Elsevier

Blood Reviews

Volume 34, March 2019, Pages 1-15
Blood Reviews

Review
Epidemiology of myelodysplastic syndromes: Why characterizing the beast is a prerequisite to taming it

https://doi.org/10.1016/j.blre.2018.09.001Get rights and content

Abstract

Myelodysplastic syndromes (MDS) consist of a heterogeneous group of myeloid neoplasms characterized by inefficient hematopoiesis, variable cytopenias and a considerable risk of progression to acute myeloid leukemia. Epidemiological assessment of MDS has been hampered by evolving diagnostic criteria and delayed classification of MDS as cancers until 2001. The poorly-understood nature of these neoplasms combined with the lack of effective therapies for decades contributed to suboptimal case ascertainment and underreporting. The annual age-adjusted incidence in the United States is approximately 4.0/100,000 persons, and the incidence substantially rises with age. Beyond age, other risk factors include male gender, obesity, smoking, and prior receipt of radiotherapy or chemotherapy, but most cases remain idiopathic in nature. The overall 5-year survival probability remains relatively poor at approximately 31% without a clear temporal improvement in outcomes despite the approval of three MDS-specific therapies since 2004 and increasing use of allogeneic hematopoietic stem cell transplantation. Better understanding of epidemiological trends of MDS will likely require incorporation of the key genetic determinants of the disease into consistent diagnostic paradigms that go beyond traditional morphologic assessments. The heterogeneity of the disease and lack of uniformly-defined genetic markers makes such a task difficult. Thorough case ascertainment and reporting efforts can provide vital insights that could inform treatment decisions and eventually improve the outcomes of patients with MDS.

Introduction

Myelodysplastic syndromes (MDS) are a varied collection of clonal myeloid neoplasms associated with irregular and ineffective hematopoiesis. MDS clinically manifests with a diverse range of peripheral cytopenias. Resultant complications include infection, bleeding, and cardiopulmonary compromise. MDS is also characterized by an appreciable risk of progression to acute myeloid leukemia (AML) [1]. Stratification of such risk in combination with requirements for transfusion guides the current management of MDS. Only the hypomethylating agent (HMA) azacitidine and allogeneic stem cell transplantation (alloSCT) have shown a proven survival benefit (particularly in the higher-risk setting) [2,3]. Increasing understanding of the pathogenesis of MDS is nurturing the development of better therapeutic approaches which may soon be incorporated into standard-of-care clinical practice [4]. Forays into the epidemiology of MDS, however, have and will likely continue to marry this understanding with the selection of those patients most likely to respond to certain therapies.

Section snippets

MDS as an epidemiologic challenge: classification evolution and early reporting barriers

In 1973, there were <150 reported cases of patients with a diagnosis of MDS by modern standards from a reasonable sum of data [5]. Two categories of “dysmyelopoietic syndromes” (chronic myelomonocytic leukemia [CMML] and refractory anemia with excess blasts [RAEB]) were initially established in 1976 by the French-American-British (FAB) Co-operative Group Leukemia Classification. These classifications were further expanded into five categories which would prove to be durable and would be known

Incidence

As a result of the difficulties in developing durable MDS diagnostic criteria and the distinct classification of MDS in different systems, the reported disease incidence has been a moving target. The initial SEER-based age-adjusted MDS incidence rate in 2001 was 3.28 cases per 100,000 population per year based on 2246 reported new cases [13]. This incidence increased slightly over the next three years to 3.80 [14] cases per 100,000 population in 2004 [14,15]. Early SEER data on MDS incidence

Prevalence

In 1973, one of the first studies of MDS prevalence, based on described clinical and morphological features that by today's standards would be diagnosed as such, documented the existence of 143 total cases worldwide [5]. By means of more standardized diagnostic criteria and robust reporting media we now know the prevalence of MDS >40 years later is much more of a burden than this first estimate. However, the same limitations that plague both registry-based and claims-based analyses also make it

Etiology and predispositions for disease development

The pathogenesis of MDS has been linked to somatic mutations in many of the crucial genes involved in cell cycle regulation (histone modification, RNA splicing, DNA transcription or methylation, or tumor suppression) in addition to chromosomal abnormalities (most commonly deletions in the long arm of chromosome 5 or monosomy 7) [4]. Nearly 90% of MDS patients harbor one of these abnormalities and a median of three somatic mutations are detected in MDS patients [[37], [38], [39]]. What

Survival: much more to be improved

As per recent SEER data, patients with MDS have poor long-term survival when compared to other cancers (31.3% five-year overall survival). (Fig. 7) However, the various subtypes under the MDS umbrella exhibit different disease characteristics, aggressiveness, as well as differences in survival.

