Myelodysplastic Syndromes: Dissecting the Heterogeneity

Myelodysplastic syndromes (MDS) represent a heterogeneous spectrum of disorders that require selective therapy on the basis of each patient’s specific clinical features, predominantly prognostic subgroups, age, and performance status. Factors associated with the clinical and biologic nature of MDS need to incorporate the two primary discerning features of the disease—the defective differentiation of the patient’s hematopoietic cells that results in marrow failure and expansion of the abnormal clone for those patients who undergo evolution to or toward acute myeloid leukemia (AML). To aid the grouping of relatively similar prognostic subsets of patients with MDS for clinical trial design and analysis, the International Prognostic Scoring System (IPSS) has often been used, and it employs the statistically weighted variables of marrow blast percentage, cytogenetic categories, and number of cytopenias. Guidelines for the management of MDS have been generated by using evidencebased data. For lower-risk disease (IPSS low and intermediate-1), therapy is aimed predominantly at hematologic improvement, whereas treatment for higher-risk disease (intermediate-2 and high) focuses on altering disease natural history. In the past decade, additional clinical and cytogenetic variables and methods have been generated regarding the diagnostic and prognostic evaluation of MDS patients. These methods include the WHO morphologic classification of MDS and prognostic systems that incorporate this morphologic categorization as well as patients’ need for RBC transfusions. These and other reports have demonstrated the heterogeneity that persists within MDS and have indicated the need for further dissection of the disease. Two such articles accompany this editorial. The article by Schanz et al describes a large cohort of patients with primary MDS, untreated as well as treated, for whom outcome analysis was evaluated. Schanz et al used the IPSS for MDS to categorize these patients’ diseases, with major focus on determining the impact of modification of the cytogenetic risk groups on clinical outcomes. Good-, intermediate-, and poor-risk cytogenetic categories, as described by the IPSS, were modified by subdividing the poor-risk category into more refined subgroups. By using this method, the authors demonstrated that patients from more highly selected cytogenetic subgroups experienced differing clinical outcomes associated with prognostic impact that were similar to those generated by high marrow blast counts. Of interest were the findings that these subgroups maintained prognostic utility for those patients who were subsequently treated with lowor high-intensity therapies. To collectively investigate the numerous potential additional prognostic variables, the International Working Group for Prognosis in MDS has analyzed databases from 15 institutions worldwide and recently developed a revised IPSS. Considerable value was generated by further subdividing the cytogenetic subgroups as well as including clinical parameters in addition to marrow blasts (including depth of cytopenias, age, performance status, and marrow fibrosis). Incorporating the growing number of molecular variables implicated in the pathogenesis of MDS into newer prognostic systems should prove useful for improved assessment of the clinical disparity between patients with MDS and for management of their diseases. Patients with del(5q) MDS have a distinctive form of the disease with a remarkably high responsiveness to the drug lenalidomide. However, the durability of the responses and the potential for AML evolution of these patients are quite variable. Long-term outcomes are poorer in patients with del(5q) MDS with additional cytogenetic lesions than in those with del(5q) MDS alone. The article by Jadersten et al demonstrated that a substantial subset of patients with lower-risk del(5q) MDS have TP53 mutations with intramedullary cell overexpression of p53 protein as assessed by immunohistochemistry. The relatively high incidence of this molecular abnormality was detected by using sensitive next-generation sequencing techniques. Patients with mutated TP53 were also shown to have poorer erythroid and cytogenetic responses to lenalidomide and a higher potential for AML evolution. The levels of p53 increased during disease progression. These findings, with prognostic and therapeutic implications, indicate the existing heterogeneity even within an MDS subtype possessing a single cytogenetic abnormality. More to the point regarding the multifaceted biologic lesions underlying MDS subsets, additional molecular features in del(5q), such as ribosomal biogenesis dysfunction and altered microRNA levels, also contribute to the phenotype of these patients. Patients with del(5q) have haploinsufficiency of the ribosomal protein RPS14, which activates p53 and causes marrow cell apoptosis, an effect that is blocked by lenalidomide. In addition, the thrombocytosis experienced by these patients likely relates to the decreased levels of several microRNAs (miR145, miR146). Despite the relatively straightforward morphologic features of MDS subgroups, the heterogeneity of their clinical outcomes appears to be associated with a variety of molecular abnormalities. By using microarray technology, distinctive gene expression profiles of MDS marrow CD34 cells were demonstrated in patient subsets (eg, those with stable disease compared with those whose disease evolved to AML within 14 months) together with a poor-risk gene expression signature associated with the propensity of patients with MDS to undergo AML evolution. Other gene expression profile studies have shown that among the most significantly deregulated gene pathways in early MDS were immunodeficiency, apoptosis, and chemokine signaling, whereas advanced MDS was characterized by deregulation of DNA damage response and checkpoint pathways. Recently, TET2 gene mutations were found in approximately 20% of patients with MDS and were associated with improved prognosis. Telomere dynamics are altered in MDS; telomeres shorten along with disease progression, which leads to genetic instability and susceptibility to additional molecular alterations as the disease persists. Editorials