Heterogeneity in the myelodysplastic syndromes: moving toward a better understanding

Abstract

Th e myelodysplastic syndromes (MDS) are a group of heterogeneous, malignant hematopoietic stem cell disorders. While they collectively result in ineff ective hematopoiesis, with aberrant cellular maturation resulting in chronic peripheral cytopenias, their clinical presentation and course are quite variable [1]. At one end of the spectrum, low-risk disease has a fairly indolent course, noting that younger patients have a reported median survival of over 11 years [2]. However, those with unfavorable characteristics have a worse prognosis. Patients with high risk features have a poor overall survival ( 1 year on average regardless of age at diagnosis), as well as a relatively high propensity for transformation into acute leukemia [2]. Th e disparity between high and low risk MDS underscores a need to better defi ne its pathogenesis, and determine mechanisms that may explain diff erences between the various subtypes. Diagnostic criteria for MDS are clearly defi ned by the French – American – British (FAB) or World Health Organization (WHO) classifi cation systems [1]. Unfortunately, these do not provide signifi cant insight into the underlying pathophysiology, and by themselves, cannot reliably predict clinical course. To aid in prognostication and help guide treatment decisions, various clinical scoring systems have been developed. Th e International Prognostic Scoring System (IPSS) is considered the most utilized, as it was validated to predict survival and time to leukemic progression in 816 treatment-naive patients with MDS [2]. Th is system assigns points to each of three key areas (bone marrow blast percentage, karyotype and peripheral cytopenias), and patients can be grouped into low, intermediate (1 and 2) and high risk categories. Blast percentage and unfavorable cytogenetics are more heavily weighted toward a negative outcome. Median overall survival ranges from 5.7 to 0.4 years for those with low versus high risk disease, and rates of leukemic transformation also correspond with the IPSS scale. A revised scoring system (IPSS-R) was recently published following evaluation of over 7000 patients with MDS [3]. Cytogenetics, bone marrow blast percentage and peripheral cytopenias remain the basis for the new system; however, severity of cytopenias is considered in scoring. In addition, the karyotype is expanded into fi ve risk categories (previously three), and blast percentage 10 is given the highest negative weight compared to 20 in the prior system. Consistent with the original IPSS, overall survival in the IPSS-R was longest in the lowest risk group (8.8 years), noting a progressive decline with less favorable features, and only 0.8 years in the very high risk group. Similarly, median times until 25% of the population developed acute leukemia were 14.5 years and 0.7 years, respectively. While often helpful, there are several limitations with these prognostic scoring systems. Only those with de novo disease were included for evaluation in both the IPSS and revised versions. Patients were also given only supportive therapies until leukemic transformation; it is unclear how more readily available disease-modifying treatments, including hypomethylating agents, lenalidomide or stem cell transplant, would impact survival and leukemic evolution in these scales. And while these can give an indication as to potential clinical course, they still do not address fundamental differences in underlying pathophysiology of MDS subtypes. Indeed, the underlying pathogenesis of MDS is incompletely understood at present. A possible role of the matrix metalloproteinases (MMPs), and their regulation, has been raised in hematologic malignancies, including MDS [4]. With their ability to cause degradation of many components of the extracellular matrix, a role for MMPs in the invasive and metastatic potential of solid tumors would seem more plausible. However, these proteins may serve other functions, including cell growth and diff erentiation, which would be more relevant in the hematologic malignancies. In this issue of Leukemia and Lymphoma , Melo et al . report a potential role of aberrant regulation of MMPs in MDS [5]. Th ey found signifi cantly lower levels of the tissue inhibitor of metalloproteinase-2 (TIMP-2) in those with acute myeloid leukemia (AML) and MDS compared to healthy controls, with lowest levels being seen in patients with AML or WHO high-risk MDS. Unfortunately, the TIMP-2 levels were not able to diff erentiate between low and high risk disease based on the IPSS scale, nor were they