SP-007 MYELODYSPLASTIC SYNDROMES: OLD AND NEW CLASSIFICATION AND PROGNOSTIC SYSTEMS

Abstract

The myelodysplastic syndromes (MDS) consist of a heterogeneous spectrum of myeloid clonal hemopathies. This presentation will focus on the recently defined prognostic clinical and molecular abnormalities intrinsic to the aberrant marrow hematopoiesis in MDS as they relate to clinical features and potential for disease progression. The Revised International Prognostic Scoring System (IPSS-R) provides a recently refined and improved method for clinically evaluating the prognosis of MDS patients. Novel components of this scoring method compared to the IPSS include: 5 rather than 3 cytogenetic prognostic subgroups with specific and new classifications of a number of less common cytogenetic subsets, splitting the low marrow blast percentage value, and depth of cytopenias. Other differentiating clinical features in the IPSS-R were additive to the five major parameters for predicting survival although not AML evolution: age, performance status, serum ferritin and LDH levels. Recent investigations from a number of centers have validated the clinical utility of this IPSS-R system for risk analysis of both untreated and treated MDS patients. Molecular profiling has recently generated extensive data describing critical hematopoietic molecular and biologic derangements contributing to the patients’ clinical phenotypes. These studies have demonstrated the roles of specific somatic gene mutations of bone marrow cells for the development and clinical outcomes of MDS, including their propensity to progress to more aggressive stages such as AML. These mutations have been identified in more than 80% of MDS patients, including most cases with a normal karyotype. The reported abnormalities involve genes engaged in molecular signaling and differentiation, regulation of cell cycle progression, apoptosis, transcription, translation and epigenetics. Genetic alterations have included oncogenic mutations, amplifications or deletions, transcriptional RNA splicing abnormalities, epigenetic changes and/or altered telomere dynamics. Molecular features in del(5q) MDS, such as ribosomal biogenesis dysfunction, altered micro RNA (miRNA) levels and p53 mutations also contribute to the phenotype and prognosis of these patients. These specific molecular alterations in marrow cells from MDS patients explain much of the clinical heterogeneity demonstrated by this spectrum of diseases. Sequential combinations of cooperative mutations appear to be required for the disease and its progression, possibly together with epigenetic changes of specific gene expression. These molecular abnormalities are being combined with the known clinical features of the IPSS-R to develop a more precise prognostic classification schema. Further, these findings have the potential to help discover critical targets for biospecific therapy for this group of diseases.