Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2025 Sep 3:16:20406207251371298.
doi: 10.1177/20406207251371298. eCollection 2025.

Novel small-molecule therapies for myelodysplastic syndromes with IPSS-R ⩾3.5 in patients aged 60 or older: current landscape and challenges

Kehao Hou  1 , Xue Dong  1 , Wenyan Niu  2
Affiliations
Review

Novel small-molecule therapies for myelodysplastic syndromes with IPSS-R ⩾3.5 in patients aged 60 or older: current landscape and challenges

Kehao Hou et al. Ther Adv Hematol. .

Abstract

Myelodysplastic syndromes (MDS), particularly in older adults aged 60 years and above, present significant therapeutic challenges due to poor prognosis and limited treatment options. Higher-risk MDS (HR-MDS), defined by the Revised International Prognostic Scoring System score of ⩾3.5, is characterized by increased myeloblasts, severe cytopenia, and a median survival of <2 years. The pathogenesis involves complex genetic mutations, cytogenetic abnormalities, and a dysregulated bone marrow microenvironment. Current standard therapies, such as hypomethylating agents and allogeneic stem cell transplantation, are often inadequate, especially in older patients with comorbidities and limited clinical trial eligibility. This review highlights emerging targeted therapies for older HR-MDS patients, focusing on small-molecule agents for their critical advantages like patient-friendly oral delivery, lower production barriers, improved access to intracellular targets, and flexible dosing strategies. Venetoclax, an oral B-cell lymphoma-2 (BCL-2) inhibitor, has shown promise in clinical trials but requires further validation. Isocitrate dehydrogenase 1 (IDH1) inhibitors, including ivosidenib and olutasidenib, have demonstrated efficacy and tolerability, while ongoing investigations explore other novel agents like IDH2 inhibitors and FMS-like tyrosine kinase 3 (FLT3) inhibitors. By summarizing the latest advancements, this review emphasizes the importance of developing safe, effective, and personalized therapies to improve outcomes and quality of life for older patients with HR-MDS, with a focus on age-specific clinical trials.

Keywords: higher-risk myelodysplastic syndrome; novel agents; older adults; precision medicine; targeted therapies.

Plain language summary

New and emerging treatments for older adults aged 60 and above with high-risk blood disorders: current treatment options and challenges For older adults aged 60 or above with higher-risk myelodysplastic syndromes (HR-MDS), the prognosis remains challenging. These patients often face more severe disease and have limited treatment options due to age and other health issues. Standard treatments, such as stem cell transplants, are often not suitable for them, making it crucial to find safer and more effective therapies. Recent research has improved our understanding of the genetic and biological factors driving MDS, leading to the development of new small-molecule therapies that target specific aspects of the disease at the molecular level. These therapies are promising alternatives, particularly for older patients who cannot tolerate aggressive treatments. Drugs like IDH1/2 inhibitors, BCL-2 inhibitors (Venetoclax), and XPO1 inhibitors have shown positive results in trials, with some already approved or under review. Other drugs, including HDAC inhibitors, FLT3 inhibitors, and those targeting genes like TP53, ALK5, and NAE, have also shown promise in early-stage trials. Additionally, experimental treatments targeting the Hedgehog pathway and spliceosome are being studied. These new therapies are shifting the treatment approach towards more personalized care, tailored to each patient’s genetic makeup. However, long-term studies are still needed to confirm their safety and effectiveness. As the number of older adults with HR-MDS rises, it’s important to integrate these novel therapies into clinical practice. Continued research, particularly into personalized medicine, and the inclusion of more older patients in clinical trials, will be key to improving treatment outcomes and quality of life for this vulnerable group.

PubMed Disclaimer

Conflict of interest statement

The authors declare that there is no conflict of interest.

Figures

Graphical abstract
Graphical abstract
This image illustrates the mechanism and targets of novel drugs in older patients with HR-MDS, focusing on the interaction of various proteins, receptors, and drugs in the context of apoptosis and mitochondria function.
Figure 1.
An illustration depicting the mechanism and targets of novel drugs in older patients with HR-MDS. AKT, protein kinase B; Bak, Bcl-2 homologous antagonist/killer; Bax, Bcl-2 associated X protein; Bcl-2, B-cell lymphoma-2; FLT3, FMS-like tyrosine kinase 3; HDAC, histone deacetylase; HR, higher risk; IDH1/2, isocitrate dehydrogenase 1/2; IRAK4, interleukin-1 receptor-associated kinase 4; MDS, myelodysplastic syndromes; MEK, mitogen-activated protein kinase; mTP53, mutated tumor protein 53; MyD88, myeloid differentiation primary response 88; NAE, NEDD8-activating enzyme; NEDD8, neural precursor cell expressed developmentally down-regulated protein 8; RA, retinoic acid; RARα, retinoic acid receptor alpha; TCA, tricarboxylic acid; TGF-β, transforming growth factor-β; TLR, toll-like receptors; XPO1, exportin 1.
See this image and copyright information in PMC

References

    1. Cassanello G, Pasquale R, Barcellini W, et al. Novel therapies for unmet clinical needs in myelodysplastic syndromes. Cancers (Basel) 2022; 14(19): 4941. - PMC - PubMed
    1. Weller J F, Lengerke C, Finke J, et al. Allogeneic hematopoietic stem cell transplantation in patients aged 60–79 years in Germany (1998–2018): a registry study. Haematologica 2024; 109(2): 431–443. - PMC - PubMed
    1. Santini V. Advances in myelodysplastic syndrome. Curr Opin Oncol 2021; 33(6): 681–686. - PubMed
    1. Kewan T, Stahl M, Bewersdorf JP, et al. Treatment of myelodysplastic syndromes for older patients: current state of science, challenges, and opportunities. Curr Hematol Malig Rep 2024; 19(3): 138–150. - PubMed
    1. Saygin C, Carraway HE. Current and emerging strategies for management of myelodysplastic syndromes. Blood Rev 2021; 48: 100791. - PubMed

LinkOut - more resources