Moshe Mittelman, MD, presented “Efficacy and Safety of Roxadustat for Treatment of Anemia in Patients With Lower-Risk Myelodysplastic Syndrome (LR-MDS) With Low Red Blood Cell (RBC) Transfusion Burden: Results of Phase III Matterhorn Study.” MATTERHORN is a randomized, phase III, double-blind, placebo-controlled trial of roxadustat, a first-in-class hypoxia-inducible factor prolyl hydroxylase inhibitor, in transfusion-dependent ESA-refractory patients with LR-MDS. Although the trial did not meet its primary endpoint, roxadustat achieved transfusion independence in 47.5% of subjects – a population, in fact, with historically poor outcomes.

Finally, Maria Diez-Campelo, MD, PhD, presented “Durable Clinical Benefit With Ker-050 Treatment: Findings from an Ongoing Phase 2 Study in Participants With Lower-Risk MDS.” The abstract showed promising responses with KER-050, a modified activin receptor type IIA ligand trap designed to inhibit transforming growth factor-β (TGF-β) superfamily signaling and counter ineffective hematopoiesis. Dr. Diez-Campelo detailed the use of KER-050 in an ongoing phase II study of patients with LR-MDS, including 22% with previous ESA exposure. KER-050 achieved erythroid response in 51.4% and transfusion independence in 42.3% of subjects.  

In patients with high-risk MDS (HR-MDS), there is plenty of room for improving the outcomes of the current standard of care, particularly overall survival and progression to acute myeloid leukemia (AML). Novel therapies are needed in the upfront setting, with better safety profiles for this complex and frequently elderly patient population, as well as for patients previously exposed to hypomethylating agents (HMA), who typically carry a poor prognosis.  

Wei Yang, MD, presented “Preliminary Results of a Phase 2 Study of IMM01 Combined With Azacitidine (AZA) As the First-Line Treatment in Adult Patients With Higher Risk Myelodysplastic Syndromes (MDS).” The data showed us safety and efficacy of IMM01 for treatment of HR-MDS in a phase II study. IMM01 is a first-in-human recombinant signal regulatory protein α IgG1 fusion protein that targets CD47 and exerts antitumor activity by enhancing phagocytosis and stimulating T-cell responses. In a treatment-naïve cohort mostly including patients with excess blasts, responses were achieved in 82% of patients, including 36.4% complete response (CR) rate, while safety profile was similar to that of HMA. 

Similarly, Daniel Nguyen, MD, PhD, outlined results from a phase II study of vibecotamab, a CD3-CD123 bispecific T-cell engaging antibody that targets the overexpression of CD123 in leukemic stem cells and has previously demonstrated activity in AML (“A II Study of Vibecotamab, a CD3-CD123 Bispecific T-Cell Engaging Antibody, for MDS or CMML after Hypomethylating Failure and in MRD-Positive AML). The study included, among others, HR-MDS previously treated with an HMA. Overall response rate with vibecotamab was 56% (including 44% CR), a remarkable response in a cohort with previous failure to HMA. Finally, though venetoclax is not novel on the hematology scene, Jacqueline S. Garcia, MD, brought us the latest update on a phase Ib/II study of its upfront use in combination with azacitidine for treatment-naïve patients with HR-MDS (“Efficacy and Safety of Venetoclax in Combination With Azacitidine for the Treatment of Patients With Treatment-Naive, Higher-Risk Myelodysplastic Syndromes). With a regimen including 14 days of venetoclax in each 28-day cycle, more than 80% of patients achieved response or clinical benefit, including 30% CR. Median overall survival was 26 months and 39.3% of patients eventually proceeded to hematopoietic cell transplantation. 

While we cautiously await the longer-term follow-up safety results of these studies, as well as a detailed breakdown of strategies for the implementation of these novel drugs, it is safe to say these early data suggest new agents with promising efficacy are on the horizon for MDS. 

1Steensma DP, Fenaux P, Van Eygen K, et al. Imetelstat Achieves Meaningful and Durable Transfusion Independence in High Transfusion-Burden Patients With Lower-Risk Myelodysplastic Syndromes in a Phase II Study. J Clin Oncol. 2021;39(1):48-56. doi:10.1200/JCO.20.01895 

Dr. Adrianzen Herrera indicated no conflicts of interest.   

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