The median overall survival (OS) from diagnosis for RA (now included within MDS-SLD in the 2016 WHO classification) and RARS (now MDS-RS in the 2016 WHO classification) remain the most favorable compared

Prognostic considerations: an ever-evolving field

The heterogeneity of MDS makes accurate prognostication for the individual patient difficult. The different subtypes of MDS have different rates of leukemic transformation and exhibit variable OS. The natural course of disease has traditionally been predicted by standardized prognostic tools such as the IPSS, IPSS-R, WPSS, as well as the MD Anderson Global Prognostic Scoring System (MDAPSS), which account for other clinical metrics to gauge the aforementioned risk, but more importantly guide

Progress and pitfalls in practice patterns

As previously mentioned, the last 15 years have seen the advent of newly-available therapies for MDS (including three FDA approvals) and possibly modest improvements in the survival of patients with MDS. It is reasonable to posit that the former has led to the latter, yet practice patterns over the same timeframe may or may not explain some of these findings.

The use of the HMAs has increased since their FDA-approval and guideline-recommendation for frontline treatment of HR-MDS. Initial reports

Cost and resource burden

Financial burden stemming from the care of patients with MDS has been studied in the context of Medicare expenditure - 80% of MDS patients are aged 65 years or older at diagnosis and are Medicare eligible. From 2003 to 2005, before the approval and widespread use of HMAs and lenalidomide, the average Medicare payment for a patient with MDS was $16,000–$25,000, which is a figure more than double that for the general Medicare population [25,160]. An analysis of cost of care for MDS patients

Conclusion

The characterization of MDS as a malignancy and the beginning of MDS reporting to population-based cancer registries represent a major step forward in the epidemiological research of this understudied disease. As MDS patients are frequently cared for in the outpatient setting, more active strategies for case ascertainment are important to improve the completeness of patient identification. Both the incidence and prevalence of MDS will increase as the population continues to age and an

Funding details

Not applicable.

Disclosures/competing interests

All authors report no relevant disclosures/competing interests

A.M.Z. had a consultancy with and received honoraria from AbbVie, Otsuka, Pfizer, Celgene, Ariad, Agios, Novartis, Acceleron, Astellas, Daiichi Sankyo and Takeda; and received honoraria from and was a speaker for Takeda. None of these relationships were involved in this work

Acknowledgements

Amer Zeidan is a Leukemia and Lymphoma Society Scholar in Clinical Research and is also supported by a NCI’s Cancer Clinical Investigator Team Leadership Award (CCITLA).

References (169)

  • J. Neukirchen et al.

    Incidence and prevalence of myelodysplastic syndromes: data from the Dusseldorf MDS-registry

    Leuk Res

    (2011)
  • J.M. Guralnik et al.

    Prevalence of anemia in persons 65 years and older in the United States: evidence for a high rate of unexplained anemia

    Blood

    (2004)
  • M.A. Sekeres

    The epidemiology of myelodysplastic syndromes

    Hematol Oncol Clin North Am

    (2010)
  • R. Buckstein et al.

    Estimating the prevalence of myelodysplastic syndromes in patients with unexplained cytopenias: a retrospective study of 322 bone marrows

    Leuk Res

    (2009)
  • E. Papaemmanuil et al.

    Clinical and biological implications of driver mutations in myelodysplastic syndromes

    Blood

    (2013)
  • D.P. Steensma et al.

    Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes

    Blood

    (2015)
  • S.M. Smith et al.

    Clinical-cytogenetic associations in 306 patients with therapy-related myelodysplasia and myeloid leukemia: the University of Chicago series

    Blood

    (2003)
  • S. Bhatia

    Therapy-related myelodysplasia and acute myeloid leukemia

    Semin Oncol

    (2013)
  • L.A. Godley et al.

    Therapy-related myeloid leukemia

    Semin Oncol

    (2008)
  • J.E. Churpek et al.

    The evolving challenge of therapy-related myeloid neoplasms

    Best Pract Res Clin Haematol

    (2013)
  • J.A. Malmgren et al.

