ReviewEpidemiology of myelodysplastic syndromes: Why characterizing the beast is a prerequisite to taming it
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).
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