title: The lower risk MDS patient at risk of rapid progression.
abstract: Most patients with myelodysplastic syndrome (MDS) are classified at diagnosis as having a low/INT-I or INT-II/high risk disease, based on the classical International Prognostic Scoring System (IPSS) criteria. The low/INT-I risk patients are usually managed mildly with supportive care, including red blood cell (RBC) transfusions, erythroid stimulating agents (ESAs), other cytokines (G-CSF, platelet stimulating agents), as well as thalidomide and lenalidomide. Some patients receive immunosuppressive therapy, and iron chelation is indicated in iron overloaded patients. Aggressive approach (hypomethylating agents, chemotherapy and stem cell transplantation) is usually not applied in such patients. Occasionally, we observe a "low risk" patient with rapid progression of disease and poor outcome. Can we identify demographic, clinical, laboratory, cellular-biological and/or molecular parameters that can predict "poor prognostic features" (PPF) in "low risk" MDS patients? Clinical and laboratory parameters have been reported to be associated with poor prognosis, in addition to the known "classical" IPSS criteria. These include older age, male gender, poor performance status, co-morbidities, degree of anemia, low absolute neutrophile count (ANC) and platelet counts, RBC transfusion requirements, high serum ferritin, high LDH, bone marrow (BM) fibrosis, increased number of BM CD34+ cells and multi-lineage dysplasia. Certain immunophenotypes (low CD11b, high HLA-Dr, CD34, CD13 and CD45), clonal granulocytes, multiple chromosomal abnormalities, chromosomal instability, short telomeres and high telomerase activity were also reported as PPF. Studies of apoptosis identified Bcl-2 expression and high caspase 3 as PPF, while the reports on survivin expression have been confusing. Recent exciting data suggest that methylation of p15 INK4b and of CTNNA1 (in 5q-), high level of methylation of other genes, absence of the TET2 mutation, down regulation of the lymphoid enhancer binding factor 1 (LEF1), mutation of the polycomb-associated gene ASXL1 and a specific 6-gene signature in gene expression profiling - are all associated with poor prognosis in MDS. Do we have data suggesting a different treatment for "low risk" MDS patients displaying PPF? Two teams, the combined Nordic-Italian and the GFM groups have reported an improved survival with ESAs. The GFM has achieved prolonged survival with iron chelation. Recently, encouraging data with survival advantage in azacitidine-treated patients have been published, including a few INT-I patients. Finally, data suggest that low/INT-I MDS patients who undergo stem cell transplantation (SCT0 do better than INT-II/high risk patients). In summary, some patients, classified as "low risk MDS" carry PPF. An appropriate therapeutic approach is indicated. Future updated classifications and prospective trials may lead to a better outcome.
authors.affiliation: Department of Medicine, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel. moshemt@tasmc.health.gov.il
authors.forename: Moshe
authors.initials: M
authors.lastname: Mittelman
authors.forename: Howard S
authors.initials: HS
authors.lastname: Oster
authors.forename: Michael
authors.initials: M
authors.lastname: Hoffman
authors.forename: Drorit
authors.initials: D
authors.lastname: Neumann
mesh_terms: D000367:Age Factors; D000943:Antigens, Differentiation / Q000097:blood; D000970:Antineoplastic Agents / Q000627:therapeutic use; D053148:Caspase 3 / Q000096:biosynthesis / Q000235:genetics; D002869:Chromosome Aberrations; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000096:biosynthesis / Q000235:genetics; D016207:Cytokines / Q000627:therapeutic use; D019175:DNA Methylation / Q000235:genetics; D017707:Erythrocyte Transfusion; D005260:Female; D005293:Ferritins / Q000097:blood; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D051034:Inhibitor of Apoptosis Proteins; D000077269:Lenalidomide; D007958:Leukocyte Count; D008077:Lipoproteins, LDL / Q000097:blood; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis / Q000235:genetics; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000628:therapy; D010976:Platelet Count; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics; D012307:Risk Factors; D012737:Sex Factors; D000077022:Survivin; D013792:Thalidomide / Q000031:analogs & derivatives / Q000627:therapeutic use; D051178:alpha Catenin / Q000096:biosynthesis / Q000235:genetics; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D000943:Antigens, Differentiation; D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; C495273:CTNNA1 protein, human; D050762:Cyclin-Dependent Kinase Inhibitor p15; D016207:Cytokines; D007166:Immunosuppressive Agents; D051034:Inhibitor of Apoptosis Proteins; C497573:LEF1 protein, human; D008077:Lipoproteins, LDL; D051821:Lymphoid Enhancer-Binding Factor 1; D008869:Microtubule-Associated Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D000077022:Survivin; D051178:alpha Catenin; D013792:Thalidomide; D005293:Ferritins; D020794:Receptor Protein-Tyrosine Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D000077269:Lenalidomide; D000094963:Axl Receptor Tyrosine Kinase; C000722289:AXL protein, human