Myelodysplastic Syndrome: What the IPSS Score Means and How MDS Is Treated

Research-informed explainer — last updated April 12, 2026

Myelodysplastic syndrome (MDS) is a bone marrow disorder in which immature blood cell precursors fail to develop properly, leading to low blood counts and — in a significant minority of patients — transformation into acute myeloid leukemia. Treatment depends almost entirely on risk stratification: low-risk patients often need only supportive care and anemia management, while high-risk patients require hypomethylating agent therapy and consideration of allogeneic stem cell transplant.

This article draws on research from four specialists who co-developed the tools and treatments that define modern MDS care. Mikkael Sekeres, MD, Professor of Medicine and Chief of the Division of Hematology at the Sylvester Comprehensive Cancer Center, co-authored the revised IPSS (IPSS-R) risk scoring system (3,088 citations), published the foundational paper distinguishing clonal hematopoiesis from MDS (1,892 citations), and contributed to TP53-targeted therapy research. Richard Stone, MD, Director of the Adult Acute Leukemia Program at Dana-Farber Cancer Institute, led the pivotal randomized azacitidine trial (1,802 citations) and the lenalidomide trial for 5q-deletion MDS (1,313 citations) — the two most widely used active treatments for MDS. Michael Savona, MD, Beverly and George Rawlings Director of Hematology Research and Professor of Medicine at Vanderbilt University, developed the molecular IPSS (IPSS-M, 766 citations) that adds genomic mutations to risk prediction and contributed to the luspatercept trial for lower-risk MDS (528 citations). Courtney DiNardo, MD, Professor at MD Anderson Cancer Center, contributed to the 2022 ICC classification of myeloid neoplasms (2,487 citations) that refined how MDS is separated from AML.

What is MDS and how is it different from leukemia?

MDS is characterized by dysplastic (abnormally shaped) blood cell precursors in the bone marrow and cytopenias — low levels of red blood cells, white blood cells, or platelets — in the peripheral blood. Unlike AML, MDS cells have not fully lost their ability to differentiate, and blast counts (immature leukemia cells) are typically below 20% of the marrow.

The 2022 International Consensus Classification that Dr. DiNardo contributed to (2,487 citations) updated the blast threshold distinguishing MDS from AML. MDS is now classified as having fewer than 10% blasts, with a category of "MDS/AML" for 10–19%, and AML requiring 20% or more. This revised boundary reflects the biologic continuum between MDS and AML and has practical implications: patients near the threshold may be treated more like AML or more like MDS depending on their overall picture.

Clonal hematopoiesis vs. MDS: an important distinction

Not everyone with abnormal blood counts has MDS. Dr. Sekeres co-authored the landmark 2015 paper in Blood (1,892 citations) establishing the term "clonal hematopoiesis of indeterminate potential" (CHIP) — the presence of somatic mutations in blood cells without evidence of MDS, another blood cancer, or cytopenia of sufficient severity to diagnose MDS. CHIP is extremely common in older adults (detectable in over 10% of people over 70) and carries an approximately 0.5–1% per year risk of progressing to a hematologic malignancy. Most people with CHIP do not need treatment but benefit from monitoring.

The key distinction is that MDS requires both dysplasia on bone marrow biopsy and measurable cytopenias meeting specific thresholds. A positive mutation result alone — even for MDS-associated mutations like ASXL1, TET2, or SF3B1 — does not make a diagnosis of MDS.

How risk is scored: IPSS-R and IPSS-M

Risk stratification in MDS is the cornerstone of treatment decisions. The revised IPSS (IPSS-R) co-authored by Dr. Sekeres, published in Blood in 2012 (3,088 citations), incorporates five variables:

1. Cytogenetic category (good, intermediate, poor, or very poor)
2. Marrow blast percentage
3. Hemoglobin level
4. Platelet count
5. Absolute neutrophil count

These five variables generate a score that places patients in one of five categories: very low, low, intermediate, high, and very high. Median overall survival ranges from 8.8 years for very-low-risk patients to 0.8 years for very-high-risk patients without treatment. The IPSS-R directly guides treatment: very-low and low-risk patients focus on managing symptoms and cytopenias; intermediate-risk and above increasingly prompt discussion of active treatment or transplant.

