Myelodysplastic Syndromes (MDS)

Myelodysplastic syndromes (MDS) are clonal disorders of hematopoietic stem cells that cause cytopenias and often progress to acute myeloid leukemia (AML).^1,2 

The classification of MDS was most recently revised by the World Health Organization (WHO) in 2016 and 2022, and clinical practice guidelines focusing on the diagnosis and treatment of these disorders have been developed by national and international working groups.^1,3 In the United States, guidelines by the National Comprehensive Cancer Network (NCCN) are typically followed.⁴ European guidelines are based on the European LeukemiaNet (ELN) recommendations amended in 2014 as well as the European Society for Medical Oncology (ESMO) MDS guidelines.^2,5

Classification Guidelines for MDS

In 2016, the WHO presented a revision of the previous classification developed in 2008, adding clinical, prognostic, morphologic, immunophenotypic, and genetic information discovered since the first classification.³

The 2016 WHO classification changed the terminology for adult MDS, removing the terms “refractory anemia” and “refractory cytopenia.” The revised terminology included “myelodysplastic syndrome” and the various modifiers: single and multilineage dysplasia, ring sideroblasts, excess blasts, and the del(5q) cytogenetic abnormality. These disease modifiers were the basis of several subtypes³:

• MDS with single lineage dysplasia (MDS-SLD)
• MDS with multilineage dysplasia (MDS-MLD)
• MDS with ring sideroblasts (MDS-RS)
• MDS with excess blasts (MDS-EB-1), with 5% to 9% blasts in the bone marrow
• MDS with excess blasts (MDS-EB-2), with 10% to 19% blasts in the bone marrow
• MDS with isolated del(5q)
• MDS, unclassifiable (MDS-U)

In 2022, the International Consensus Classification (ICC) and the WHO published another revision to the classification of myeloid neoplasms.^6,7 In this fifth and updated WHO classification guidelines, a 10% threshold is defined for dysplasia and the number of dysplastic lineages is considered optional for differentiation.^6,7 

Also in this latest WHO classification, MDS entities are grouped into two main categories: MDS with defining genetic abnormalities and MDS that is morphologically defined. MDS with defining genetic abnormalities includes the following subtypes⁷: 

• MDS with low blasts and isolated 5q deletion (MDS-5q)
• MDS with low blasts and SF3B1 mutation (MDS-SF3B1)
• MDS with biallelic TP53 inactivation (MDS-biTP53)

MDS that is morphologically defined includes the following subtypes⁷: 

• MDS, hypoplastic (MDS-h)
• MDS with low blasts (MDS-LB)
• MDS with increased blasts (MDS-IB1), with 5% to 9% blasts in the bone marrow or 2% to 4% blasts in the peripheral blood
• MDS with increased blasts (MDS-IB2), with 10% to 19% blasts in the bone marrow or 5% to 19% blasts in the peripheral blood or Auer rods
• MDS with fibrosis (MDS-f), also with increased blasts of 5% to 19% blasts in the bone marrow or 2% to 19% blasts in the peripheral blood

Additionally, the unclassifiable (MDS-U) subtype was removed from the classification.⁷

The classification of types of myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) overlap syndromes, which are malignancies that present overlapping pathologic and molecular features of MDS and MPN, has been also revised in the following syndromes⁷:

• Chronic myelomonocytic leukaemia
• Myelodysplastic/myeloproliferative neoplasm with neutrophilia
• Myelodysplastic/myeloproliferative neoplasm with SF3B1 mutation and thrombocytosis
• Myelodysplastic/myeloproliferative neoplasm, not otherwise specified

Read more about MDS types

National and International Guidelines for MDS

NCCN Guidelines for MDS

The NCCN provides comprehensive guidelines for the management of MDS, with a focus on risk stratification and treatment options. Key points in these guidelines include⁴:

• Risk stratification, as NCCN guidelines emphasize the importance of risk stratification based on clinical, cytogenetic, and molecular factors. This stratification may allow a tailored treatment approach and prognostic assessment.
• Treatment options, as the guidelines outline various therapeutic approaches based on risk categories, including supportive care, transfusion management, and pharmacologic interventions.
• Disease monitoring, as the guidelines emphasize the need for regular monitoring to assess treatment response, disease progression, and the potential need for therapeutic modifications.

ELN Guidelines for MDS

The ELN provides evidence-based recommendations for the diagnosis and management of MDS, highlighting the incorporation of molecular genetic data, including specific gene mutations, into risk stratification algorithms to refine prognostic assessments.⁵

ESMO Guidelines for MDS

The ESMO guidelines provide an overview of the diagnostic workup, risk assessment, and treatment options for MDS, with a focus on individualized patient management. Similar to other guidelines, the ESMO guidelines stress the importance of risk stratification based on clinical parameters, cytogenetics, and molecular characteristics to guide treatment decisions.²

Read more about MDS diagnosis

Guidelines for MDS Diagnosis and Prognosis

The diagnosis of MDS requires a physical examination and a microscopic examination of blood and bone marrow, relying on cytogenetics, flow cytometry, and mutation analysis.¹ US and European guidelines recommend a mandatory diagnostic work-up in patients with MDS, including^2,4,5:

• Peripheral blood smear;
• Bone marrow aspirate;
• Bone marrow biopsy;
• Cytogenetic analysis;
• Fluorescence in situ hybridization (FISH);
• Flow cytometry; and
• Immunophenotyping.

