Objectives

The goal of the National MDS Study was to establish a publicly available resource to facilitate the study of the natural history of MDS. This was accomplished through: 1) Creation of a rich, multi-institutional clinical database associated with a longitudinal biorepository of consistently processed blood and bone marrow specimens collected prospectively from participants with MDS and participants with precursor conditions such as idiopathic cytopenia of undetermined significance (ICUS), idiopathic dysplasia of undetermined significance (IDUS) and clonal cytopenia of indeterminant significance (CCUS); [ND1.1]and 2) Support for investigator-initiated studies of MDS that will have high-impact for MDS patients, including basic science, clinical, health outcomes and epidemiological research. The design of the study is described in https://doi.org/10.1080/10428194.2019.1616186

Background

Myelodysplastic syndromes (MDS), a spectrum of heterogeneous hematopoietic stem cell disorders, vary in clinical severity, response to therapy, and propensity toward progression to acute myeloid leukemia. These acquired clonal disorders result from somatic mutations within the hematopoietic stem or progenitor cell population. Understanding the natural history and the risk of developing adverse outcomes or myeloid leukemia is dependent on access to well-annotated biospecimens linked to robust clinical and molecular data. To facilitate the acquisition and distribution of MDS biospecimens to the wider scientific community and support scientific discovery in this disease, the National MDS Natural History study was initiated in 2016 by the National Heart, Lung, and Blood Institute (NHLBI) and was conducted in collaboration with VA hospitals and medical centers supported by the National Cancer Institute (NCI).

Participants

Patients with suspected MDS or MDS/myeloproliferative neoplasms (MPN) overlap disorder, who were either undergoing diagnostic workup and bone marrow assessments or newly diagnosed with MDS within the past 6-months and undergoing clinical evaluation and bone marrow assessments to confirm MDS or evaluate disease status, were enrolled across 161 centers. Participants were required to be 18 years or older; have no prior treatment of MDS at entry and through time of the entry bone marrow aspirate; no treatment with hematopoietic growth factors in prior 6 months; no diagnosis of a solid tumor or hematologic malignancy within two years prior to enrollment except for in situ cancer of the skin (basal or squamous cell), cervix, bladder, breast or prostate; no treatment with radiation therapy in the two years prior to registration; no non-hormonal treatment for malignancy within the two years prior to registration; no established hereditary bone marrow failure syndrome; no known primary diagnosis of aplastic anemia, classical paroxysmal nocturnal hemoglobinuria, amegakaryocytic thrombocytopenic purpura, or large granular lymphocyte leukemia; and not enrolled in the Connect MDS/Acute Myeloid Leukemia (AML) Disease Registry. A total of 2,115 participants were enrolled into the study with 1,214 identified for longitudinal follow-up. Of the longitudinal cohort, 510 were diagnosed with MDS, 302 with clonal cytopenias of undetermined significance (CCUS), 156 considered at-risk (participants with dysplasia, abnormal karyotype, or a genetic mutation), 114 ICUS, 103 MDS/MPN, and 29 AML with <30% blasts. The remaining 901 enrolled participants did not fit these groups and were not followed further.

Design

The design was a multi-center, prospective cohort study enrolling patients from centers in NCI’s National Clinical Trials Network (NCTN) and the NCI Community Oncology Research Program (NCORP). Participants were evaluated at baseline during which participant histories, baseline laboratory tests, quality of life assessments, environmental exposure determination, and diagnostic information including reports and treatment history were collected. Biospecimens obtained include peripheral blood and bone marrow, as well as eyebrow hair follicles and buccal cells. Slides were created from the collected bone marrow and peripheral blood to support histopathological review using a consistent, rigorous multi-stage review process that compared the diagnosis by the enrolling site and the MDS Study central pathologists, with adjudication by independent 3rd party. Based on both this histological assessment, and targeted genetic testing of DNA from the bone marrow, participants were classified into either the longitudinal cohort with follow-up every 6 months, or the cross-sectional cohort which marked the completion of their involvement in the study. For the longitudinal cohort, disease evaluation and medical examination, collection of peripheral blood samples and lab testing, quality of life assessments, and bone marrow sample collection (if the procedure was clinically required) occurred every 6 months. All biological samples collected from participants at each visit were submitted to the Central Lab and Biorepository at the Moffitt Cancer Center for processing and storage with the goal of maintaining these samples for future research. A subset of the longitudinal cohort has paired whole genome sequences from bone marrow and peripheral blood that were taken at study entry; these are available through dbGaP and NHLBI’s TOPMed program. Digital histopathological slide images are available through BioData Catalyst.

