How I Treat How we treat lower-risk myelodysplastic syndromes

Myelodysplastic syndromes (MDSs) are clonal stem cell disorders characterized by ineffective hematopoiesis leading to blood cytopenias, and by a high incidence of progression to acute myeloid leukemia (AML). The pathophysiology of MDS is a multistep process involving genetic changes detectable by conventional cytogenetic techniques or smaller anomalies detectable only by more sophisticated methods like single nucleotide polymorphism array technology or sequencing techniques. Somatic mutations, now detected in most MDS cases, can involve genes encoding signaling molecules (NRAS, KRAS, CBL, JAK2, FLT3), epigenetic regulators (TET2, ASXL1, EZH2, UTX, IDH1, IDH2, DNMT3A, SETBP1), splicing factors (SF3B1, SRSF2, ZRSF2, U2AF1), and transcription regulators (RUNX1, NPM1 and TP53). Widespread gene hypermethylation, on the other hand, is a major finding during progression of MDS. Main prognostic factors in MDS include the number and importance of cytopenias, marrow blasts percentage, and marrow cytogenetic abnormalities combined in a “classic” International Prognostic Scoring System (IPSS) (that was very recently revised [IPSS-R]) that distinguishes between various subgroups with significantly different risk of progression to AML and survival. Other prognostic factors include the presence of grade >2 marrow fibrosis, certain somatic gene mutations, and possibly some flow cytometry parameters, but the last 2 tests are currently not routinely performed in most laboratories. Although the division is schematic, it is customary since publication of the classic IPSS to separate MDS into “higher risk” (corresponding to IPSS high or intermediate-2) and “lower risk” (corresponding to IPSS low or intermediate-1). Higher-risk MDS carry a major risk of progression to AML and short survival, and treatment in those patients should aim, whenever possible, to modify the natural disease course. Treatments used in higher-risk MDSs therefore include allogeneic stem cell transplantation (SCT); the hypomethylating agents (HMAs), azacitidine (AZA), and decitabine; and, although currently less often, chemotherapy (mainly intensive anthracycline-AraC combinations). In lowerrisk MDS, the risk of AML progression is less and survival is longer, with approximately one-half of those elderly patients dying from a cause other than the consequences of MDS or AML. In those patients, the main priority is generally the treatment of cytopenias, mainly of anemia (usually the predominant cytopenia), and the improvement in quality of life. Still, some of those patients may be identified, either rapidly by their revised IPSS score or by other biological characteristics, or subsequently by their resistance to first-line treatment as having a poorer prognosis, and they may benefit from treatments generally applied to higher-risk MDS.