    Therapy-related myelodysplastic syndrome following primary breast cancer

    Leuk Res

    (2016)
  • J. Pedersen-Bjergaard et al.

    Therapy-related acute myeloid leukemia and myelodysplasia after high-dose chemotherapy and autologous stem cell transplantation

    Blood

    (2000)
  • D.A. Eichenauer et al.

    Therapy-related acute myeloid leukemia and myelodysplastic syndromes in patients with Hodgkin lymphoma: a report from the German Hodgkin Study Group

    Blood

    (2014)
  • A. Abou Zahr et al.

    Therapy-related myelodysplastic syndromes, or are they?

    Blood Rev

    (2017)
  • Y. Du et al.

    Smoking and alcohol intake as risk factors for myelodysplastic syndromes (MDS)

    Leuk Res

    (2010)
  • A.M. Zeidan et al.

    Current therapy of myelodysplastic syndromes

    Blood Rev

    (2013)
  • P. Fenaux et al.

    Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study

    Lancet Oncol

    (2009)
  • P. Mathew et al.

    The 5q- syndrome: a single-institution study of 43 consecutive patients

    Blood

    (1993)
  • J. Cermak et al.

    A prognostic impact of separation of refractory cytopenia with multilineage dysplasia and 5q- syndrome from refractory anemia in primary myelodysplastic syndrome

    Leuk Res

    (2003)
  • J.V.T. Montoro et al.

    Study of Causes of death in patients with Myelodysplastic Syndrome: a Single Institution experience

    Blood

    (2011)
  • E.J. Lee et al.

    The evolving field of prognostication and risk stratification in MDS: recent developments and future directions

    Blood Rev

    (2016)
  • M. Alzahrani et al.

    Improving revised International Prognostic Scoring System Pre-Allogeneic Stem Cell Transplantation does not Translate into Better Post-Transplantation Outcomes for patients with Myelodysplastic Syndromes: a Single-Center experience

    Biol Blood Marrow Transplant

    (2018)
  • A. Quintas-Cardama et al.

    A prognostic model of therapy-related myelodysplastic syndrome for predicting survival and transformation to acute myeloid leukemia

    Clin Lymphoma Myeloma Leuk

    (2014)
  • P.L. Greenberg et al.

    Revised international prognostic scoring system for myelodysplastic syndromes

    Blood

    (2012)
  • M. Stahl et al.

    Management of lower-risk myelodysplastic syndromes without del5q: current approach and future trends

    Expert Rev Hematol

    (2017)
  • A. Abou Zahr et al.

    New Insights into the Pathogenesis of MDS and the rational therapeutic opportunities

    Expert Rev Hematol

    (2016)
  • R.M. Shallis et al.

    The genetic and molecular pathogenesis of myelodysplastic syndromes

    Eur J Haematol

    (2018)
  • J.M. Bennett et al.

    Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group

    Br J Haematol

    (1976)
  • J.M. Bennett et al.

    Proposals for the classification of the myelodysplastic syndromes

    Br J Haematol

    (1982)
  • WHO

    History of the Development of the ICD

    (1992)
  • J.A. Hirsch et al.

    ICD-10: history and Context

    AJNR Am J Neuroradiol

    (2016)
  • A.M. Noone et al.

    About the SEER registries. National Cancer Institute Surveillance, Epidemiology, and End Results Program

    (2018)
  • X. Ma et al.

    Myelodysplastic syndromes: incidence and survival in the United States

    Cancer

    (2007)
  • J. Weed et al.

    Reactive granulomatous dermatitis presenting as subcutaneous nodules and cords in a patient with advanced myelodysplastic syndrome

    Ann Hematol

    (2017)
  • A. Wang et al.

    Rheumatologic Manifestations of Hematologic Neoplasms

    Curr Rheumatol Rev

    (2017)
  • A.M. Zeidan et al.

    The importance of erythroblast enumeration in myeloid neoplasia

    Ann Hematol

    (2017)
  • Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) SEER*Stat Database: Incidence - SEER...
  • Bureau USC

    QuickFacts United States

    (2018)
  • N. Gangat et al.

    Survival trends in primary myelodysplastic syndromes: a comparative analysis of 1000 patients by year of diagnosis and treatment

    Blood Cancer J

    (2016)
  • L. Lv et al.

    Case-control study of risk factors of myelodysplastic syndromes according to World Health Organization classification in a Chinese population

    Am J Hematol

    (2011)
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