Conclusions

The study has assembled a comprehensive worldclass clinical database from over 2,100 participants with suspected or newly diagnosed MDS or MDS/MPN overlap disorders including extensive quality of life assessments, laboratory data, and exposure history. Clinical data are linked to histopathology slides, and high-quality biospecimens from hematopoietic and germline tissues. Participants were enrolled from diverse centers across the United States. These resources are now made available to the scientific community to support investigator-initiated research.

DeZern AE, Gillis N, Otterstatter M, et al. A novel approach to defining progression in MDS and precursor myeloid conditions in the MDS Natural History Study. Blood Adv. 2026;10(8):2743-2753. doi:10.1182/bloodadvances.2025018770

Publications

Gillis N, Colin-Leitzinger C, Tang YH, Otterstatter M, Sherman S, Zhang L, Moscinski LC, Walker ME, Painter JS, Abel GA, Al Baghdadi T, Deeg HJ, Foran JM, Gore SD, Harrington AM, Kroft SH, Liu JJ, Saber W, Virani S, Bejar R, Lindsley RC, Padron E, Walter MJ, Komrokji R, DeZern AE, Sekeres MA. Am J Hematol. 2026 Jun;101(6):1407-1420. Clinical, Genetic, and Pathologic Variability in Myelodysplastic Syndromes and Precursor Conditions Across Race, Ethnicity, and Sex. Epub 2026 Mar 29.PMID: 41906220 https://doi.org/10.1002/ajh.70279

DeZern AE, Gillis N, Otterstatter M, Abel G, Padron E, Deeg HJ, Al Baghdadi T, Liu J, Xie Z, Zhang L, Moscinski L, Kroft S, Harrington A, Foran J, Komrokji R, Starczynowski D, Gore S, Saber W, Bejar R, Lindsley RC, Sherman S, Lee C, DiFronzo N, Walter M, Sekeres MA. A novel approach to defining progression in MDS and precursor myeloid conditions in the MDS Natural History Study. Blood Adv. 2026 Apr 28;10(8):2743-2753. doi: 10.1182/bloodadvances.2025018770.PMID: 41671442 https://doi.org/10.1182/bloodadvances.2025018770

Sekeres MA, DeZern AE, Otterstatter M, Padron E, Al Baghdadi T, Foran JM, Komrokji RS, Abel GA, Saber W, Gore SD, Lee C, Bejar R, Liu JJ, Deeg HJ, Sherman S, Lindsley RC, Walter MJ, Gillis N.

Exposure to Agent Orange and association with myelodysplastic syndromes. Blood Adv. 2026 May 12;10(9):3054-3058. doi: 10.1182/bloodadvances.2025019262.PMID: 41734386 https://doi.org/10.1182/bloodadvances.2025019262

DeZern A, Goll J, Jensen T, Srivatsan S, Gillis N, Abel G, Padron, E, Deeg J, Al Baghdadi T, Liu JL, Komrokji R, Gore S., Saber W, Bejar R, Walter M, Lindsley RC, Sherman S, DiFronzo N, Sekeres M; Correlation between peripheral blood and bone marrow mutations among patients with MDS from the National MDS Study. Blood Neoplasia 2024; 1 (3): 100026. doi: https://doi.org/10.1016/j.bneo.2024.100026