Dr. Savona and colleagues published the molecular IPSS (IPSS-M) in 2022 (766 citations), adding 31 gene mutations to the IPSS-R framework. This refined risk prediction significantly — approximately one-third of patients are reclassified when genomic data are added — and helps identify patients whose disease looks lower-risk by cell counts but carries high-risk molecular features that predict transformation.

Treatment for lower-risk MDS: managing anemia

The most common problem in lower-risk MDS is transfusion-dependent anemia. The main approaches are:

Erythropoiesis-stimulating agents (ESAs): Erythropoietin or darbepoetin alfa stimulates red blood cell production. They are most effective in patients with low serum erythropoietin levels and low transfusion burden.

Lenalidomide for del(5q) MDS: Patients with MDS and deletion of the long arm of chromosome 5 have a specific vulnerability to lenalidomide (an immunomodulatory drug). Dr. Stone led the pivotal MDS-003 trial published in the New England Journal of Medicine in 2006 (1,313 citations): among 148 patients with transfusion-dependent del(5q) MDS, 67% became transfusion-independent with lenalidomide. This is the closest thing to a targeted therapy for a specific MDS subtype and remains the standard of care for del(5q) patients.

Luspatercept: A transforming growth factor-beta ligand trap that promotes late-stage red blood cell maturation. Dr. Savona contributed to the MEDALIST trial published in the New England Journal of Medicine in 2020 (528 citations): among 229 lower-risk MDS patients with ring sideroblasts who had failed or were ineligible for ESAs, 38% of luspatercept-treated patients achieved transfusion independence versus 13% of placebo patients. Luspatercept is now approved for transfusion-dependent lower-risk MDS with ring sideroblasts.

Treatment for higher-risk MDS: hypomethylating agents

For patients with intermediate-2 or high IPSS-R risk (or IPSS-M intermediate or higher), hypomethylating agents are the primary treatment. Dr. Stone co-led the Cancer and Leukemia Group B (CALGB) randomized trial of azacitidine (1,802 citations), which enrolled 191 MDS patients and demonstrated that azacitidine improved response rate (60% vs. 5%), time to AML transformation or death (21 vs. 13 months), and quality of life compared with supportive care — establishing azacitidine as the first effective MDS treatment and earning FDA approval.

A subsequent international phase 3 trial to which Dr. Stone contributed (1,137 citations) also demonstrated the value of azacitidine in older AML patients with high blast counts, extending the role of hypomethylating agents to the MDS-AML transition zone.

Decitabine, a related hypomethylating agent, has similar efficacy and is an alternative when azacitidine is not feasible. Neither drug produces a cure — responses typically last 18–24 months before progression — making transplant the only potentially curative option for eligible patients.

TP53-mutant MDS: a challenging subgroup

Patients with TP53 mutations face particularly poor outcomes. Dr. Sekeres contributed to a study of eprenetapopt (APR-246), a small molecule that restores wild-type p53 function to mutant p53 protein, combined with azacitidine (441 citations). In 55 patients with TP53-mutant MDS or AML, the complete response rate was 33%, with 17% achieving complete MRD negativity — promising for a population with few effective options. Trials of this and related TP53-targeting approaches are ongoing.

Questions to ask your doctor

• What is my IPSS-R risk score, and what does it predict about my disease course?
• Has my marrow been tested for the molecular mutations included in the IPSS-M, and does that change my risk category?
• Do I have del(5q) as part of my cytogenetic abnormalities, which would make me a candidate for lenalidomide?
• If I need active treatment, should I start azacitidine or decitabine, and what is the typical response timeline?
• Am I young enough and healthy enough to be considered for allogeneic stem cell transplant, which is the only potentially curative approach?
• What is the difference between MDS and clonal hematopoiesis, and could my blood count abnormalities represent the latter?

The bottom line

MDS spans a wide spectrum — from indolent low-risk disease requiring only watchful waiting and anemia management to aggressive high-risk disease that behaves nearly like AML. The IPSS-R risk score and molecular IPSS are the essential tools for matching treatment intensity to disease severity. Lower-risk patients benefit from del(5q)-specific lenalidomide or luspatercept for anemia; higher-risk patients need hypomethylating agent therapy and transplant evaluation. Comprehensive molecular testing at diagnosis has become essential for accurate risk stratification.