Predicting survival and leukemic evolution in patients with myelodysplastic syndrome.

Myelodysplastic syndromes (MDS) are a group of hematologic disorders that occur mainly in older persons and are characterized by peripheral cytopenias and an increasing risk of progression into acute myeloid leukemia (AML). The impressive heterogeneity of the natural history of MDS, ranging from indolent conditions with near normal life expectancy to forms rapidly progressing to leukemia, complicates clinical decisionmaking regarding therapeutic modalities and timing of interventions. In 1982, the French-American British (FAB) co-operative group proposed a classification of MDS based on morphological criteria. For the following 20 years this classification represented the benchmark for clinical management and investigational studies in MDS. However, considerable heterogeneity was observed within FAB subgroups, raising the need for prognostic systems with a better ability to predict survival and leukemic progression in MDS patients. Various prognostic models were proposed based on demographic and disease-related variables, including age, peripheral cytopenias, bone marrow blast count, lactate dehydrogenase level and karyotypic abnormalities. In 1997 an International MDS Risk Analysis Workshop defined the International Prognostic Scoring System (IPSS), which combines information on bone marrow blast percentage, cytogenetic abnormalities and number of peripheral cytopenias detected at the time of the diagnosis, enabling the distinction of four risk groups with different survivals and risks of leukemia evolution. The IPSS has been extensively validated in independent patient populations, and despite some discrepancies, has become the gold standard for clinical trials and decisionmaking. In 2002, the WHO formulated a new proposal for the classification of MDS. This new classification is based on variables which had been demonstrated to be able to stratify survival and leukemic progression in MDS patients, including a unior multi-lineage hematopoietic dysplasia, narrower blast count intervals and specific cytogenetic abnormalities. The unresolved question of the distinction between MDS and AML was also addressed with different proposals, such as lowering the bone marrow blast threshold to define progression into acute leukemia, comprising therapy-related AML and MDS in a sole category, and recognizing a new entity defined as acute myeloid leukemia with multilineage dysplasia. The prognostic relevance of this classification was recently confirmed in retrospective studies by different groups. Among patients with MDS without excess blasts, an isolated involvement of the erythroid lineage has been confirmed to be associated with a better prognosis than that of multilineage dysplasia. The relevance of this observation has been strengthened by the finding that patients with purely erythroid disorders aged 70 years or older have a life expectancy not significantly shorter than that of the general population. As far as advanced MDS are concerned, the definition of two categories of refractory anemia with excess blasts has been proven to identify two groups of patients with significantly different survival and risks of leukemic evolution. Interesting data have also been emerging on the ability of the WHO classification to guide clinical decisionmaking regarding therapeutic choices. Patients with unilineage dysplasia have been shown to have a significantly higher probability of responding to treatment with hematopoietic growth factors compared to those with multilineage dysplasia, while patients with 5q deletion were found to have a high response rate to lenalidomide. In this issue of Haematologica/the Hematology Journal, the Düsseldorf MDS registry reports the first prospective validation of the WHO classification on a large cohort of MDS patients. This study confirms the results of previous retrospective analyses, substantiating the clinical utility of the proposed WHO classification. In particular, the significant difference in both survival and risk of leukemic evolution between patients with isolated erythroid involvement and those with multilineage dysplasia has been validated. The WHO proposal has raised some concern regarding minimal diagnostic criteria for formulating the diagnosis of refractory anemia, in particular when the diagnosis of MDS has to be based exclusively on morphological criteria, as well as for correctly classifying patients into WHO categories. In this regard, flow cytometric immunophenotyping might be of help in discriminating between MDS and other acquired anemias. In addition it might be useful to identify patients with ringed sideroblasts through the detection of mitochondrial ferritin, and those with multilineage dysplasia with high sensitivity and specificity. The implementation of the WHO classification compels a refinement of the role of demographic and disease-related prognostic factors within MDS subgroups. The IPSS was shown to retain a significant prognostic value in MDS patients classified according to WHO criEDITORIALS & PERSPECTIVES