HMAs Explored in High-Risk MDS, but Transplant Remains the Only Curative Option

The treatment landscape for high-risk myelodysplastic syndromes (HR MDS) is evolving, moving from supportive care toward a model increasingly guided by molecular diagnosis. The initial step in managing these patients involves accurate risk classification and stratification.

“If a patient comes to me with a rapidly changing hemogram, then that suggests a more aggressive malignancy than MDS,” Elizabeth A. Griffiths, MD, said during a presentation at the NCCN 2025 Annual Congress: Hematologic Malignancies in San Diego, California.¹ “The stability of counts, specifically stable cytopenia over a period of at least 3 months, is required to render this diagnosis.”

Taking this approach often helps to exclude other potential causes, including nutritional deficiencies, coincident viral infections, and hereditary bone marrow failure.² The major criterion in the differential diagnosis is dysplasia of 10% or greater or ring sideroblasts of 15% or greater (or 5% or greater in the presence of an SF3B1 mutation).²

For patients with high-risk disease, the NCCN guidelines recommend hypomethylating agents (HMAs). A critical decision point is determining whether a patient is a candidate for transplantation.³ For those who are transplant ineligible, the preferred regimen is azacitidine (Vidaza), decitabine (Dacogen), or the combination of decitabine and cedazuridine (Inqovi).

In some cases, an HMA with or without venetoclax (Venclexta), ivosidenib (Tibsovo) with or without azacitidine, or olutasidenib (Rezlidhia) with or without azacitidine is appropriate.³

“It’s important to remember that these therapies have to be applied on schedule and for an extended course,” Griffiths said. “If you treat patients for an inadequate time, you can accrue toxicities, which doesn’t really benefit the patient.”

HMA doublets in higher-risk MDS have also been explored but have not met with much success. There have been some large phase 3 randomized clinical trials that have left much to be desired. The one doublet that might be promising involves HMA and venetoclax.⁴

The phase 1b study (NCT02942290) investigated safety and efficacy of venetoclax at the recommended phase 2 dose (400 mg for 14 days per 28-day cycle) in combination with azacitidine (75 mg/m² for 7 days per 28-day cycle) for treatment-naive HR MDS. “These were relatively younger patients,” Griffiths commented. “Most of them received 4 cycles of therapy or more. The median time to complete response [CR] was about 3 months, and the duration of CR was almost 17 months.” Median overall survival was 26.0 months, with 1- and 2-year survival estimates of 71.2% and 51.3%, respectively.

IDH1 and IDH2 Mutations

For patients with specific mutations, targeted therapies offer new options. In October 2023, the FDA approved ivosidenib for adults with relapsed or refractory MDS with a susceptible IDH1 mutation.⁵ The approval was based on findings from the AG120-C-001 trial (NCT02074839), an open-label, single-arm, multicenter trial of 18 adult patients with relapsed or refractory MDS with an IDH1 mutation. IDH1 mutations were detected in peripheral blood or bone marrow by a local or central diagnostic test and confirmed retrospectively by the Abbott RealTime IDH1 assay.

In the trial, the CR rate was 38.9% (95% CI, 17.3%-64.3%). The median time to CR was 1.9 months (range, 1.0-5.6 months), and the median CR duration was not estimable (range, 1.9-80.8+ months).

For patients with an IDH2 mutation, enasidenib (Idhifa) is an option. The inhibitor was evaluated in a 2-arm multicenter study (NCT03383575) for safety and efficacy. In arm A, patients received the combination of enasidenib and azacitidine for newly diagnosed IDH2-mutated MDS, and in arm B, patients received enasidenib monotherapy for IDH2-mutated MDS after prior HMA therapy.⁶

Fifty patients with IDH2-mutated MDS enrolled: 27 in arm A and 23 in arm B. In patients with newly diagnosed MDS (arm A), the overall response rate (ORR) was 74%, 26% of patients had a CR, and the overall median survival was 26 months. In arm B, ORR was 35%, 22% had a CR, and the overall median survival was 20 months.⁶ The median age of patients was 73 years. The most common adverse events were neutropenia (40%), nausea (36%), constipation (32%), and fatigue (26%).

“I think this is a promising approach, and it is now included in the NCCN guidelines,” Griffiths said.

Low-Risk MDS

In low-risk MDS, imetelstat, a first-in-class telomerase inhibitor, is undergoing evaluation in the phase 2/3 IMerge trial (NCT02598661).⁷ The agent interrupts the function of telomerase. Malignant stem cells upregulate expression of telomerase in order to continue dividing. If telomerase is inhibited, it could cause apoptosis within the malignant compartment and allow recovery of the healthier stem cells, which could have disease-modifying potential.^7,8

“The IMerge trial is interesting because patients were enrolled based on IPSS [International Prognostic Scoring System] and not by IPSS-R [Revised IPSS] or IPSS-M [Molecular IPSS],” Griffiths said. “Further, some patients within the low-risk IPSS cohort had intermediate- and higher-risk disease, so this agent may have some activity in higher-risk MDS as well,” Griffiths continued.

Allogeneic Stem Cell Transplantation

Griffiths emphasized that although there are reasonable therapies that offer improvements in transfusion dependence and improvements in leukemia transformation for patients with high-risk MDS, transplant remains the only curative therapy. “When I see a patient for the first time in my clinic, I always discuss allogeneic transplant, and I do this irrespective of age,” Griffiths said. “I think in our center, the absolute cutoff for transplant is 85 years of age.”

“Oral HMAs may offer improved convenience and may improve [adherence]. Clinical trials of HMA doublets have not demonstrated superiority but may be a bridge to transplant, which remains the only curative therapy,” Griffiths concluded.

REFERENCES

1. Griffiths EA. Emerging treatment strategies for high-risk myelodysplastic syndromes. Presented at: NCCN 2025 Annual Congress: Hematologic Malignancies; October 10-11, 2025; San Diego, CA.

2. Valent P, Orazi A, Steensma DP, et al. Proposed minimal diagnostic criteria for myelodysplastic syndromes (MDS) and potential pre-MDS conditions. Oncotarget. 2017;8(43):73483-73500. doi:10.18632/oncotarget.19008

3. NCCN. Clinical Practice Guidelines in Oncology. Myelodysplastic syndromes, version 1.2026. Accessed October 9, 2025. https://www.nccn.org/professionals/physician_gls/pdf/mds.pdf

4. Garcia JS, Platzbecker U, Odenike O, et al. Efficacy and safety of venetoclax plus azacitidine for patients with treatment-naive high-risk myelodysplastic syndromes. Blood. 2025;145(11):1126-1135. doi:10.1182/blood.2024025464

5. FDA approves ivosidenib for myelodysplastic syndromes. FDA. October 24, 2023. Accessed October 27, 2025. https://tinyurl.com/yc53cne5

6. DiNardo CD, Venugopal S, Lachowiez C, et al. Targeted therapy with the mutant IDH2 inhibitor enasidenib for high-risk IDH2-mutant myelodysplastic syndrome. Blood Adv. 2023;7(11):2378-2387. doi:10.1182/bloodadvances.2022008378

7. 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

8. Platzbecker U, Santini V, Fenaux P, et al. Imetelstat in patients with lower risk myelodysplastic syndromes who have relapsed or are refractory to erythropoiesis-stimulating agents (IMerge): a multinational, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2024;403(10423):249-260. doi:10.1016/S0140-6736(23)01724-5