The NCCN guidelines highlight the importance of the revised International Prognostic Scoring System (IPSS-R) in MDS, as it provides a risk stratification that is more accurate than the WHO Prognostic Scoring System (WPSS) or the Lower-Risk Prognostic Scoring System (LR-PSS).⁴ The ELN guidelines also recommend stratification using the IPSS.⁵

Read more about MDS prognosis

Guidelines for MDS Treatment

Lower-Risk Treatment Guidelines

For patients with lower-risk MDS, the NCCN recommends guidelines including⁴:

• Clinical monitoring;
• Psychosocial support;
• Red blood cell (RBC) transfusions and iron chelation;
• Antibiotics to address bacterial infections;
• Revlimid^® (lenalidomide) for patients with MDS with del(5q);
• Epoietin alfa or Aranesp^® (darbepoetin alfa) if serum erythropoietin (EPO) level is lower than 500 mU/mL;
• Immunosuppressive therapy with Atgam^® (equine antithymocyte globulin [ATG]) if serum EPO level is higher than 500 mU/mL; and
• Vidaza^® (azacitidine), Dacogen^® (decitabine), or Inqovi^® (decitabine/cedazuridine) if the patient presents with symptomatic multilineage cytopenia.

The ESMO guideline recommendations for lower-risk patients include²:

• RBC transfusions and iron chelation;
• Revlimid if the patient presents with MDS del(5q);
• Erythropoiesis-stimulating agents (ESAs), especially EPO alpha, if the patient has lower-risk without del(5q), a limited or absent transfusion requirement, and serum EPO lower than 500 mU/mL; and 
• ESAs and granulocyte-colony-stimulating factor (G-CSF) if the patient has lower-risk without del(5q), a limited or absent transfusion requirement, and serum EPO lower than 500 mU/mL.

The ELN guideline recommendations for lower-risk patients include⁵:

• RBC transfusion and iron chelation;
• ESAs if the patient has serum EPO lower than 500 mU/mL and/or a limited or absent transfusion requirement;
• Revlimid for patients with MDS del(5q) and a serum EPO higher than 500 mU/mL who have transfusion-dependent anemia; and
• ATG with cyclosporin A (CSA) in patients under 60 years of age who present with bone marrow blasts <5%, normal cytogenetics, and transfusion dependency.

Read more about MDS treatment

Higher-Risk Treatment Guidelines

The NCCN sets different guidelines for the treatment of higher-risk patients. For patients in this category, the NCCN recommends allogeneic stem cell transplantation (alloSCT) if the patient is a transplant candidate and a stem cell donor is available. The transplantation may be preceded by treatment with Vidaza, Dacogen, or high-intensity chemotherapy. If transplantation is not an option, Vidaza or Dacogen are recommended, as well as enrollment in a clinical trial.⁴ 

The ESMO and ELN guidelines both recommend alloSCT in higher-risk patients who are under 70 years of age and have a good performance status. Vidaza is recommended when transplantation is not possible. Most patients undergo six courses of Vidaza in subcutaneous injections of 75 mg/m2/day for 7 consecutive days every 28 days. As per randomized trial findings, Vidaza is favored compared to conventional treatments, such as supportive care and low-dose Cytosar-U^® (cytarabine).^2,5

Read more about MDS therapies

References

1. Kasprzak A, Kaivers J, Nachtkamp K, et al. Guidelines for myelodysplastic syndromes: converting evidence into action? Int J Environ Res Public Health. 2021;18(14):7629. doi:10.3390/ijerph18147629
2. Fenaux P, Haase D, Santini V, Sanz GF, Platzbecker U, Mey U; ESMO Guidelines Committee. Myelodysplastic syndromes: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021;32(2):142-156. doi:10.1016/j.annonc.2020.11.002
3. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391-2405. doi:10.1182/blood-2016-03-643544
4. Greenberg PL, Stone RM, Al-Kali A, et al. NCCN Guidelines® Insights: myelodysplastic syndromes, version 3.2022. J Natl Compr Canc Netw. 2022;20(2):106-117. doi:10.6004/jnccn.2022.0009 
5. Malcovati L, Hellström-Lindberg E, Bowen D, et al. Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet. Blood. 2013;122(17):2943-2964. doi:10.1182/blood-2013-03-492884
6. Lee C, Kim HN, Kwon JA, et al. Implications of the 5th edition of the World Health Organization Classification and International Consensus Classification of myeloid neoplasm in myelodysplastic syndrome with excess blasts and acute myeloid leukemia. Ann Lab Med. 2023;43(5):503-507. doi:10.3343/alm.2023.43.5.503
7. Khoury JD, Solary E, Abla O, et al. The 5th edition of the World Health Organization classification of haematolymphoid tumours: myeloid and histiocytic/dendritic neoplasms. Leukemia. 2022;36(7):1703-1719. doi:10.1038/s41375-022-01613-1

Reviewed by Debjyoti Talukdar, MD, on 6/21/2023.

---

Diana Diez Gaspar, PharmD, PhD

Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.