Gorak E, Otterstatter M, Al Baghdadi T, Gillis N, Foran JM, Liu JJ, Bejar R, Gore SD, Kroft SH, Harrington AM, Saber W, Starczynowski DT, Rollison DE, Zhang L, Moscinski LC, Wilson SH, Thompson J, Borchert C, Sherman S, Hebert D, Walker ME, Padron E, DeZern A, Sekeres MA. Discordant Pathologic Diagnoses of Myelodysplastic Neoplasms and Their Implications for Registries and Therapies. Blood Adv 2023; bloodadvances.2023010061. doi: https://doi.org/10.1182/bloodadvances.2023010061

Abel GA, Hebert D, Lee C, Rollison DE, Gillis N, Komrokji RS, Foran JM, Liu JJ, Al Baghdadi T, Deeg HJ, Gore SD, Saber W, Wilson SH, Otterstatter M, Thompson J, Borchert C, Padron E, DeZern A, Cella D, Sekeres MA. Health-Related Quality of Life and Vulnerability among People with Myelodysplastic Syndromes: A US National Study. Blood Adv. 2023 May 5:bloodadvances.2022009000. doi: 10.1182/bloodadvances.2022009000. Epub ahead of print. PMID: 37146263. https://ashpublications.org/bloodadvances/article/doi/10.1182/bloodadvances.2022009000/495681/Health-Related-Quality-of-Life-and-Vulnerability

DeZern, A. E., Goll, J. B., Lindsley, R. C., Bejar, R., Wilson, S. H., Hebert, D., Deeg, J., Zhang, L., Gore, S., Al Baghdadi, T., Maciejewski, J., Liu, J., Padron, E., Komrojki, R., Saber, W., Abel, G., Kroft, S. H., Harrington, A., Grimes, T., Reed, H., … Walter, M. J. (2023). Utility of targeted gene sequencing to differentiate myeloid malignancies from other cytopenic conditions. Blood advances, 7(14), 3749–3759. https://doi.org/10.1182/bloodadvances.2022008578

Miller, C. A., Walker, J. R., Jensen, T. L., Hooper, W. F., Fulton, R. S., Painter, J. S., Sekeres, M. A., Ley, T. J., Spencer, D. H., Goll, J. B., & Walter, M. J. (2022). Failure to Detect Mutations in U2AF1 due to Changes in the GRCh38 Reference Sequence. The Journal of molecular diagnostics : JMD, 24(3), 219–223. https://doi.org/10.1016/j.jmoldx.2021.10.013

Sekeres, M. A., Gore, S. D., Stablein, D. M., DiFronzo, N., Abel, G. A., DeZern, A. E., Troy, J. D., Rollison, D. E., Thomas, J. W., Waclawiw, M. A., Liu, J. J., Al Baghdadi, T., Walter, M. J., Bejar, R., Gorak, E. J., Starczynowski, D. T., Foran, J. M., Cerhan, J. R., Moscinski, L. C., Komrokji, R. S., … Epling-Burnette, P. K. (2019). The National MDS Natural History Study: design of integrated data and sample biorepository to promote research studies in myelodysplastic syndromes. Leukemia & lymphoma, 60(13), 3161–3171. https://doi.org/10.1080/10428194.2019.1616186

Padron, E., Ball, M. C., Teer, J. K., Painter, J. S., Yoder, S. J., Zhang, C., Zhang, L., Moscinski, L. C., Rollison, D. E., Gore, S. D., Bejar, R., Walter, M. J., Sekeres, M. A., Komrokji, R. S., & Epling-Burnette, P. K. (2018). Germ line tissues for optimal detection of somatic variants in myelodysplastic syndromes. Blood, 131(21), 2402–2405. https://doi.org/10.1182/blood-2018-01-827881

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